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Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape
Abstract
Liposomes were the first nanoscale drug to be approved for clinical use in 1995. Since then, the technology has grown considerably, and pioneering recent work in liposome-based delivery systems has brought about remarkable developments with significant clinical implications. This includes long-circulating liposomes, stimuli-responsive liposomes, nebulized liposomes, elastic liposomes for topical, oral and transdermal delivery and covalent lipid-drug complexes for improved drug plasma membrane crossing and targeting to specific organelles. While the regulatory bodies’ opinion on liposomes is well-documented, current guidance that address new delivery systems are not. This review describes, in depth, the current state-of-the-art of these new liposomal delivery systems and provides a critical overview of the current regulatory landscape surrounding commercialization efforts of higher-level complexity systems, the expected requirements and the hurdles faced by companies seeking to bring novel liposome-based systems for clinical use to market.
... The integration of materials that impart elasticity on the outer surface also contributes to the high elasticity of transfersomes. The high degree of elