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Drug delivery vehicles with improved encapsulation efficiency: Taking advantage of specific drug-carrier interactions
Expert Opinion on Drug Delivery
Abstract
Introduction:
Drug encapsulation strategies are vital for the delivery of poorly soluble, fragile or toxic compounds. Increasing a drug's encapsulation efficiency in drug carrier particles can achieve a stronger therapeutic effect along with minimized side effects. For these reasons, new encapsulation methods are developed by using new materials and various types of drug-carrier interaction.
Areas covered:
Strategies used for drug encapsulation are discussed in this review, focusing particularly on approaches leading to high encapsulation ratios resulting from specific interactions between the drug and the carrier. In the first part, classical encapsulation by hydrophobic self-assembly, its limitations and improvements are briefly discussed. Following this, encapsulation strategies for specific drugs are reviewed, where particular kinds of interaction play a role between the drug and the encapsulating material, which can lead to dramatically increased entrapment. Such specific approaches can be utilized more generically for various classes of molecules with similar properties, with regard to their ability to participate in a given kind of interaction.
Expert opinion:
With the focus on delivering a high drug dose precisely to the site of action, high encapsulation efficiency is the first thing to consider in drug development. Academic research shows considerable interest in specific encapsulation, and it seems to be an established trend now to design drug delivery particles to achieve the most favorable properties. The authors believe the research in this area will focus on material properties and interactions between the drug and the carrier to ensure high drug loading into particles.
... In all of these cases, an effective delivery of therapeutic agents and nutrients plays the most important role. The appropriate method of administering therapeutic agents ensures their required effect on human health and minimal side effects [6,7]. Food supplements should also be administered in a way that guarantees their supportive effects on the human body. ...
... In general, the administration of poorly soluble, toxic or sensitive drugs is improved using encapsulation. Additionally, side effects can be limited [6]. The most common route of encapsulated agent administration is oral administration [13,14]. ...
... In medicine, many encapsulation methods have been developed by using new materials and various types of drug-carrier interactions [6]. The use of encapsulation methods in medicine is very traditional and has been studied intensively. ...
There is a growing demand for efficient medical therapies without undesired side effects that limit their application. Targeted therapies such as deliveries of pharmacologically active compounds to a specific site of action in the human body are still a big challenge. Encapsulation is an effective tool for targeted deliveries of drugs and sensitive compounds. It has been exploited as a technique that can manage the required distribution, action and metabolism of encapsulated agents. Food supplements or functional foods containing encapsulated probiotics, vitamins, minerals or extracts are often part of therapies and currently also a consumption trend. For effective encapsu-lation, optimal manufacturing has to be ensured. Thus, there is a trend to develop new (or modify existing) encapsulation methods. The most-used encapsulation approaches are based on barriers made from (bio)polymers, liposomes, multiple emulsions, etc. In this paper, recent advances in the use of encapsulation in the fields of medicine, food supplements and functional foods are highlighted, with emphasis on its benefits within targeted and supportive treatments. We have focused on a comprehensive overview of encapsulation options in the field of medicine and functional preparations that complement them with their positive effects on human health.
... Chlorine ligands can be replaced with a polymer s carboxylate group, leading to a stable formulation from which cisplatin can be recovered in physiological conditions. Such a strategy is supposed to improve encapsulation efficiency (vs., for example, that of passive liposomal encapsulation, which does not exceed 18%) (91)(92)(93) In and Ga Empty liposomes are initially loaded with the chelating agent, and immediately prior to administration, the drug is formed in situ by incubation with another metal complex with a smaller binding constant, leading to 90% encapsulation of In and Ga in liposomes (91,94,95) 225 Ac 225 Ac is encapsulated by liposomes. After 30 days, 225 Ac retention as high as 81% of the initially encapsulated radioactivity was achieved (91,96) Electrostatic interactions ...
... Chlorine ligands can be replaced with a polymer s carboxylate group, leading to a stable formulation from which cisplatin can be recovered in physiological conditions. Such a strategy is supposed to improve encapsulation efficiency (vs., for example, that of passive liposomal encapsulation, which does not exceed 18%) (91)(92)(93) In and Ga Empty liposomes are initially loaded with the chelating agent, and immediately prior to administration, the drug is formed in situ by incubation with another metal complex with a smaller binding constant, leading to 90% encapsulation of In and Ga in liposomes (91,94,95) 225 Ac 225 Ac is encapsulated by liposomes. After 30 days, 225 Ac retention as high as 81% of the initially encapsulated radioactivity was achieved (91,96) Electrostatic interactions ...
... Such a strategy is supposed to improve encapsulation efficiency (vs., for example, that of passive liposomal encapsulation, which does not exceed 18%) (91)(92)(93) In and Ga Empty liposomes are initially loaded with the chelating agent, and immediately prior to administration, the drug is formed in situ by incubation with another metal complex with a smaller binding constant, leading to 90% encapsulation of In and Ga in liposomes (91,94,95) 225 Ac 225 Ac is encapsulated by liposomes. After 30 days, 225 Ac retention as high as 81% of the initially encapsulated radioactivity was achieved (91,96) Electrostatic interactions ...
With the development of nanotechnology, significant progress has been made in the design, and manufacture of nanoparticles (NPs) for use in clinical treatments. Recent increases in our understanding of the central role of macrophages in the context of inflammation and cancer have reinvigorated interest in macrophages as drug targets. Macrophages play an integral role in maintaining the steady state of the immune system and are involved in cancer and inflammation processes. Thus, NPs tailored to accurately target macrophages have the potential to transform disease treatment. Herein, we first present a brief background information of NPs as drug carriers, including but not limited to the types of nanomaterials, their biological properties and their advantages in clinical application. Then, macrophage effector mechanisms and recent NPs-based strategies aimed at targeting macrophages by eliminating or re-educating macrophages in inflammation and cancer are summarized. Additionally, the development of nanocarriers targeting macrophages for disease diagnosis is also discussed. Finally, the significance of macrophage-targeting nanomedicine is highlighted, with the goal of facilitating future clinical translation.
... 4.2-14.5%) when compared to the traditional nanomedicines [21,22]. Traditional encapsulation approaches suffer from poor EE (~15%) [21] and DLC (generally less than 10%) [22]. ...
... when compared to the traditional nanomedicines [21,22]. Traditional encapsulation approaches suffer from poor EE (~15%) [21] and DLC (generally less than 10%) [22]. In our study, 20% of the DTX content was chosen with the best DLC and EE (14.5% and 86.9%, respectively). ...
Poor selectivity, low bioavailability and serious systemic side-effects have limited the application of traditional chemotherapy method for treatment of prostate cancer. Stimuli-responsive drug delivery systems for chemotherapy are mainly based on the unique characteristics of tumor microenvironment. In this study, the GSH-sensitive poly-TTG-SS@DTX NPs (DTX-loaded poly-Tetraethylene glycol nanoparticles) were designed and synthesized, which were characterized with nanosized diameter (92.8 ± 2.5 nm) and negatively charged surface charge (−24.7 ± 5.56 mV). Experiments in vitro showed that poly-TTG-SS@DTX NPs had good compatibility to healthy cells and strong anti-tumor effect because of rapid and sustained drug release of DTX from poly-TTG-SS@DTX NPs under the tumor-microenvironment condition. The cellular activity remained greater than 90% when the concentration of poly-TTG-SS NPs reached as high as 100 µg/mL treated on healthy cells. The killing effect of DTX loading NPs group on C4-2 cells was stronger than that of free anti-tumor drug and free DTX combined with the blank nano-carrier (25.21% vs 19.93% vs 20.96%). In conclusion, poly-TTG-SS@DTX NPs may provide a new therapeutic strategy for the chemotherapy of prostate cancer.
Graphical Abstract
... Different parameters can affect the rate of solidification of microparticles, directly influencing the encapsulation efficiency. The encapsulating system must ensure the delivery of enzymes in their native folding state and structure so that their biological activity is sustained [186]. Nevertheless, the encapsulating process' success depends on the characteristics of coating materials and the stability of active compounds in the core, along with the adequacy of the delivery system for its application [187]. ...
... However, protein release from the microparticles can be limited if the interaction is too strong. As an alternative, a co-encapsulated excipient can intermediate the interaction between the protein and polymer [186,189]. ...
Enzymes are versatile biomolecules with broad applications. Since they are biological molecules, they can be easily destabilized when placed in adverse environmental conditions, such as variations in temperature, pH, or ionic strength. In this sense, the use of protective structures, as polymeric capsules, has been an excellent approach to maintain the catalytic stability of enzymes during their application. Thus, in this review, we report the use of polymeric materials as enzyme encapsulation agents, recent technological developments related to this subject, and characterization methodologies and possible applications of the formed bioactive structures. Our search detected that the most explored methods for enzyme encapsulation are ionotropic gelation, spray drying, freeze-drying, nanoprecipitation, and electrospinning. α-chymotrypsin, lysozyme, and β-galactosidase were the most used enzymes in encapsulations, with chitosan and sodium alginate being the main polymers. Furthermore, most studies reported high encapsulation efficiency, enzyme activity maintenance, and stability improvement at pH, temperature, and storage. Therefore, the information presented here shows a direction for the development of encapsulation systems capable of stabilizing different enzymes and obtaining better performance during application.
... The physicochemical properties of drugs (solubility, partition coefficient, hydrogen bonding, complexation, bioisosterism) are the first thing to pay attention to. For example, a completely different strategy should be applied for the loading of hydrophilic and hydrophobic drugs into the same carrier [58][59][60]. ...
... However, it should be taken into consideration that encapsulation efficiency might be different in this case, as it was shown for doxorubicin, mitomycin C, camptothecin, methotrexate, verapamil, and 9AC drugs immobilizing into carbon-iron carriers [64]. On the other hand, one drug can interact with the carriers in many ways; this property allows for using various carriers that will be equally efficient at encapsulating the same molecule [60,[65][66][67][68][69]. ...
The increased research activity aiming at improved delivery of pharmaceutical molecules indicates the expansion of the field. An efficient therapeutic delivery approach is based on the optimal choice of drug-carrying vehicle, successful targeting, and payload release enabling the site-specific accumulation of the therapeutic molecules. However, designing the formulation endowed with the targeting properties in vitro does not guarantee its selective delivery in vivo. The various biological barriers that the carrier encounters upon intravascular administration should be adequately addressed in its overall design to reduce the off-target effects and unwanted toxicity in vivo and thereby enhance the therapeutic efficacy of the payload. Here, we discuss the main parameters of remote-controlled drug delivery systems: (i) key principles of the carrier selection; (ii) the most significant physiological barriers and limitations associated with the drug delivery; (iii) major concepts for its targeting and cargo release stimulation by external stimuli in vivo. The clinical translation for drug delivery systems is also described along with the main challenges, key parameters, and examples of successfully translated drug delivery platforms. The essential steps on the way from drug delivery system design to clinical trials are summarized, arranged, and discussed.
... Given a certain amount of drug involved in a preparation method, the encapsulation efficiency provides quantitative information about the amount of drug successfully transferred into a particular carrier [35]. Moreover, it is a relevant parameter to consider when a specific dose of therapeutic must be delivered precisely to the site of action [36]. Finally, from an economic point of view, as many drugs are costly, it can determine whether a system will be commercialized or not [34,36] (see Section 2.6). ...
... Moreover, it is a relevant parameter to consider when a specific dose of therapeutic must be delivered precisely to the site of action [36]. Finally, from an economic point of view, as many drugs are costly, it can determine whether a system will be commercialized or not [34,36] (see Section 2.6). It is also important in biosensing and biopreservation to understand the sensing performance or uptake of biotherapeutics. ...
Metal–organic frameworks (MOFs) combined with biomacromolecules, viruses and cells have emerged as novel biocomposites for application to drug delivery, biosensing, biospecimen preservation, and cell and virus manipulation. The integration of biological entities into MOF matrices generates MOF biocomposites with functional characteristics that cannot be observed in the separate components, such as enhanced chemical and thermal stability, resistance to proteases, MOF-conferred selectivity, and controlled release. In this review, we will discuss these functional properties and applications of the biocomposites obtained by the encapsulation of (i) proteins, (ii) carbohydrates, (iii) nucleic acids, and (iv) viruses or cells in a MOF matrix. Finally, we review the post functionalization of MOF-based drug carriers with lipids as a potential route to enhance the dispersion, stability in biological fluids, and blood circulation time of MOF-based drug delivery systems.
... 58 This is a critical issue that many researchers tend to address, since loading capacity is an important item for pharmaceutical dosages. 59 A decent drug loading capacity not only helps to reduce production cost but also improves therapeutic effects and decreases safety risk of excipients. 60 Loading content and encapsulation efficiency are two frequently used indexes to characterize drug loading properties for certain formulations. ...
Therapeutics based on proteins and peptides have profoundly transformed the landscape of treatment for diseases, from diabetes mellitus to cancers, yet the short half-life and low bioavailability of therapeutic proteins and peptides hinder their wide applications. To break through this bottleneck, biomolecules-loaded polymersomes with strong adjustability and versatility have attracted more and more attentions recently. Loading proteins or peptides into polymersomes is the first but extremely important step towards developing high-quality formulation products. However, increasing protein and peptide loading content is quite challenging due to the inherent nature of self-assembled vesicle formation mechanism and physiochemical characteristics of biomacromolecules. This review highlights the potential of polymersomes as the next-generation therapeutic proteins and peptides carrier and emphatically introduces novel approaches and recent progress to achieve satisfactory encapsulation capability of polymersomes for proteins and peptides. On the one hand, with the help of intermolecular interactions, such as electrostatic, lipid–protein, and hydrophobic interactions, the drug loading could be significantly improved. On the other hand, loading improvement could be attained through innovation of preparation methods, ranging from modified traditional film hydration techniques to the novel phase-guided assembly method.
... In addition, the entrapment efficiency can also be impacted by the drug partitioning between the melted lipid and aqueous medium. The decrease in the solubility of a drug in lipids due to the cooling of molten lipids depicts the importance of determining the amount of drug mixed with the lipid particles and the amount of drug solubilized in other structures within the formulation [89]. ...
Lipid nanoparticles (LNPs) have gained prominence as primary carriers for delivering a diverse array of therapeutic agents. Biological products have achieved a solid presence in clinical settings, and the anticipation of creating novel variants is increasing. These products predominantly encompass therapeutic proteins, nucleic acids and messenger RNA. The advancement of efficient LNP-based delivery systems for biologics that can overcome their limitations remains a highly favorable formulation strategy. Moreover, given their small size, biocompatibility, and biodegradation, LNPs can proficiently transport therapeutic moiety into the cells without significant toxicity and adverse reactions. This is especially crucial for the existing and upcoming biopharmaceuticals since large molecules as a group present several challenges that can be overcome by LNPs. This review describes the LNP technology for the delivery of biologics and summarizes the developments in the chemistry, manufacturing, and characterization of lipids used in the development of LNPs for biologics. Finally, we present a perspective on the potential opportunities and the current challenges pertaining to LNP technology.
... A greater therapeutic effect and fewer side effects can be obtained by improving a drug's encapsulation efficiency in drug carrier particles. 61 However, compared to standard formulations, the cost of the ingredients and the formulation process may be higher, they are less reproducible, and significant differences exist in how the polymers react with heat, hydrolysis, and biological agents. 62,63 In order to encapsulate the insulin, metal-organic framework crystals weighing 2 mg were soaked for 30 min at room temperature in an insulin solution. ...
Parenteral administration of insulin remains the most common route of administration, causing local hypertrophy at the injection sites because of multiple daily injections. Because of this, there is an interest and effort in oral insulin administration that is convenient and mimics the physiology of endogenous insulin secreted in the liver. However, oral insulin encountered different challenges due to abundant enzyme degradation, the presence of a mucus layer, and the underlying intestinal epithelial membrane barrier in the gastrointestinal tract. This narrative review reviewed the literature dealing with novel oral insulin delivery approaches. Various pieces of literature were searched, filtered, and reviewed from different sources, and the information obtained was organized, formulated, and finalized. Oral insulin has been formulated and extensively studied in various novel delivery approaches, such as nanoparticles, microspheres, mucoadhesive patches, encapsulations, hydrogels, ionic liquids, liposomes, and complexation. The efficiency of these formulations demonstrated improved efficiency and potency compared to free oral insulin delivery, but none of them have greater or equivalent potency to subcutaneous insulin. Future studies regarding dose-dependent therapeutic efficacy and the development of new novel formulations to produce comparable oral insulin to subcutaneous insulin are warranted to further support the suitability of the current platform for oral insulin delivery.
... Drug delivery technology is rapidly evolving when numerous medication delivery technologies are used to boost the effectiveness and cost-effectiveness of treatment procedures ( Figure 1). 1 Microparticulate drug carriers were developed as a result of these endeavors to provide innovative drug carrier systems. 2 Multiparticulate systems are important because they are simple to build and can control drug release in various ways, such as rate control, site control, or both. 3 Multiparticulate systems are expected to improve drug absorption because they are more likely to be distributed uniformly throughout the absorption site. ...
... The encapsulation efficiency is another significant factor during the development of the PDRN delivery system, which depends mainly on the interactions between the carrier and the drug. The higher encapsulation efficiency leads to stronger therapeutic effects while decreasing the probability of having side effects [35]. Therefore, it is mandatory to evaluate the encapsulation efficiency of the developed chitosan/PDRN polyplex, which depends on the interactions between the chitosan (carrier) and the PDRN (drug). ...
Polydeoxyribonucleotide (PDRN) is an accelerated diabetic wound healing therapy with promising abilities to promote cell growth, angiogenesis, collagen synthesis, and reduce inflammation where its sustainable delivery and release behavior is critical to ensure effective wound healing properties. Therefore, a nanopolyplex was developed here, by encapsulating PDRN with chitosan to affirm its delivery systematically. The physicochemical characterization revealed its successful encapsulation which facilitates the gradual release of PDRN. In vitro studies of the polyplex demonstrated no cytotoxicity and enhanced cell proliferation and migration properties with high antimicrobial activities. In vivo, wound healing studies in Wistar rats dorsal skin defect model induced with diabetes mellitus affirm the highest wound healing activity and wound closure rate by chitosan/PDRN polyplex treatment. Considerably high histopathological changes such as epithelialization, collagen deposition, blood vessels, and hair follicle formation were observed under the polyplex treatment. The immunohistochemical analysis for platelet endothelial cell adhesion molecule (CD31) and cluster of differentiation (CD68) revealed the ability of polyplex to increase CD31 expression and decrease CD68 expression thereby promoting the wound healing process. Collectively, these results suggest that significantly accelerated, high-quality wound healing effects could be obtained by the developed chitosan/PDRN polyplex and thus it could be introduced as a potential therapeutic product for diabetic wound healing.
... The swelling capability of polymer-based hydrogels is particularly noteworthy, as it allows them to absorb and retain significant amounts of water and biological fluids [44,45], rendering them a highly desirable material for use in medicine and healthcare applications [46,47]. This property enables the polymer-based hydrogels to create a unique environment that facilitates essential biological interactions [48,49], such as cell proliferation [50,51], adhesion [52,53], and differentiation [54,55]. Consequently, polymerbased hydrogels have emerged as promising candidates for tissue engineering [56][57][58] and regenerative medicine applications [59,60]. ...
Polymer-based hydrogels are hydrophilic polymer networks with crosslinks widely applied for drug delivery applications because of their ability to hold large amounts of water and biological fluids and control drug release based on their unique physicochemical properties and biocompatibility. Current trends in the development of hydrogel drug delivery systems involve the release of drugs in response to specific triggers such as pH, temperature, or enzymes for targeted drug delivery and to reduce the potential for systemic toxicity. In addition, developing injectable hydrogel formulations that are easily used and sustain drug release during this extended time is a growing interest. Another emerging trend in hydrogel drug delivery is the synthesis of nano hydrogels and other functional substances for improving targeted drug loading and release efficacy. Following these development trends, advanced hydrogels possessing mechanically improved properties, controlled release rates, and biocompatibility is developing as a focus of the field. More complex drug delivery systems such as multi-drug delivery and combination therapies will be developed based on these advancements. In addition, polymer-based hydrogels are gaining increasing attention in personalized medicine because of their ability to be tailored to a specific patient, for example, drug release rates, drug combinations, target-specific drug delivery, improvement of disease treatment effectiveness, and healthcare cost reduction. Overall, hydrogel application is advancing rapidly, towards more efficient and effective drug delivery systems in the future.
... Also, the encapsulating carrier can help in delivering the drug to specified target in the body [15]. Two categories of loading approaches can be used to obtain a certain drug dose in the delivery device, these are: 1. ...
... Liposomal drug loading methods are generally classified as passive or active based on different mechanisms, as shown in Fig. 1A. As a hydrophobic drug, meloxicam is commonly loaded in liposomes via passive loading method, where the drug is typically incorporated in liposomal membrane co-currently with liposome formation [39,40]. Passive drug loading usually reduces liposome stability and is much less efficient than active drug loading. ...
Temporomandibular joint (TMJ) osteoarthritis is a common osteochondral degenerative disease which can severely affect patient's mouth opening and mastication. Meloxicam (MLX), one of the most widely used non-steroidal anti-inflammatory drugs, is the main clinical therapy for the treatment of TMJ osteoarthritis. However, the clinical effect is greatly compromised because of its poor water solubility and high lipophilicity. In the present study, we developed an actively-loaded liposomal formulation, namely MLX-Ca(AC)2Lipo, using meglumine to enhance aqueous solubility and divalent metal (Ca2+) solution to improve encapsulation efficiency. By the formation of the nano-bowl shaped MLX-Ca precipitates inside the liposomes, MLX-Ca(AC)2Lipo successfully achieved an optimal encapsulation efficiency as high as 98.4% compared with previous passive loading method (60.6%). Additionally, MLX-Ca(AC)2Lipo maintained stable, and the slow drug release not only prolonged the duration of drug efficacy but also improved bioavailability. It was shown in the in vitro and in vivo tests that MLX-Ca(AC)2Lipo downregulated the synthesis of the inflammatory factors (such as prostaglandin-E2) and as a consequence reduced chondrocytes apoptosis and extracellular matrix degeneration. Furthermore, the intra-articular injection of MLX-Ca(AC)2Lipo enhanced bioinspired lubrication of TMJ, protecting the cartilage from progressive wear. In summary, MLX-Ca(AC)2Lipo with dual-functions of anti-inflammation and lubrication is a promising nanomedicine for the treatment of TMJ osteoarthritis by intra-articular injection.
... Notably, NP4, composed of PHA, showed a higher entrapment efficiency of PTX than that of NP1, composed of PLGA. As the amount of PHA increased, entrapment efficiency also gradually increased, which might have improved the therapeutic effects and reduced side effects [42]. ...
Biodegradable nanoparticles (NPs) are preferred as drug carriers because of their effectiveness in encapsulating drugs, ability to control drug release, and low cytotoxicity. Although poly(lactide co-glycolide) (PLGA)-based NPs have been used for controlled release strategies, they have some disadvantages. This study describes an approach using biodegradable polyhydroxyalkanoate (PHA) to overcome these challenges. By varying the amount of PHA, NPs were successfully fabricated by a solvent evaporation method. The size range of the NPS ranged from 137.60 to 186.93 nm, and showed zero-order release kinetics of paclitaxel (PTX) for 7 h, and more sustained release profiles compared with NPs composed of PLGA alone. Increasing the amount of PHA improved the PTX loading efficiency of NPs. Overall, these findings suggest that PHA can be used for designing polymeric nanocarriers, which offer a potential strategy for the development of improved drug delivery systems for sustained and controlled release.
... -Reducing the effect of toxicity, -Enhancing the solubility, -Protecting the drug from exterior conditions (enzymes, oxidation, and pH), -Improving availability and circulation time. Also, the encapsulating carrier can help in delivering the drug to specified target in the body [15]. ...
... The intervention of nanoparticle drug delivery is needed because Prostate Cancer (PC) is the most commonly diagnosed male malignancy in the western world [35]. The development of drug resistance and progression to metastasis are common clinical implications of those who are actively managing PC. ...
A major problem associated with prostate cancer treatment is the development of drug resistance. The development of drug resistance often leads to prostate cancer metastasis and prostate cancer-targeted drug delivery systems can be utilized to address this problem. Traditional drug delivery systems have many challenges, including the inability to control the drug release rate, target site inaccuracy, susceptibility to the microenvironment, poor drug solubility, and cytotoxicity of chemotherapeutics to non-malignant cells. As a result, there is an urgent need to formulate and functionalize a drug delivery system that better controls drug release. This study was designed to quantify the release of SC-514 from SC-514 Polylactic-Co-Glycolic Acid (PLGA) nanoparticles and conjugate SC-514-PLGA coated nanoparticles with the NF- κβ antibody, as well as fats. This study further explored new methods to quantify the release of SC-514 drug from the SC-514-PLGA coated nanoparticles after utilizing Liquid Chromatography–Mass Spectrometry (LC-MS) as the standard method to quantify SC-514 drug released. After quantification was completed, cell viability studies indicated that the ligand conjugated nanoparticles demonstrated a considerable ability to reduce tumor growth and SC-514 drug toxicity in the PC-3 cell line. The prepared drug delivery systems also possessed a significantly lower toxicity (P<0.05), bettered controlled-release behaviors in prostate cancer, and increased the solubility of SC-514 in comparison to free SC-514. SC-514 released from SC-514-PLGA, SC-514-PLGA-NF- κβAb, and SC-514-PLGA-Fat nanoparticles, significantly inhibited tumor growth when compared to that of free SC-514. The anti-cancer therapeutic effects of SC-514 were improved through the encapsulation of SC-514 with a PLGA polymer. The functionalized SC-514-PLGA nanoparticles can further control burst release. The new methods utilized in this study for quantifying drug release, may prove to be as effective as the current standard methods, such as LC/MS.
... According to the results obtained in this section, it could be concluded that, intermolecular hydrogen bonds have important role in the stability of physisorption, also can be useful in developing carbon nanocarriers for DOX and on the basis of target environmental conditions, i.e. pH of target medium, suitable samples can be used for DDS systems to optimize drug release conditions. Also, other nanocarrier structures such as multi walled carbon nanotube and hybrid CNT-polymer could be used to improve drug encapsulation capability [78,79]. ...
In this work, interaction and bond properties of anticancer drug doxorubicin (DOX), armchair single-walled carbon nanotube (SWCNT), and hydroxyl- and carboxyl-functionalized SWCNT (ƒ-SWCNT) have been investigated based on DFT theory to design, improve and expand carbon nanotube (CNT) drug carriers which is applied in biomedical systems such as drug delivery systems. Geometrical, structural, electrical, bonding and thermodynamic properties as well as optimized geometry, adsorption energies, quantum molecular descriptors, topological parameters and frontier molecular orbitals of different drug arrangements on CNT at the highest equilibrium at WB97XD/6–31 + G (d, p) level of theory at aqueous and gas phases were explored. Our calculations showed that hydrogen bonds between active sites of DOX molecules and hydroxyl- and carboxyl-functionalized CNTs played a more important role than those with pristine CNTs in the adsorption and fixation of the studied complexes as well as their thermodynamic energy. Using quantum theory of atoms in molecules (QTAIMs) method, intermolecular interactions and corresponding parameters at critical bonding points in aqueous and gas phases were also investigated. Evaluation of the results obtained from the natural bond orbital (NBO) analysis showed that the direction of electron movement was generally from drug molecule to CNT.
... Indeed, after 7 days in the release medium, the NPs were extracted with acetonitrile revealing that 25-26% AEA still remained encapsulated. 14 The results indicate that about 40% of AEA was captured in the outer layers of NPs surface and rapidly diffused to the release medium. Reaming drug would be slowly released as the polymeric matrix erosion occurs in accordance with other studies carried out with curcumin encapsulated in PCL and PLGA NPs (46) and bosentan monohydrate loaded in PCL NPs (47). ...
Anandamide (AEA), an endogenous cannabinoid, has a relevant antihypertensive effect. However, its cardioprotective role has been barely explored due to unfavorable physico-chemical properties and, sometimes, undesirable psychoactive effects. In this context, drug encapsulation in nanocarriers could overcome the limitations associated with the administration of AEA in free form. The aim of the present study was to encapsulate AEA in poly-e-caprolactone/Pluronic® F127 nanoparticles (AEA/PCL/PF127 NPs) by means of electrospraying, to characterize their physico-chemical properties and cytocompatibility and to evaluate their effect in an in vivo model of cardiovascular remodeling caused by hypertension. AEA/PCL/PF127 NPs were characterized in terms of morphology, size, polydispersity, Z-potential, hydrophilicity, thermal and spectroscopic properties. Also, the encapsulation and loading efficiencies and in vitro release of AEA were analyzed. AEA/PCL/PF127 NPs (700-1000 nm) showed adequate cytocompatibility. For the cardiovascular remodeling studies, normotensive (WKY) and hypertensive (SHR) male rats were treated or not with AEA/PCL/PF127 NPs (5 mg/Kg, intraperitoneal injection) weekly for 1 month. Inflammatory markers and hemodynamic, structural and cardiac functional parameters were monitored. In SHR, the treatment with AEA/PCL/PF127 NPs reversed all altered cardiovascular markers and parameters (p <0.05). Overall, nanoformulated AEA obtained by electrospraying proved to be effective for the treatment of hypertension and its comorbidities, especially cardiovascular remodeling.
... Imprecise or inaccurate measurement of EE may not only misguide the screening of formulations but also lead to mal-dosing or even undesired side effect in clinical applications (Wallace et al., 2012;Zhang et al., 2017). According to the definition, EE can be calculated by measuring total nanocarrier-associated drugs (W N ) first, followed by dividing by total drug amount (W T ), which is the sum of both free drugs (W F ) and W N , or alternatively by measuring W F first and deducting W F from W T to get W N , followed by dividing by W T (Fig. 1A) (He et al., 2011;Niu et al., 2012;Kita and Dittrich, 2011;Yeo and Park, 2004). Both options require complete separation of free drugs from nanocarriers first by various methods such as centrifugation, ultrafiltration, dialysis and gel permeation column chromatography (Ohnishi et al., 2015). ...
Entrapment efficiency (EE) is a crucial parameter for the evaluation of nanocarriers. The accurate measurement of EE demands clear separation of nanocarriers from free drugs, which so far has not been clearly validated due to a lack of functional tools to identify nanocarriers. Herein, an environment-responsive water-quenching fluorophore was employed to label and identify model nanocarriers, polycaprolactone nanoparticles (PN), methoxy polyethylene glycol-poly(d,l-lactic acid) polymeric micelles (PM) and solid lipid nanoparticles (SLN). The separation process of three commonly used methods (centrifugation, ultrafiltration and gel permeation chromatography) was visualized by live imaging. The separation efficiency of the centrifugation method is very poor, especially for PM (40 nm), SLN (100 nm) and PN (100 nm); only PN (200 nm) can be efficiently separated but at a consumption of enormous energy. The ultrafiltration method shows the best separation efficiency with only 0.32-0.93% of leakage of the nanocarriers. Gel permeation chromatography exhibits good separation as well but suffers from low recovery, a potential factor that might compromise the accuracy of EE measurement. In conclusion, the ultrafiltration method is the method of choice for efficient separation and accurate measurement of EE.
... [3][4] Drug loading into liposomes is achieved by either passive loading or active loading. [5][6] In passive loading, dried lipid film is hydrated by an aqueous solution containing the drug. In active loading, drug is internalized to preformed liposomes by introducing a transmembrane pH gradient. ...
Use of nano carriers to treat cancer is attractive due to their advantages such as the sustained release of drugs and ability to target specific regions of the body where treatment is needed. However, loading water insoluble chemotherapeutic drugs into liposomes is challenging. In this study, we developed a method to encapsulate water-insoluble drug (piperlongumine) in liposomes by complexing piperlongumine with β-Cyclodextrin. Liposomes encapsulated with piperlongumine incubated with COLO 205 and PC-3 cell lines and demonstrated that viability of COLO 205 and PC-3 cells decreases to 7% and 41% respectively when the piperlongumine concentration is at 20 μM.
... Our results point to tenfold difference in drug 119 4.2 Common Types of CoreÀShell Nanoparticles loading for PLGA-PEG-PLGA NPs when equal volumes of organic solvent and water phase were used compared to experiments with 10 times larger antisolvent volume. Additionally, in order to minimize or avoid free drug crystallization during solvent shifting and NP formation, polymer/stabilizing agent and drug concentration should be adjusted in a way to support simultaneous drug nucleation and polymer aggregation (Lebouille et al., 2014;Kita and Dittrich, 2011;Koliqi et al., 2016;Djurdjic et al., 2015). This is especially important for extremely hydrophobic drugs as, due to their very low water solubility, the drug may start to precipitate as unprotected crystals at a faster pace, compared to polymer aggregation. ...
Core–shell (CS) nanoparticles (NPs) offer unique possibilities to improve cancer targeting by conquering tumor complexity and heterogeneity in order to reach different subpopulation of cells, improve tumor cell internalization, and fight intrinsic drug resistance. Major classes of CS NP platforms such as amphiphilic block copolymer CS NPs, polymer-peptide hybrid CS NPs and polymer-lipid hybrid CS NPs have evolved over the years to multistage bio-responsive CS NPs. These novel systems have huge potential to overcome obstacles and enable traffic of the carrier at the specific cellular and subcellular level. Recently, porous metal-organic framework NPs, formed by the self-assembly of organic bridging ligands and metal connecting centers, have been developed for drug delivery, thus offering a way to maximize dug loading, optimize release kinetics, and solve some of the limitations of polymer nanocarriers. Additionally, this peculiar porous structure poses great challenges for surface modification, offering different modules for targeting drugs and imaging agents.
Over the last two decades, lipid nanoparticles (LNPs) have evolved as an effective biocompatible and biodegradable RNA delivery platform in the fields of nanomedicine, biotechnology, and drug delivery. They are novel bionanomaterials that can be used to encapsulate a wide range of biomolecules, such as mRNA, as demonstrated by the current successes of COVID‐19 mRNA vaccines. Therefore, it is important to provide a perspective on LNPs for RNA delivery, which further offers useful guidance for researchers who want to work in the RNA‐based LNP field. This perspective first summarizes the approaches for the preparation of LNPs, followed by the introduction of the key characterization parameters. Then, the in vitro cell experiments to study LNP performance, including cell selection, cell viability, cellular association/uptake, endosomal escape, and their efficacy, were summarized. Finally, the in vivo animal experiments in the aspects of animal selection, administration, dosing and safety, and their therapeutic efficacy were discussed. The authors hope this perspective can offer valuable guidance to researchers who enter the field of RNA‐based LNPs and help them understand the crucial parameters that RNA‐based LNPs demand.
Higher drug loading employed in nanoscale delivery platforms is a goal that researchers have long sought after. But such viewpoint remains controversial because the impacts that nanocarriers bring about on bodies have been seriously overlooked. In the present study we investigated the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin (PLD). We prepared PLDs with two different drug loading rates: high drug loading rate, H-Dox, 12.9% w/w Dox/HSPC; low drug loading rate, L-Dox, 2.4% w/w Dox/HSPC (L-Dox had about 5 folds drug carriers of H-Dox at the same Dox dose). The pharmaceutical properties and biological effects of H-Dox and L-Dox were compared in mice, rats or 4T1 subcutaneous tumor-bearing mice. We showed that the lowering of doxorubicin loading did not cause substantial shifts to the pharmaceutical properties of PLDs such as in vitro and in vivo stability (stable), anti-tumor effect (equivalent effective), as well as tissue and cellular distribution. Moreover, it was even more beneficial for mitigating the undesired biological effects caused by PLDs, through prolonging blood circulation and alleviating cutaneous accumulation in the presence of pre-existing anti-PEG Abs due to less opsonins (e.g. IgM and C3) deposition on per particle. Our results warn that the effects of drug loading would be much more convoluted than expected due to the complex intermediation between nanocarriers and bodies, urging independent investigation for each individual delivery platform to facilitate clinical translation and application.
As a result of the catastrophic rise in the incidence and transmission of neurodegenerative disorders (CNS), around 24.3% of the world's population was predicted to have Alzheimer's disease (AD), or Parkinson's disease (PD) in 2015. A wide range of drugs have been created over the last three to four decades to address different neurological conditions. Many of the drugs listed for treating cerebral diseases cannot reach the brain because of the blood–brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), which are biological barriers to the brain. As a result, their effectiveness in treating cerebral disorders is reduced. Phytopharmaceuticals are generally preferred over chemically generated medicines because to their slightly greater patient compliance and lower negative effects. However, special administration techniques that have the ability to drastically change the ADME properties of these potential drugs are required for them to reach their maximum therapeutic index. The intranasal medication delivery channel via an olfactory neural pathway has successfully demonstrated the high efficacy and minimal side effects of the direct targeting technique for the delivery of drugs in the brain in neurological disorders. There are numerous natural compounds that have been studied for the treatment of neuronal disorders and their effective delivery to the targeted site of the brain, including crude extracts of Curcuma longa, Centella Asiatica, Gingko Biloba, Theobroma cacao, Withania somnifera, Bacopa monnieri, etc. and pure substances like—Bilobalide, Quercetin, (-)-Epigal. In comparison to their conventional forms, the therapeutic efficacy, stability, and release kinetics of these extracts/phytocompounds’ nanoformulations are produced and evaluated. And in mouse models of AD produced by commercial medicines, the results of these nanoformulations showed considerably greater neuroprotective efficacy. This shows that the formulations based on natural compounds have the potential to improve the pathological condition of AD and may be pursued as a prospective candidate for clinical research to determine its effectiveness in humans.KeywordsNanomedicineNovel drug delivery systemsOlfactory pathwaysTherapeutic indexBlood–brain barrier (BBB)Blood-cerebrospinal fluid barrier (BCSFB)
Long-acting formulations are designed to reduce dosing frequency and simplify dosing schedules by providing an extended duration of action. One approach to obtain long-acting formulations is to combine long-acting prodrugs (LA-prodrug) with existing or emerging drug delivery technologies (DDS). The design criteria for long-acting prodrugs are distinct from conventional prodrug strategies that alter absorption, distribution, metabolism, and excretion (ADME) parameters. Our review focuses on long-acting prodrug delivery systems (LA-prodrug DDS), which is a subcategory of long-acting formulations where prodrug design enables DDS formulation to achieve an extended duration of action that is greater than the parent drug. Here, we define LA-prodrugs as the conjugation of an active pharmaceutical ingredient (API) to a promoiety group via a cleavable covalent linker, where both the promoiety and linker are selected to enable formulation and administration from a drug delivery system (DDS) to achieve an extended duration of action. These LA-prodrug DDS results in an extended interval where the API is within a therapeutic range without necessarily altering ADME as is typical of conventional prodrugs. The conversion of the LA-prodrug to the API is dependent on linker cleavage, which can occur before or after release from the DDS. The requirement for linker cleavage provides an additional tool to prolong release from these LA-prodrug DDS. In addition, the physicochemical properties of drugs can be tuned by promoiety selection for a particular DDS. Conjugation with promoieties that are carriers or amenable to assembly into carriers can also provide access to formulations designed for extending duration of action. LA-prodrugs have been applied to a wide variety of drug delivery strategies and are categorized in this review by promoiety size and complexity. Small molecule promoieties (typically MW<1000Da) have been used to improve encapsulation or partitioning as well as broaden APIs for use with traditional long-acting formulations such as solid drug dispersions. Macromolecular promoieties (typically MW>1000Da) have been applied to hydrogels, nanoparticles, micelles, dendrimers, and polymerized prodrug monomers. The resulting LA-prodrug DDS enable extended duration of action for active pharmaceuticals across a wide range of applications, with target release timescales spanning days to years.
Background:
Microsponges are polymeric delivery devices composed of porous microspheres that range in size from 5 to 300 micrometers. These have been explored for biomedical applications such as targeted drug delivery, transdermal drug delivery, anticancer drug delivery, and bone substitutes.
Objective:
The purpose of this study is to conduct a comprehensive analysis of recent developments and prospects for a microsponge-based drug delivery system.
Methods:
The current study analyzes how the Microsponge Delivery System (MDS) is made, how it works, and how it can be used for a wide range of therapeutic purposes. The therapeutic potential and patent information of microsponge-based formulations were systematically analyzed. The authors summarize various effective techniques for developing microsponges, such as liquid-liquid suspension polymerization, quasi-emulsion solvent diffusion method, water-in-oil-in-water (w/o/w) emulsion solvent diffusion, oil-in-oil emulsion solvent diffusion, lyophilization method, porogen addition method, vibrating orifice aerosol generator method, electro-hydrodynamic atomization method, and ultrasound-assisted microsponge.
Results:
Microsponge may reduce the side effects and increase drug stability by positively altering drug release. Drugs that are both hydrophilic and hydrophobic can be loaded into a microsponge and delivered to a specific target.
Conclusion:
The microsponge delivery technology offers numerous advantages over conventional delivery systems. Microsponges, which are spherical sponge-like nanoparticles with porous surfaces, have the potential to increase the stability of medications. They also efficiently decrease the undesirable effects and alter drug release.
Catalysis has always been part of the development of mankind; from the fermentation of alcoholic drinks, through the development of fertilisers in the agricultural revolution and production of bulk chemicals in the 20th Century. Today, society demands improved production routes with greater product output and energy efficiency; the ultimate goal to achieving this would be having all catalytic reactions in concert, effectively functioning like a biological cell.
Metal organic frameworks (MOFs) are a relatively new type of hybrid material. Their crystalline porous structure, built up from organic and inorganic building blocks, presents a vast array of composition, porosity and functionality offering enormous potential in catalytic systems.
This book examines the latest research and discovery in the use of MOFs in catalysis, highlighting the extent to which these materials have been embraced by the community. Beyond presenting a digest of recent research by major players in the field, the book presents the strategies behind recent developments, providing a lasting reference for seasoned researchers and newcomers to the field.
Triptolide (as an effective antitumor drug) is limited in clinical application because of its poor solubility and absorption in-vivo . Herein, we prepared folic acid modified polymer micelles to encapsulate triptolide and enhance its biologicalavailability coupled with antitumor effect. We prepared nano-micelles of triptolide through thin lipid film hydrational method. Physical properties and in vitro release characterization of Fol-Plla-cl-Peg-Plla-cl-Tmicelles were evaluated, while bioavailability of the formulation in rats was investigated. Tumor targeting potential of micelles was determined by observing the uptake of A549 cells. In-Vitro antitumor activity of micelles and free triptolide (API) was investigated with MTT assay. The prepared polymer material exhibited no cytotoxicity. The particle size distribution of Fol-Plla-cl-Peg-Plla-cl-T micelles was uniform and small, with good stability and high efficiency of entrapment. Triptolide In-Vitro release from micelles demonstrated slow and continuous released for 24 h. Compared with API, the half-life of micelles was prolonged, whilst its bioavailability in-vivo was increased by about 6.35 times. More importantly, Fol-Plla-cl-Peg-Plla-cl-T micelles significantly improved the antitumor activity of triptolide and showed good tumor targeting potential. Fol-Plla-cl-Peg-Plla-cl-T micelles could improve the bioavailability and antitumor activity of triptolide, amid demonstration of good tumor targeting and high safety.
The outcomes of monotherapy could not satisfy clinical cancer treatment owing to the challenges of tumor heterogeneity, multi-drug resistance, tumor metastasis and relapse. In response, the significance of combinational cancer therapy has been highlighted. Traditional combinational schemes usually utilize "free" drug for multi drug administration, independently. The diverse pharmacokinetics and biodistribution greatly hinder the antitumor effects and cause systematic toxicity. To tackle the hinderance, various nanoparticulate drug delivery systems (Nano-DDSs) have been developed. However, conventional Nano-DDSs encapsulate drugs into carrier materials through noncovalent interactions, resulting in low drug loading, fixed multi drug encapsulation ratio, chemical instability and carrier-associated toxicity. Recently, carrier-free nanocombos based on self-assembling small-molecule prodrugs (SPNCs) have emerged as a versatile Nano-DDSs for multiple drug delivery. Benefited by the self-assembly capability, SPNCs could be facilely fabricated with distinct merits of ultra-high drug loading, adjustable drug ratio and negligible carrier-associated toxicity. Herein, we summarize the latest trends of SPNCs. First, a basic review on self-assembling small-molecule prodrugs is presented. Additionally, facile techniques to prepare SPNCs are introduced. Furthermore, advanced combinational therapies based on SPNCs are spotlighted with special emphasis on synergistic mechanisms. Finally, future prospects and challenges are discussed.
Background: Double emulsions (DEs) are water-in-oil-in-water (or oil-in-water-in-oil) droplets with the potential to deliver combinatory therapies due to their ability to co-localize hydrophilic and hydrophobic molecules in the same carrier. However, DEs are thermodynamically unstable and only kinetically trapped. Extending this transitory state and rendering DEs more stable, would widen the possibilities of real-world applications, yet characterization of their stability in physiologically-relevant conditions is lacking.
Methods: In this work, we used microfluidics to produce lipid-stabilized DEs with reproducible monodispersity and high encapsulation efficiency. We investigated DE stability under a range of physicochemical parameters such as temperature, pH and mechanical stimulus.
Results: Stability through time was inversely proportional to temperature. DEs were significantly stable up to eight days at 4 ° C, five days at room temperature and two days at 37 ° C. When encapsulating a cargo, DE stability decreased significantly. When exposed to a pH change, unloaded DEs were only significantly unstable at the extremes (pH 1 and 13), largely outside physiological ranges. When exposed to flow, unloaded DEs behaved similarly regardless of the mechanical stimulus applied, with approximately 70% remaining after 100 flow cycles of 10s.
Conclusions: These results indicate that lipid-stabilized DEs produced via microfluidics could be tailored to endure physiologically-relevant conditions and act as carriers for drug delivery. Special attention should be given to the composition of the solutions, e.g. osmolarity ratio between inner and outer solutions, and the interaction of the molecules, e.g. carrier and cargo, involved in the final formulation.
Seven new Casiopeinas® were synthesized and properly characterized. These novel compounds have a general formula [Cu(N-N)(Indo)]NO3, where Indo is deprotonated indomethacin and N-N is either bipyridine or phenanthroline with some methyl-substituted derivatives, belonging to the third generation of Casiopeinas®. Spectroscopic characterization suggests a square-based pyramid geometry and voltammetry experiments indicate that the redox potential is strongly dependent on the N-N ligand. All the presented compounds show high cytotoxic efficiency, and most of them exhibit higher efficacy compared to the well-known cisplatin drug and acetylacetonate analogs of the first generation. Computational calculations show that antiproliferative behavior can be directly related to the volume of the molecules. Besides, a chitosan (CS)-polyacrylamide (PNIPAAm) nanogel was synthesized and characterized to examine the encapsulation and release properties of the [Cu(4,7-dimethyl-1,10-phenanthroline)(Indo)]NO3 compound. The results show good encapsulation performance in acidic conditions and a higher kinetic drug release in acidic media than at neutral pH. This result can be described by the Peppas-Sahlin model and indicates a release mechanism predominantly by Fick diffusion.
A growing need for developing novel technologies for obtaining better quality products with enhanced process efficiency has created promise for application of ultrasound in the area of food and pharmaceutical processing. This chapter offers discussion on the governing mechanisms for the improvement based on the use of ultrasound, different ultrasonic reactor configurations, as well as the selection of operating conditions for the specific applications of encapsulation and crystallization. The effects of ultrasound during the processing such as liquid circulation, turbulence, and local hot spots drive the observed intensification. Analysis of reactor designs revealed that there is a need for development of continuous reactors with usage of a large number of transducers so as to give the desired processing benefits based on uniform distribution of cavitational activity. It has been also elucidated that application of ultrasound under the desired conditions can give advantages such as greater control over particle size, enhanced solubility of drugs, controlled crystallization, and production of nanomaterials. Overall, this chapter has clearly demonstrated the advantages of ultrasound and highlights the need for specific efforts required for exploitation at commercial scale.
The current research work aims to study the pharmacokinetic and nasal ciliotoxicity of donepezil liposome-based in situ gel to treat Alzheimer's disease. The physicochemical properties and first-pass metabolism of donepezil HCl result in low concentrations reaching the brain post oral administration. To overcome this problem, donepezil HCl-loaded liposomes were formulated using the ethanol injection method. The donepezil HCl-loaded liposomes were spherical with a size of 103 ± 6.2 nm, polydispersity index of 0.108 ± 0.008, and entrapment efficiency of 93 ± 5.33 %. The optimized in situ gel with donepezil HCl-loaded liposomes showed 80.11 ± 7.77 % drug permeation than donepezil HCl solution-based in situ gel (13.12 ± 4.84 %) across sheep nasal mucosa. The nasal ciliotoxicity study indicated the safety of developed formulation for administration via nasal route. The pharmacokinetics and biodistribution study of developed formulation showed higher drug concentration (1239.61 ± 123.60 pg/g) in the brain after nasal administration indicating its better potential via the nasal pathway. To treat Alzheimer's disease, the administration of liposome-based in situ gel through the nasal pathway can therefore be considered as an effective and promising mode of drug delivery.
Lipid nanoparticles have attracted significant interests in the last two decades, and have achieved tremendous clinical success since the first clinical approval of Doxil in 1995. At the same time, lipid nanoparticles have also demonstrated enormous potential in delivering nucleic acid drugs as evidenced by the approval of two RNA therapies and mRNA COVID-19 vaccines. In this review, an overview on different classes of lipid nanoparticles, including liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, is first provided, followed by the introduction of their preparation methods. Then the characterizations of lipid nanoparticles are briefly reviewed and their applications in encapsulating and delivering hydrophobic drugs, hydrophilic drugs, and RNAs are highlighted. Finally, various applications of lipid nanoparticles for overcoming different delivery challenges, including crossing the blood–brain barrier, targeted delivery, and various routes of administration, are summarized. Lipid nanoparticles as drug delivery systems offer many attractive benefits such as great biocompatibility, ease of preparation, feasibility of scale-up, nontoxicity, and targeted delivery, while current challenges in drug delivery warrant future studies about structure–function correlations, large-scale production, and targeted delivery to realize the full potential of lipid nanoparticles for wider clinical and pharmaceutical applications in future.
Electrostatic interactions include weak attractive and repulsive interactions based on the magnitude and polarity of the charge the particle possess. These charges could play a substantial role if the concept of electrostatic interaction is applied in the field of nano-medicine. Surface charge is one of the most important armament of a researcher in the field of drug delivery. However, in recent times, not much attention has been paid to its attributes. Surface charge influences several processes like stability, drug delivery, cytotoxicity, bio-distribution, cell uptake, permeation of biological barriers, etc. This review highlights the importance of surface charge at the cellular and molecular level. We also emphasize on how a researcher can use surface charge to advance the current delivery systems in various desired applications.
Hyaluronic acid (HA) particles with divinyl sulfone (DVS) crosslinking at 10% mole ratio (HA macromolecule repeating units) were prepared and demonstrated as versatile drug carriers with sustainable and long-term release capabilities for cancer drugs, corticosteroid, and antibiotics. Two different methods were chosen in drug loading process; encapsulation for cancer drugs, 5-fluorouracil (5FU), mitomycin C (MMC), and doxorubicin (Dox), and dual drug conjugation for anti-inflammatory glucocorticoid dexamethasone (Dex) and antibiotic ciprofloxacin (Cipro) drugs, respectively. It was demonstrated that HA particles prepared during drug encapsulation were attained smaller sizes with 833 ± 46, 867 ± 50, 728 ± 41 nm for 5FU, MMC, and Dox, respectively. Bare and drug loaded HA particles were shown to be blood compatible with the highest hemolytic ratio of 3.1 ± 0.12% for HA-Dex-Cipro conjugates and fairly good blood clotting index with minimum 71.7 ± 6.0% for MMC encapsulated HA particles. Drug release studies from HA particles indicated that depending on the types of cancer drugs, it is possible to gradually release the drug in long-term up to 300 h in linear fashions with the highest release of 9.34 ± 2.25 mg/g for 5FU. Similarly, drug conjugated HA-Dex-Cipro particles were also showed linear dual drug release up to 100 h at physiological conditions, pH 7.4 and 37.5 °C.
Docetaxel (DTX) was loaded in nanoliposomes based on a new remote loading method using mannitol and acetic acid as hydration buffer. DTX loading conditions were optimized, and the final formulations were prepared according to the best parameters which were HSPC/mPEG2000-DSPE/Chol (F1), HSPC/mPEG2000-DSPE/DPPG/Chol (F2), HSPC/mPEG2000-DSPE/DSPG/Chol (F3), at molar ratios of 85/5/10, 80/5/5/10, 80/5/5/10, respectively. DTX-liposomes were found of desired size (~115 nm) and homogeneity (PDI ≤ 0.2), high drug encapsulation efficacy (34–67%) and DTX concentration, and favorable stability. Passive loaded counterparts liposomes showed three times lower encapsulation efficacy compared to the remote loaded liposomes. The drug release of remote loaded liposomes in plasma 50% was significantly more controlled and less in comparison with their passive loaded counterparts (p < 0.0001). The IC50 values of formulations were determined on MCF-7, 4T1, TUBO, NIH/3T3 cell lines. The biodistribution of iodinated docetaxel as free or liposomal form exhibited significantly greater accumulation of DTX-liposomes in tumors than that of free docetaxel due to the EPR effect. In vivo experiment with BALB/c mice bearing 4T1 or TUBO breast carcinoma tumors also showed that DTX-liposomes could significantly delay tumor growth and prolonged the survival time in comparison with control and Taxotere groups at the similar dose of 8 mg/kg. F1 and F2 formulations were stable and showed good anti-tumor activity and merit further investigation.
Self-assembly of amphiphilic polymers in aqueous solution builds up versatile carrier platforms for therapeutic delivery. Amphiphilic polymers specifically provide “hydrophobic pockets” for the encapsulation of water-insoluble small-molecule drugs, along with effective strategies to control the cargo release. Random and block copolymers have been separately demonstrated to affect the cargo encapsulation and release. In this study, we present self-assembled structures of blended random and block copolymers to tune the encapsulation and release of lipophilic cargo molecules. The hydrophilic–lipophilic balance (HLB) within the polymeric (co-)assemblies greatly affects their cargo loading capacity. Meanwhile, the disulfide moieties within the polymeric assemblies allow controlled cargo release upon a redox stimulus such as glutathione. The triggered release of encapsulated cargos is affected by the overall HLB, the reactivity, and accessibility of the disulfide species within the polymeric assemblies.
The 5-year mortality rate for heart failure borders on 50%. The main cause is an ischaemic cardiac event where blood supply to the tissue is lost and cell death occurs. Over time, this damage spreads and the heart is no longer able to pump efficiently. Increasing vascularisation of the affected area has been shown to reduce patient symptoms. The growth factors required to do this have short half-lives making development of an efficacious therapy difficult. Herein, the angiogenic growth factor Vascular Endothelial Growth Factor (VEGF) is complexed electrostatically with star-shaped or linear polyglutamic acid (PGA) polypeptides. Optimised PGA-VEGF nanomedicines provide VEGF encapsulation of > 99% and facilitate sustained release of VEGF for up to 28 days in vitro. The star-PGA-VEGF nanomedicines are loaded into a percutaneous delivery compliant hyaluronic acid hydrogel. Sustained release of VEGF from the composite nano-in-gel system is evident for up to 35 days and the released VEGF has comparable bioactivity to free, fresh VEGF when tested on both Matrigel® and scratch assays. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. Therefore, we report the development of novel, self-assembling PGA-VEGF nanomedicines and their incorporation into a hyaluronic acid hydrogel that is compatible with medical devices to enable minimally invasive delivery to the heart. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. This formulation provides the basis for optimal spatiotemporal delivery of an angiogenic growth factor to the ischaemic myocardium.
The achievement of desirable pharmacokinetic parameters from particulate drug delivery systems are dependent on the physical characteristics of the systems namely, particle dimension, loading of therapeutic agent, encapsulation efficiency, in vitro release kinetics. This study aimed to evaluate the main and interaction effects of the formulation variables on those physical characteristics and also to optimize the best combination of the variables to formulate small size particles with high encapsulation efficiency. The results showed that all the process variables (amount of polycaprolactone and stirring speed) except the amount of surfactant contributed significantly to the parameters previously mentioned. The best optimized formulation was experimentally validated for the closeness to the theoretical estimates.
As it was mentioned in the previous chapters, the efficiency of medication is dependent on several parameters such as drug release profile, drug transport mechanisms, and most importantly the interaction between a drug and its surrounding environment in the human body.
Each drug has some pharmacological properties that can produce biological effects on the human body; these effects are engendered by the interactions between the drug and specific receptors at the drug’s site of action.
As stated in the last chapter, a drug delivery system is responsible to influence and determine the concentration profile of a drug, the kinetics of drug release, the site, and duration of drug action, and finally prevent the unwelcome side effects of a drug.
Because of the harsh and hydrophilic environment of the body, some more potent but poor water-soluble drugs molecule become developed by Shij et al. (Nano Lett 10:3223–3230, 2010 [1]).
Drug concentration must be placed between two thresholds, referred as the minimum effective concentration and the maximum toxic concentration, to be effective and nontoxic. Usually, a drug is released in three manners.
There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or β-cyclodextrin were synthesized. Using poly(β-benzyl L-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison to free drug. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, this type of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.
T cell acute lymphoblastic leukemia (T-ALL) is caused by clonal expansion of variant T cell progenitors and is considered as a high risk leukemia. Contemporary single chemotherapy has a limited effect due to dynamic and versatile properties of T-ALL. Here IRAK1/4 inhibitor and ABT-737 were co-encapsulated into polyethylene glycol modified poly (lactic-co-glycolic acid) nanoparticles (IRAK/ABT-NP) to enhance synergistic therapy of T-ALL. The formulation was optimized to achieve high drug loading using Box-Behnken design and response surface methodology. The optimal parameter comprised 2.98% polymer in acetonitrile, a ratio of oil phase to water phase of 1:8.33, and 2.12% emulsifier concentration. High drug loading and uniform spherical shape was achieved. In vitro release study showed sustained release of IRAK1/4 inhibitor for 72 hours as well as sustained release of ABT-737 for more than 120 hours. Uptake efficiency of IRAK/ABT-NP and induced apoptotic T-ALL fraction by IRAK/ABT-NP were much higher than the IRAK1/4 and ABT-737 combined solution. IC50 of IRAK/ABT-NP was two-fold lower than free drug combination in Jurkat cells. Additionally, we conducted in vivo experiments in which IRAK/ABT-NP exhibited greater cytotoxicity toward T-ALL cells, the capacity to significantly restore white blood cell number in peripheral blood, and improved survival time of T-ALL mouse model compared to the IRAK1/4 and ABT-737 combined solution.
Unlabelled:
Colloidal nanocarriers, in their various forms, have the possibility of providing endless opportunities in the area of drug delivery. The current communication embodies an in-depth discussion of colloidal nanocarriers with respect to formulation aspects, types, and site-specific drug targeting using various forms of colloidal nanocarriers with special insights to the field of oncology. Specialized nanotechnological approaches like quantum dots, dendrimers, integrins, monoclonal antibodies, and so forth, which have been extensively researched for targeted delivery of therapeutic and diagnostic agents, are also discussed. Nanotechnological patents, issued by the U.S. Patent and Trademark Office in the area of drug delivery, are also included in this review to emphasize the importance of nanotechnology in the current research scenario.
From the clinical editor:
Colloidal nanocarriers provide almost endless opportunities in the area of drug delivery. While the review mainly addresses potential oncological applications, similar approaches may be applicable in other conditions with a requirement for targeted drug delivery. Technologies including quantum dots, dendrimers, integrins, monoclonal antibodies are discussed, along with US-based patents related to these methods.
A methotrexate (MTX)-layered double hydroxide (LDH) hybrid have been developed as a drug delivery system, in which an anticancer drug, MTX, was intercalated into a 2-dimensional LDH nanovehicle to form a nanohybrid. According to the comparative cell viability studies between MTX only and its LDH nanohybrid on MTX sensitive and resistant cell culture lines, it was found that the MTX-LDH nanohybrid could bypass the MTX resistance and eventually inhibit cancer cell proliferation very effectively compared to free MTX, due to an enhanced permeability and retention effect of MTX-LDH nanoparticles even in dihydrofolate reductase-overexpressing MTX-resistant cells. This is definitely associated with the uptake mechanism via a clathrin-mediated endocytic pathway for the MTX-LDH nanohybrid particles, the same as for the LDH nanocarrier only, which is completely different from the cellular uptake mechanism for MTX only, the reduced folate carrier (RFC) and/or the folatereceptor entries.
Lipoplexes and polyplexes, electrostatic complexes between a plasmid DNA and cationic lipids or polymers are chemical systems that are developed for gene delivery. Considerable efforts have been done to delineate the exact knowledge of their entry mechanisms and the intracellular routing of the plasmid DNA that are of major importance for the designing of these gene delivery systems. While the uptake of lipoplexes made with several types of cationic lipids proceeds mainly by the clathrin-dependent pathway, it appears that for polyplexes the uptake pathway is more dependent on the polymer and the cell types. So, after an overview of the current knowledge of different endocytic pathways, we present here a selection of current reports related to the entry mechanisms and intracellular routing of plasmid DNA complexed with select cationic polymers. The review includes the role of glycosaminoglycans, cell polarization and cell cycle in the polyplex uptake and their transfection efficiency. We also report current data showing that the insertion of specific kappaB motifs in the nucleic acid sequence provides an increase of the plasmid import into the nucleus. This has been demonstrated by fluorescence methods suitable to investigate the intracellular trafficking of pDNA. Overall, it appears that polyplex uptake proceeds both by the clathrin-dependent pathway and a clathrin-independent (cholesterol-dependent) pathway. These two entry mechanisms are not exclusive and can occur simultaneously in the same cell. Both of them lead to cell transfection but polyplexes still need improvements for clinical use.
Initial burst is one of the major challenges in protein-encapsulated microparticle systems. Since protein release during the initial stage depends mostly on the diffusional escape of the protein, major approaches to prevent the initial burst have focused on efficient encapsulation of the protein within the microparticles. For this reason, control of encapsulation efficiency and the extent of initial burst are based on common formulation parameters. The present article provides a literature review of the formulation parameters that are known to influence the two properties in the emulsion-solvent evaporation/extraction method. Physical and chemical properties of encapsulating polymers, solvent systems, polymer-drug interactions, and properties of the continuous phase are some of the influential variables. Most parameters affect encapsulation efficiency and initial burst by modifying solidification rate of the dispersed phase. In order to prevent many unfavorable events such as pore formation, drug loss, and drug migration that occur while the dispersed phase is in the semi-solid state, it is important to understand and optimize these variables.
The polarity and accessibility to the interior of several dendrimers using phenanthrene, anthracene and tetrabenzonaphtalene as probe molecules have been investigated. In addition the prospective application of the dendrimers as drug carriers was evaluated by incorporating 5(6)-methylbenzo[1,2-c]1,2,5-oxadiazole N 1-oxide] (1) and 2′-(benzo[1,2-c] 1,2,5-oxadiazol-5(6)-yl(N1-oxide) methylidene]-1-methoxy methane hydrazide (2). These compounds have antichagasic therapeutic activity but very low water solubility, which limits their application. Polypropylene imine dendrimers with amine terminal groups (DAB-16AT and DAB-32AT) and polyamide amine (PAMAM) dendrimers with carboxylate terminal groups (PAMAM-32CT), with amine terminal groups, (PAMAM-8AT and PAMAM-32AT) and with hydroxyl terminal groups (PAMAM-32OHT) were chosen for this study. Approximately one molecule of phenanthrene or anthracene was encapsulated in PAMAM-32CT, PAMAM-32AT, PAMAM-32OHT and DAB-32AT dendrimers. However, slight encapsulation was observed working with PAMAM-8AT and DAB-16AT. The studies with tetrabenzonaphtalene show that the guest molecule might only be partially caged within the dendrimer host. However, for relatively insoluble solutes the efficiency to encapsulate can be dictated by the saturation in the aqueous phase besides the dendrimer capacity to dissolve it. These dendrimers are also able to encapsulate and consequently solubilize 1 and 2 oxadiazol. However, PAMAM dendrimers are better for encapsulation and retention due to guest-host specific interactions. These interactions can be diminished by lowering the pH to allow a controlled deliverance of the drug.
Dendritic macromolecules, such as hyperbranched polymers are increasingly being studied in the context of encapsulation. The intensive research on encapsulation using hyperbranched polymers is motivated by factors such as a cost-effective polymer synthesis and a customizable property profile. Hence, in the past few years, hyperbranched polymers have been employed as carriers for several guest molecules such as dyes, pharmaceuticals, cosmetics, catalysts, and aromatic hydrocarbons. However, hyperbranched polymers compete not only with perfectly structured dendrimers but also with conventional carrier molecules in terms of price and performance criteria such as processability, loading capacity, delivery efficiency and/or reduction of toxic side effects. This article aims at reviewing the research and development (R&D) in the field of encapsulation using hyperbranched polymers. Based on a summary of the most relevant R&D results and encapsulation technologies in this area, progress and challenges are discussed and new emerging applications are described. The most prominent emerging applications include the encapsulation and/or controlled release of (i) unstable or sensitive components (such as those used in the field of personal care), (ii) pharmaceutical substances (using hyperbranched carrier polymers with a narrow molar mass distribution), and (iii) inorganic nanoparticles to design versatile nanoreactors for catalytic applications.
Polymers are used as carriers for the delivery of drugs, proteins, targeting moieties, and imaging agents. Several polymers, poly(ethylene glycol) (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), and poly(lactide-co-glycolide) (PLGA) copolymers have been successfully utilized in clinical research. Recently, interest in polymer conjugation with biologically active components has increased remarkably as such conjugates are preferably accumulated in solid tumors and can reduce systemic toxicity. Based on the site and the mode of action, polymer conjugates possess either 'tuned' degradable or non-degradable bonds. In order to obtain such bonds, most of the strategies involve incorporation of amino acids, peptides or small chains as spacer molecules through multiple steps to include protections and deprotections. There is a need to design efficient synthetic methods to obtain polymeric conjugates with drugs and other bioactive components. Designs should aim to decrease the steric hindrance exhibited by polymers and the biocomponents. In addition, the reactivity of polymer and drug must be enhanced. This is especially true for the use of high molecular weight linear polymers and bulkier unstable drugs such as steroids and chemotherapeutic agents. Further, it is essential to elucidate the structure activity relationship (SAR) of a drug when it is conjugated with a polymer using different conjugation sites, as this can vary the efficacy and mechanism of action when compared with its free form. This review will discuss the current synthetic advances in polymer-conjugation with different bioactive components of clinical importance. In addition, the review will describe the strategies for reduction of steric hindrance and increase in reactivity of the polymers, drugs and bioactive agents and highlight the requisite structure activity relationship in polymer–drug bioconjugates. Finally, we will focus on passive and active targeting of polymeric drug delivery systems to specific site of drug action.
BACKGROUND: The aim of the work presented was to synthesize a series of amphiphilic hyperbranched poly[(amine‐ester)‐ co ‐( D , L ‐lactide)] (HPAE‐ co ‐PLA) copolymers and study the formation of copolymeric micelles. These copolymeric micelle systems are expected to be potential candidates for applications in protein drug delivery.
RESULTS: The chemical structures of the copolymers were confirmed by Fourier transform infrared spectroscopy, ¹³ C NMR and thermogravimetric analysis. Fluorescence spectroscopy and dynamic light scattering confirmed the formation of copolymeric micelles of the HPAE‐ co ‐PLA copolymers. The maintenance of stability of bovine serum albumin (BSA) during release from micelles in vitro was also measured using circular dichroism and fluorescence spectrometry.
CONCLUSION: Novel hyperbranched HPAE‐ co ‐PLA copolymers have been synthesized. Conjugation of PLA to HPAE was proved to be an available method for the preparation of micelles for protein delivery. The BSA‐loaded micelles showed enhanced encapsulation efficiency and the structural stability of BSA was retained during the release process. The hyperbranched polymeric micelles could be useful as drug carriers for protein drug delivery systems. Copyright © 2008 Society of Chemical Industry
The complexing, solubilizing and amorphizing abilities toward oxaprozin (a poorly water-soluble anti-inflammatory agent) of
some β-cyclodextrin derivatives (hydroxypropyl-βCd, heptakis-2,6-di-O-methyl-βCd (DIMEB) amorphous randomly substituted methyl-βCd
(RAMEB) and semi-crystalline methyl-βCd (CRYSMEΒ)) were investigated and compared with those of natural (α-, β-, γ-) cyclodextrins.
The role of both the cavity size, the amorphous or crystalline state and the presence and type of substituent on the ability
of cyclodextrins in establishing effective interactions with the drug has been evaluated. Equimolar drug-cyclodextrin solid
systems were prepared by blending, kneading, co-grinding, sealed-heating, coevaporation, and colyophilization. Drug-carrier
interactions were studied in both the liquid and solid state by phase-solubility analysis, differential scanning calorimetry,
X-ray powder diffractometry, FT-IR spectroscopy and scanning electron microscopy. βCd showed the best performance among the
natural Cds, indicating that its cavity was the most suitable for accommodating the drug molecule. The presence of substituents
on the rim of the βCd cavity significantly improved its complexing and solubilizing effectiveness towards the drug, and methylated
derivatives were better than the hydroxy-propylated ones The amorphous nature of the partner was also important: among the
examined methyl-derivatives, RAMEB proved to be the most effective in performing solid state interactions and in improving
drug wettability and dissolution properties.
Thioguanine, a chemotherapeutic drug employed in the treatment of leukemia, is, like other amphiphilic drugs, very permeant and presents a high ability to escape from the liposomal membrane. For this reason, it is very important to know which parameters can enhance the relatively low encapsulation of thioguanine. In this way, the influence of four factors (pH, content of cholesterol, charge of lipids, and time of sonication) on the encapsulation of such drug in dehydration-rehydration liposomes was studied using a 24 factorial design. In this study, the maximal encapsulation efficiency obtained was 14.07 mmol/mol of lipid and time of sonication was the unique factor whose influence on the encapsulation was statistically significant (P < 0.05). The energy input concomitant to higher periods of sonication seems to facilitate the entrapment of the drug into the bilayer. Among the two-way interactions, time charge and pH-charge presented levels of significance less than 0.05. In liposomes with negative charge (10% phosphatidic acid), time of sonication barely influenced on the encapsulation, but in stearylamine-containing liposomes, higher times of sonication were necessary to achieve a better yield of encapsulation. More complex was the effect of the pH-charge interaction. At pH 4.7, liposomes with phosphatidic acid favoured the encapsulation, while at pH 7.4, liposomes with stearylamine encapsulated more drug. The different extent of encapsulation in the function of pH and charge only could be explained by the different charge born by the positive and negative liposomes depending on the pH.
Gamma radiation was used in every step of the synthesis of a sequential interpenetrating polymer network made of two “smart” polymers: poly(acrylic acid) (PAAc) and poly (N-isopropylacrylamide) (PNIPAAm), the latter grafted onto polypropylene (PP) films (PP-g-PNIPAAm) with the aim of developing medicated coatings for medical devices. Three steps were followed for obtaining net-PP-g-PNIPAAm-inter-net-PAAc: graft copolymerization of PNIPAAm onto PP films by gamma pre-irradiation oxidative method, cross-linking of PP-g-PNIPAAm by gamma irradiation in water to form the first network, with or without N,N′-methylenebis(acrylamide) (MBAAm), and finally the formation of the second network through the polymerization and cross-linking of AAc inside cross-linked PP-g-PNIPAAm by a low gamma radiation dose of 2.5 kGy. The films were characterized regarding the amount of grafted polymers and their composition (FTIR-ATR), thermal behavior (DSC), temperature- and pH-responsive swelling and contact angle (critical pH 6 and lower critical solution temperature ∼33 °C), and loading and release rate of vancomycin. Drug loading was driven by specific interactions between vancomycin and PAAc. Drug-loaded films sustained the delivery for several hours at pH 7.4 and provided release rate values adequate for killing bacteria attempting to adhere the surface of the films.
Micelles of poly(ethylene oxide)-block-poly(β-benzyl-l-aspartate) (PEO-PBLA) were loaded with doxorubicin (DOX) and were characterized in relation to their use as drug vehicles. First, an oil-in-water emulsion method was developed to load DOX in PEO-PBLA micelles. The level of DOX in PEO-PBLA micelles was 5–12% w/w. Whereas the mean diameter of unloaded, PEO-PBLA micelles was ca., 19 nm, the mean diameter of PEO-PBLA micelles loaded with DOX was ≈37 nm. Minimal chemical degradation of DOX occurred as a result of loading in PEO-PBLA micelles. In addition, DOX in PEO-PBLA micelles was less susceptible to chemical degradation than free DOX in aqueous solution. There was evidence for retention of DOX in PEO-PBLA micelles even after freeze-drying and reconstitution in water. Lastly, PEO-PBLA micelles served as drug depots, slowly releasing DOX (days), even in the presence of 10% w/v serum albumin. The results suggest a number of pharmaceutical advantages of PEO-PBLA micelles for the delivery of DOX.
Dual targeting can in principle be achieved by using intrinsically active carriers that not only deliver the conjugated drug but also otherwise influence the pathological process. Potential carriers of this kind are monoclonal antibodies, certain interferons and interleukins, as well as certain enzymes, peptide hormones and antivirally active (glyco)-proteins. The low molecular weight protein lysozyme, that is easily filtered and reabsorbed in kidney tubular cells, was used as a carrier for renal delivery of various drugs including anti-bacterial agents. The carrier itself can add to the anti-infective effect through its lysing effect on bacterial cell walls. Albumins derivatized with various sugars were used for delivery of the anti-inflammatory drug naproxen to hepatocytes, endothelial cells and Kupffer cells. Naproxen-albumin exhibited a potent hepatoprotective effect if delivered to sinusoidal cell types. Negatively charged and enzymatically active protein carriers can contribute to therapeutic effects, among others, through receptor antagonism and detoxification of endotoxins. Some (glyco)-proteins, designed as a drug carrier for anti-HIV agents, exhibited an intrinsic antiviral activity even without coupling of antiviral drugs. This activity was caused by an increased negative charge of the particular (glyco)-proteins. The in vitro IC50 values of some of these polyanionic proteins were in the nanomolar concentration range. The mechanism of action was found to be inhibition of a post binding virus/cell fusion event. The particular negatively charged albumins (NCAs) showed, in the therapeutic dose range, favorable pharmacokinetics with regard to lymphatic distribution and residence time in the blood stream. They have little acute toxicity and, in contrast to other polyanionic compounds, such as dextran sulfate are readily biodegradable. The NCAs lack an anticoagulant activity and exhibit low immunogenicity. Importantly, a high activity against primary clinical HIV isolates was observed. We detected a high affinity binding to the V3 loop of the envelope glycoprotein gpl20, explaining the potent effect on virus/cell fusion and HIV-I replication as well as the significant activity on syncytium-inducing HIV variants. The particular antiviral proteins can in principle be applied as intrinsically active drug carriers for the targeting of nucleoside analogues such as AZT, protease inhibitors and glycosidase inhibitors. A major advantage would be the concomitant blocking of sequential steps in the viral replication process with the aims to obtain synergism and prevention of drug resistance.
The study of the encapsulation efficiency of various drugs in liposomal drug delivery systems is of pharmaceutical importance. MLV liposomes, formed as multilamellar vesicles (MLV), contain many hydrophobic domains in the membranes; hence they are particularly useful for the encapsulation of hydrophobic drugs, such as steroids, in their bilayers. The encapsulation behaviour of four selected steroidal drugs, namely, hydrocortisone, triamcinolone, triamcinolone acetonide, and triamcinolone hexacetonide were studied. The MLV liposomes were prepared with a constant phospholipid/cholesterol molar ratio of 1/0.5 and increasing phospholipid/drug weight ratio. In order to reduce the number of factors influencing the encapsulation, a fully hydrogenated phospholipid, high-purity cholesterol, and NanopureTM water without any additives were used for preparing the MLV liposomes. The drug concentrations, both in the dispersion medium (supernatant) and in the liposomes, were determined by measuring the UV absorption of the drug at 25°C.It was found that the encapsulation of steroids was affected by the input concentration of the drug. In addition, the encapsulation efficiencies of the steroids and the encapsulation capacities of the MLV liposomes were found to be influenced by both the hydrophobicity (characterized by the surface tension) and the aqueous solubility of the drugs and also by the molecular weight of the steroids.
Calcium alginate (CA) beads loaded with intercalated complexes of propranolol HCl (PPN) and magnesium aluminum silicate (MAS), which serve as microreservoirs, were prepared using an ionotropic gelation method. The surface and matrix morphology, drug entrapment efficiency, thermal behavior, mechanical properties, and PPN release of the CA beads were characterized. The results showed that the molecular interaction of MAS with PPN and sodium alginate (SA) resulted in PPN–MAS intercalated complex particles as microservoirs and denser matrix structure formation in the CA beads. The small particles of the PPN–MAS complexes were embedded on the surface and in the matrix of the CA beads, which was revealed using SEM and EDX. The PPN entrapment efficiency of the PPN–MAS complex-loaded CA beads was significantly higher than that of the PPN-loaded CA beads. Increased MAS content caused an increase in PPN entrapment efficiency, thermal stability, and the strength of the CA beads. Moreover, the PPN–MAS complexes in the CA beads could remarkably reduce the initial burst of PPN release as well as its release rate in both 0.1 M HCl and phosphate buffer at pH 6.8, depending on the MAS content added. Additionally, the PPN–MAS complex-loaded CA beads also produced a sustained release pattern of PPN in simulated gastro-intestinal conditions. In conclusion, the CA beads containing drug–clay intercalated complexes as microreservoirs could enhance drug entrapment efficiency, reduce initial burst release and modulate drug release. Furthermore, these beads represent a promising oral drug delivery system for highly water-soluble cationic drugs.
First published online as a Review in Advance on April 1, 2008 Liposomes: and . Aldo and Owe Orwar Department of
Experimental cancer treatments are aiming to deliver toxic medicines to cells inside packages that protect normal tissues and evade the body's immune system.
Hyperbranched polymers (HBPs) are highly branched macromolecules with a three-dimensional dendritic architecture. Due to their unique topological structure and interesting physical/chemical properties, HBPs have attracted wide attention from both academia and industry. In this paper, the recent developments in HBP self-assembly and their biomedical applications have been comprehensively reviewed. Many delicate supramolecular structures from zero-dimension (0D) to three-dimension (3D), such as micelles, fibers, tubes, vesicles, membranes, large compound vesicles and physical gels, have been prepared through the solution or interfacial self-assembly of amphiphilic HBPs. In addition, these supramolecular structures have shown promising applications in the biomedical areas including drug delivery, protein purification/detection/delivery, gene transfection, antibacterial/antifouling materials and cytomimetic chemistry. Such developments promote the interdiscipline researches among surpramolecular chemistry, biomedical chemistry, nano-technology and functional materials.
In July this year, Genentech submitted a biologic license application to the US Food and Drug Administration (FDA) for the antibody–drug conjugate (ADC) trastuzumab–DM1 (T–DM1). It is hoped that by coupling trastuzumab (Herceptin; Genentech/Roche) — a humanized monoclonal antibody (mAb) specific for the human epidermal growth factor receptor 2 (HER2; also known as ERBB2) — to the cytotoxic agent DM1 (emtansine; ImmunoGen), T–DM1 could provide more potent anticancer effects than trastuzumab alone, which is a blockbuster therapy for HER2-positive breast cancer.
Recent advances in medicine and biotechnology have prompted the need to develop nanoengineered delivery systems that can encapsulate a wide variety of novel therapeutics such as proteins, chemotherapeutics, and nucleic acids. Moreover, these delivery systems should be "intelligent", such that they can deliver their payload at a well-defined time, place, or after a specific stimulus. Polymeric multilayer capsules, made by layer-by-layer (LbL) coating of a sacrificial template followed by dissolution of the template, allow the design of microcapsules in aqueous conditions by using simple building blocks and assembly procedures, and provide a previously unmet control over the functionality of the microcapsules. Polymeric multilayer capsules have recently received increased interest from the life science community, and many interesting systems have appeared in the literature with biodegradable components and biospecific functionalities. In this Review we give an overview of the recent breakthroughs in their application for drug delivery.
Liposomes are structurally and functionally some of the most versatile supramolecular assemblies in existence. Since the beginning of active research on lipid vesicles in 1965, the field has progressed enormously and applications are well established in several areas, such as drug and gene delivery. In the analytical sciences, liposomes serve a dual purpose: Either they are analytes, typically in quality-assessment procedures of liposome preparations, or they are functional components in a variety of new analytical systems. Liposome immunoassays, for example, benefit greatly from the amplification provided by encapsulated markers, and nanotube-interconnected liposome networks have emerged as ultrasmall-scale analytical devices. This review provides information about new developments in some of the most actively researched liposome-related topics.
Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biological barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), offers a promising strategy of anticancer drug targeting to HER2-expressing cancer cells. Conjugation of trastuzumab to dendrimers, repeatedly branched polymers with a highly functionalized surface, can enhance the drug loading capacity. However, typical dendrimers such as cationic polyamidoamine dendrimers have exhibited a nonspecific cytotoxicity. In the present study, we developed a novel biocompatible amino acid dendrimer with potentially less toxicity by surface modification of the sixth generation lysine dendrimer with glutamate (KG6E). The synthesized KG6E showed a well-controlled particle size around 5-6 nm with low polydispersibility and negative surface potentials for negligible cytotoxicity. Next, the targeting efficiency of the fluorescent-labeled KG6E-trastuzumab conjugate was evaluated in HER2-positive (SKBR3) and -negative (MCF7) human breast cancer cell lines compared to free trastuzumab and KG6E dendrimers. The KG6E-trastuzumab conjugate was specifically bound to SKBR3 cells in a dose-dependent manner with low binding affinity to MCF7 cells. Furthermore, the conjugate was significantly internalized in SKBR3 cells and then trafficked to lysosomes. These results indicate the potential of KG6E-trastuzumab conjugates as HER2-targeting carriers for therapeutic and diagnostic approaches to cancer therapy.
Biodegradable solid particles are potential carriers for both hydrophobic and hydrophilic drugs and have been marketed for prolongation of pharmaceutical activity. In developing such particles, it is important to achieve stable encapsulation of the drugs in the particles and a controlled rate of drug release.
In this paper, the principles and techniques for preparing such particles are reviewed.
Overall, it remains difficult to identify a general approach for achieving effective entrapment and controlled release, because these qualities are determined by multiple complex factors. The encapsulation efficiency of drugs in particles can be improved through various techniques, including hydrophobic interaction, covalent bonding, ionic interaction and physical isolation. In addition, the release behaviors of drugs are strongly influenced by environmental conditions as well as the physicochemical properties of the polymers and drugs.
Solid particles with targeting ability in addition to prolongation of biological activity may have potential for development of a new type of pharmaceutical in the clinical field.
This study probes the molecular interactions between model drugs and poloxamers that facilitate dissolution rate improvements using solid dispersions. Ibuprofen and ketoprofen solid dispersions were prepared at different mole ratios using poloxamers 407 and 188. The carbonyl stretching vibration of the ibuprofen dimer shifted to higher wavenumber in the infrared spectra of 2:1 drug:carrier mole ratio solid dispersions, indicating disruption of the ibuprofen dimer concomitant with hydrogen bond formation between the drug and carrier. Solid dispersions with mole ratios >2:1 drug:carrier (up to 29:1) showed both ibuprofen hydrogen-bonded to the poloxamer, and excess drug present as dimers. X-ray diffraction studies confirmed these findings with no evidence of crystalline drug in 2:1 mole ratio systems whereas higher drug loadings retained crystalline ibuprofen. Similar results were found with ketoprofen-poloxamer solid dispersions. Thermal analysis of ibuprofen-poloxamer 407 solid dispersions and their resultant phase diagram suggested solid solutions and a eutectic system were formed, depending on drug loading. Dissolution studies showed fastest release from the solid solutions; dissolution rates from solid solutions were 12-fold greater than the dissolution of ibuprofen powder whereas the eutectic system gave a 6-fold improvement over the powder. When designing solid dispersions to improve the delivery of poorly-water soluble drugs, the nature of drug:carrier interactions, which are governed by the stochiometry of the composition, can affect the dissolution rate improvement.
Targeted drug delivery has traditionally relied on finding highly specific biochemical markers at a target location. However, recent developments in this area have shown that purely physical and physicochemical factors are as important and can be used to aid in the targeting process. Here, we review the physicochemical factors affecting the targeting and delivery process and their relation to established biochemical markers. We refer to this combined approach as multidimensional targeting (MDT). More specifically, we examine the role of MDT factors across different length scales of relevance to the drug delivery pathway. Finally, we conclude with our perspective on the future of this burgeoning area.
In this research, amphiphilic brush-like polycations were synthesized, and used to fabricate cationic nanomicelle as the carrier of 7-ethyl-10-hydroxy-camptothecin (SN-38), in order to enhance its cellular uptake, solubility and stability in aqueous media. In particular, cationic chitosan-graft-polycaprolactone (CS-g-PCL) copolymers were synthesized with a facile one-pot manner via ring-opening polymerization of epsilon-CL onto the hydroxyl groups of CS by using methanesulfonic acid as solvent and catalyst. The formation of CS-g-PCL nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. It was found that all the nanomicelles showed spherical shapes with narrow size distributions. Their sizes ranged from 47 to 113 nm, and the zeta potentials ranged from 26.7 to 50.8 mV, depending on the grafting content of PCL in CS-g-PCL, suggesting their passive targeting to tumor tissue and endocytosis potential. Water-insoluble antitumor drug, SN-38, was easily encapsulated into CS-g-PCL nanomicelles by lyophilization method. In comparison with bare CS-g-PCL nanomicelles, the corresponding SN-38-loaded nanomicelles showed increased particle sizes and a little reduced zeta potentials. With an increase of grafting PCL content, the drug encapsulation efficiency (EE) and drug loading (DL) of the nanomicelles increased from 64.3 to 84.6% and 6.43 to 8.66%, respectively, whereas their accumulative drug release showed a tendency to decrease due to the enhanced hydrophobic interaction between hydrophobic drug and hydrophobic PCL segments in CS-g-PCL. Also, the CS-g-PCL nanomicelles effectively protected the active lactone ring of SN-38 from hydrolysis under physiological condition, due to the encapsulation of SN-38 into the hydrophobic cores in the nanomicelles. Compared with free SN-38, the SN-38-loaded nanomicelles showed essential decreased cytotoxicity against L929 cell line, and bare CS-g-PCL nanomicelles almost showed non-toxicity. These results suggested the potential utilization of the CS-g-PCL nanomicelles as the carriers of hydrophobic drugs with improving the delivery and release properties.
Taxanes are potent antimitotic agents that have demonstrated efficacy in a wide range of malignancies. Due to their poor water-solubility, these cytostatic drugs were first formulated with low molecular weight surfactants, e.g. Cremophor EL (CrEL) and Tween 80 (polysorbate 80), which are known to exhibit serious adverse effects in humans. In recent years, there has been growing interest in the design of more biocompatible formulations for both paclitaxel and docetaxel. Polymer-based drug carriers represent an attractive venue given the diversity in the array of existing polymers. Most notably, biopolyesters are vastly employed in the field of biomedical research given their biocompatibility and biodegradability. Polyester-based micelles and nanoparticles have been applied to the parenteral delivery of taxanes with varying degrees of success. Block copolymer micelles possess a unique core-shell structure generated through the self-assembly of amphiphilic copolymers in aqueous media. Although these systems have shown greatly enhanced tolerability compared to formulations based on low molecular weight surfactants, in some cases their failure to retain their cargo following parenteral administration has hindered their capacity to target taxanes to solid tumours. While polyester-based nanoparticles possess comparatively greater stability and drug targeting capacity, they frequently display a significant burst effect whereby a major portion of the cargo is immediately discarded from the carrier upon injection. This review focuses on the current application of polyester-based micelles and nanoparticles to the tumour targeting of taxanes. The preparation, loading efficiencies, release kinetics, cytotoxicity and in vivo behaviour of these systems is discussed in detail.
We investigated the potential of liposomes as drug carrier for cis-diamminedichloroplatinum(II) (cis-DDP). The binding capacity, Pt release on storage, and in vitro antitumor activity was determined. It was found that the encapsulation efficiency was dependent on the NaCl concentration of the hydration medium in which cis-DDP was dissolved. In addition, cis-DDP liposomes prepared by hydration with 0.9% NaCl showed a relatively high drug leakage on storage. For cis-DDP liposomes prepared by hydration with 0.2% NaCl/4.2% mannitol or 5% mannitol the fraction of the drug associated with the liposomes was more than 90% after prolonged storage at 4°C for 50 days. Compared to the activity of free cis-DDP, cis-DDP encapsulated in liposomes showed a decreased antitumor activity in vitro against a murine gastric squamous cell carcinoma. This suggested that the antitumor activity of liposomal cis-DDP was due to leakage of cisDDP from the liposomes. However, cis-DDP recovered from PC/PS/Chol liposomes after 3 cycles of freezing and thawing was equally active as free cisDDP. From the present study it is concluded that cisDDP liposomes prepared by hydration with 5% mannitol or 0.2% NaCl/4.2% mannitol have a relatively high binding capacity, and high stability against drug leakage.
A review of the state of knowledge on nanocapsules prepared from preformed polymers as active substances carriers is presented. This entails a general review of the different preparation methods: nanoprecipitation, emulsion-diffusion, double emulsification, emulsion-coacervation, polymer-coating and layer-by-layer, from the point of view of the methodological and mechanistic aspects involved, encapsulation of the active substance and the raw materials used. Similarly, a comparative analysis is given of the size, zeta-potential, dispersion pH, shell thickness, encapsulation efficiency, active substance release, stability and in vivo and in vitro pharmacological performances, using as basis the data reported in the different research works published. Consequently, the information obtained allows establishing criteria for selecting a method for preparation of nanocapsules according to its advantages, limitations and behaviours as a drug carrier.
This work aims to investigate the influence of the formation of ion pairing between all-trans retinoic acid (RA) and a lipophilic amine (stearylamine; STE) on the drug encapsulation efficiency (EE) and stability of solid lipid nanoparticles (SLNs). The SLNs were characterized for EE and size. The EE and particle size were significantly improved and reduced, respectively, when the surfactant or co-surfactant concentration increased. However, while the formulation without STE allowed only 13% of RA encapsulation, the EE for RA-STE-loaded SLNs was 94%. The stability studies showed a significant decrease in EE for the SLNs without STE, while, for SLNs loaded with RA and STE, the EE remained constant after 360 days. The interactions among ion pairing components and the lipid matrix were investigated through small-angle X-ray scattering (SAXS). The SAXS analysis revealed the presence of RA in the crystalline form in SLNs without ion pairing, while crystalline RA was not observed in SLNs loaded with RA/amine. Skin irritation studies showed that the SLNs loaded with the ion pairing were significantly less irritating when compared to the marketed RA-cream. This novel SLN formulation represents a promising alternative for topical treatment of acne with RA.
The coupling of drugs to macromolecular carriers received an important impetus from Ringsdorf's notion of polymer-drug conjugates. Several water-soluble polymers, poly(ethylene glycol), poly[N-(2-hydroxypropyl) methacrylamide], poly(l-glutamic acid) and dextran, are studied intensively and have been utilized successfully in clinical research. The promising results arising from clinical trials with polymer-drug conjugates (e.g., paclitaxel, doxorubicin, camptothecins) have provided a firm foundation for other synthetic polymers, especially biodegradable polymers, used as drug delivery vehicles. This review discusses biodegradable polymeric micelles as an alternative drug-conjugate system. Particular focus is on A-B or B-A-B type biodegradable amphiphilic block copolymer such as polylactide, morpholine-2,5-dione derivatives and cyclic carbonates, which can form a core-shell micellar structure, with the hydrophobic drug-binding segment forming the hydrophobic core and the hydrophilic segment as a hydrated outer shell. Polymeric micelles can be designed to avoid uptake by cells of reticuloendothelial system and thus enhance their blood lifetime via the enhanced permeability and retention effect. Active tumor-targeting may be achieved by modifying the micelle surface with specific ligands. The potential application areas are discussed and future challenges are highlighted.
Linear-hyperbranched, heterobifunctional alpha,omega(n) telechelic block copolymers consisting of a linear poly(ethylene glycol) (PEG) chain and a hyperbranched polyglycerol (PG) block have been prepared in five steps, using a protected amino-functional initiator. The polyfunctionality omega(n) (OH groups) can be adjusted by the degree of polymerization (DP(n)) of the polyglycerol block. Subsequent introduction of a single biotin unit by amidation in alpha-position permitted noncovalent bioconjugation with avidin.
The hydrophilic nature of hydrogel matrices makes them disadvantageous to entrap poorly soluble therapeutic agents and greatly restricts their applications as drug-delivery systems. In this study, we demonstrated that sustained delivery of lipophilic drugs in hydrogel-based devices can be readily achieved by enhancing retention of drugs within micelles. This nanoscale drug-entrapment strategy was applied to develop a polymeric drug-eluting stent. Sirolimus, a lipophilic anti-proliferative/immunosuppressive drug, was entrapped into the hydrophobic core of Pluronic L121 micelles and then blended in a chitosan-based strip and crosslinked by an epoxy compound to fabricate test stents. It was found that the use of such a nanoscale drug-entrapment strategy was able to significantly increase the loading efficiency of lipophilic drugs, prevent the drug from aggregation and beneficially reduce its initial burst release; thus, the duration of drug release was extended considerably. When implanting the stent in rabbit infrarenal abdominal aortas, in-stent restenosis was markedly reduced and less inflammatory reaction was observed, while unfavorable effects such as delayed endothelial healing caused by the overdose of sirolimus could be significantly evaded.
Polymeric micelles consisting of amphiphilic block copolymers have emerged as a promising carrier of various drugs, but unfortunately show a limited potential for encapsulating (solubilizing) such drugs. In this study, hybrid nanoparticles consisting of monomethoxypolyethyleneglycol-polylactide block copolymer (PEG-PLA) and oleic acid calcium salt were prepared to enhance the solubilization of poorly water-soluble drugs. Micelles made of a mixture of sodium oleate and PEG-PLA at various ratios were used as the template for preparation of the nanoparticles. These mixed micelles could efficiently solubilize poorly water-soluble drugs in aqueous media, when compared with polymeric micelles made of PEG-PLA alone. Addition of calcium to the mixed micelles induced the formation of oleic acid calcium salt, resulting in hybrid nanoparticles. These hybrid nanoparticles had a high colloidal stability, neutral zeta potential, and high drug entrapment efficiency. Drugs entrapped in nanoparticles made at a high PEG-PLA ratio were protected from enzymatic degradation in serum, while drugs entrapped in the mixed micelles were not, indicating that the hybrid nanoparticles show good drug retention. These results suggested that such hybrid nanoparticles may be used to expand the availability of poorly water-soluble drugs for various therapeutic applications.
Despite that in solution we cannot detect the interaction between Ni(2+) and mitoxantrone (MIT), Ni(2+) could mediate effective and stable MIT loading into large unilamellar vesicles (LUVs). The presence of nigericin had almost no influences on MIT encapsulation. However, in the presence of NH(3), the drug loading kinetics significantly altered. UV-vis spectrum analysis revealed that the absorption profile of liposomal MIT prepared with NiSO(4) gradient method was markedly different from that of liposomal MIT prepared with pH gradient method and that of free MIT. Three liposomal formulations were prepared, which were made from DMPC/chol, DPPC/chol and HSPC/chol and named LM-m, LM-p and LM-s. The in vitro release T(1/2) values for the formulations were 15.0, 28.2 and 38.5h, respectively. Following an intravenous injection into BDF1 mice at a dose of 4 mg/kg, the MIT plasma levels at 24h time point were 3.3, 11.3 and 12.7 microg/mL, considerably compared to that of free MIT group. In L1210 ascitic model, LM-m therapy resulted in approximately 60% long-term survivor (>60 days), and increased survival times in comparison with other treatments. However, both LM-p and LM-s formulations were less therapeutically active than free MIT. In conclusion, transmembrane NiSO(4) gradient could mediate effective MIT loading, and the formulation prepared with fluid lipid had fast release rate and improved efficacy in L1210 ascitic tumor model.
Incorporation of 8-azaguanine and 6-mercaptopurine into single compartment dipalmitoyl-DL-α-phosphatidylcholine liposomes has been increased dramatically by the presence of chloranil transfer complex formation. The enhanced entrapment is due to charge. The charge transfer complex readily decomposes to the parent donor drug and chloranil acceptor. Chloranil, however, may be toxic. Using 3,5-dinitrobenzoyl-n-butylamide and 3,5-dinitrobenzoyl phosphatidylethanolamine as electron donors did not result in enhanced entrapments.
The potential application of liposomes to drug delivery has been apparent since 1965, when these phospholipid vesicles were first described by Bangham. Since then, experiments on animals have shown that liposome encapsulation can dramatically alter the distribution of drugs in the body and their rate of clearance. These pharmacokinetic differences, as well as other less well-understood effects, can result in reduced toxicity and enhanced efficacy of the encapsulated drug. The vast majority of studies on the therapeutic use of liposomes have involved the delivery of drugs used in cancer chemotherapy and metabolic storage diseases, but there is now more literature on the use of liposomes for the delivery of antimicrobial drugs and immunomodulating agents. This review briefly discusses the general properties of liposomes and the rationale for their use in antimicrobial drug delivery and immunomodulation, as well as the encapsulation of specific agents and the effect of encapsulation on the treatment of infectious diseases.
The encapsulation of radioactive metalic cations, such as 111In3+ or 67Ga3+, in the internal aqueous compartment of liposomes can be achieved with an efficiency of about 90%. The efficient loading of a high specific activity of cations into liposomes involves the transport of 111In3+ or 67Ga3+ through the lipid bilayer to an encapsulated strong chelate, such as nitrilotriacetic acid, by 8-hydroxyquinoline, in conjunction with an efficient anion-exchange resin technique for the removal of the external cations. The efficiency of loading cations to liposomes is affected markedly by the concentration of 8-hydroxyquinoline-metal, and the presence of the chelating agents in the loading incubation mixture. However, the loading efficiency is not affected by the pH of the internal aqueous compartment of liposomes over a range of pH 5-9, the concentration of the liposomes, the method of liposomal preparation, the lamellar structure of the liposomes, and the composition of liposomes. Furthermore, the loading procedures do not appear to affect the size and the permeability of liposomes. There is a good agreement in the tissue distributions of the liposomes prepared by the present loading methods and those by the conventional method of encapsulation by sonication. Liposomes entrapping high specific activity of 67Ga3+ or 111In3+ will be useful for future studies of the in vivo kinetics of liposomes by the combined techniques of scintigraphic imaging and the gamma-ray perturbed angular correlation.
The efficient loading of high levels of In-111 into the inner aqueous compartment of liposomes can be achieved using a water-soluble lipophilic chelate, acetylacetone. The loading method involves the incubation of the acetylacetone-In-111 complex with liposomes entrapping 1mM nitrilotriacetic acid. The loading process is carried out in isotonic saline, 10 mM Tris-HCI, pH 7.6, at room temperature. Results indicate that In-111 ions are concentrated in the internal aqueous compartment of liposomes by acetylacetone, which mediates the transport of In-111 ions across the outermost lipid bilayer of liposomes, permitting subsequent transfer to the encapsulated nitrilotriacetic acid. As much as 90% of the acetylacetone-chelated In-111 becomes internalized in the aqueous compartment of liposomes and bound by entrapped nitrilotriacetic acid. Using liposomes made from bovine brain shingomyelin/cholesterol, our results indicate that the loaded liposomes retain the entrapped internally bound In-111 even after incubation with serum at 37 degrees C for 24 hr.
Liposomes have been used as carriers for drugs, toxins, enzymes, proteins/peptides and other bioactive materials there are several liposomal formulations that are being investigated in preclinical and clinical trials. Achieving high encapsulation as well as retention of the encapsulated drug is very important in developing liposomes as drug carriers. A high drug-to-lipid ratio is likely to reduce the cost of formulations and also the risk of lipid-induced toxicity following their injection. Comparison of the encapsulation efficiency of the drug in liposomes with the therapeutic dose indicates whether, in principle, liposomes can be used as a delivery system for that drug. The optimization of the liposomal encapsulation of a drug is usually based on trial and error, rather than on a thorough investigation of the factors affecting it. To obtain optimum encapsulation of a drug into a liposomal preparation, parameters influencing both the liposome and the drug need to be carefully considered during the early stages of development. In this review, factors that affect encapsulation of drugs in liposomes such as liposome size and type, charge on the liposome surface, bilayer rigidity, method of preparation, remote loading, addition of ion pairing, and complexing agents and characteristics of the drug to be encapsulated are discussed.
Recently, colloidal carrier systems have been receiving much attention in the field of drug targeting because of their high loading capacity for drugs as well as their unique disposition characteristics in the body. This paper highlights the utility of polymeric micelles formed through the multimolecular assembly of block copolymers as novel core-shell typed colloidal carriers for drug and gene targeting. The process of micellization in aqueous milieu is described in detail based on differences in the driving force of core segregation, including hydrophobic interaction, electrostatic interaction, metal complexation, and hydrogen bonding of constituent block copolymers. The segregated core embedded in the hydrophilic palisade is shown to function as a reservoir for genes, enzymes, and a variety of drugs with diverse characteristics. Functionalization of the outer surface of the polymeric micelle to modify its physicochemical and biological properties is reviewed from the standpoint of designing micellar carrier systems for receptor-mediated drug delivery. Further, the distribution of polymeric micelles is described to demonstrate their long-circulating characteristics and significant tumor accumulation, emphasizing their promising utility in tumor-targeting therapy. As an important perspective on carrier systems based on polymeric micelles, their feasibility as non-viral gene vectors is also summarized in this review article.
Typical methods used for encapsulating antisense oligodeoxynucleotides (ODN) and plasmid DNA in lipid vesicles result in very low encapsulation efficiencies or employ cationic lipids that exhibit unfavorable pharmacokinetic and toxicity characteristics when administered intravenously. In this study, we describe and characterize a novel formulation process that utilizes an ionizable aminolipid (1,2-dioleoyl-3-dimethylammonium propane, DODAP) and an ethanol-containing buffer system for encapsulating large quantities (0.15--0.25 g ODN/g lipid) of polyanionic ODN in lipid vesicles. This process requires the presence of up to 40% ethanol (v/v) and initial formulation at acidic pH values where the DODAP is positively charged. In addition, the presence of a poly(ethylene glycol)-lipid was required during the formulation process to prevent aggregation. The 'stabilized antisense-lipid particles' (SALP) formed are stable on adjustment of the external pH to neutral pH values and the formulation process allows encapsulation efficiencies of up to 70%. ODN encapsulation was confirmed by nuclease protection assays and (31)P NMR measurements. Cryo-electron microscopy indicated that the final particles consisted of a mixed population of unilamellar and small multilamellar vesicles (80--140 nm diameter), the relative proportion of which was dependent on the initial ODN to lipid ratio. Finally, SALP exhibited significantly enhanced circulation lifetimes in mice relative to free antisense ODN, cationic lipid/ODN complexes and SALP prepared with quaternary aminolipids. Given the small particle sizes and improved encapsulation efficiency, ODN to lipid ratios, and circulation times of this formulation compared to others, we believe SALP represent a viable candidate for systemic applications involving nucleic acid therapeutics.
The present study was aimed at developing and exploring the use of uncoated and PEGylated newer PAMAM dendrimers for delivery of anti-cancer drug 5-fluorouracil. For this study, successive Michael addition and exhaustive amidation reactions were used to synthesize 4.0 G PAMAM dendrimers, using ethylenediamine as core and methylmethacrylate as propagating agent. The dendrimer was PEGylated using N-hydroxysuccinimide-activated carboxymethyl MPEG-5000. IR and NMR data proved the synthesis. Various physicochemical parameters, SEM, TEM, lambda(max) values, hemolytic toxicity, drug entrapment, drug release and blood-level studies of both PEGylated and non-PEGylated systems were determined and compared. The PEGylation of the systems was found to have increased their drug-loading capacity, reduced their drug release rate and hemolytic toxicity. TEM study revealed surface properties of the systems. Stability studies had shown its stability at room temperature in dark. The systems were found suitable for prolonged delivery of an anti-cancer drug by in vitro and blood-level studies in albino rats, without producing any significant hematological disturbances. PEGylation has been found to be suitable for modification of PAMAM dendrimers for reduction of drug leakage and hemolytic toxicity. This, in turn, could improve drug-loading capacity and stabilize such systems in body. The study suggests use of such PEGylated dendrimeric systems as nanoparticulate depot type of system for drug administration.
As we enter the twenty-first century, research at the interface of polymer chemistry and the biomedical sciences has given rise to the first nano-sized (5-100 nm) polymer-based pharmaceuticals, the 'polymer therapeutics'. Polymer therapeutics include rationally designed macromolecular drugs, polymer-drug and polymer-protein conjugates, polymeric micelles containing covalently bound drug, and polyplexes for DNA delivery. The successful clinical application of polymer-protein conjugates, and promising clinical results arising from trials with polymer-anticancer-drug conjugates, bode well for the future design and development of the ever more sophisticated bio-nanotechnologies that are needed to realize the full potential of the post-genomic age.
Enzyme encapsulation into liposomes is a promising technique to stabilize and prevent them from denaturation and proteolysis. We demonstrate this using acetylcholinesterase which is the main target for pesticides. In order to achieve a reasonable encapsulation yield, we analyzed the parameters involved in each step of various encapsulation procedures. The only encapsulation method which did not denature the protein was the lipid film hydration technique, however the encapsulation efficiency was usually low. The efficiency could be increased up to more than 40% by induction of a specific interaction between the enzyme and the lipid surface. Once encapsulated, the enzyme encountered another problem: the permeability barrier of the lipid membrane drastically diminished the activity of the enzyme entrapped in the liposome by reducing the entrance rate of the substrate molecules and then reducing the substrate concentration inside the liposome. To solve this problem, we controlled the permeability of the liposome wall by reconstituting a porin from Escherichia coli. We succeeded to recover the full functionality of the enzyme, while retaining the protection against denaturation and proteolytic enzymes.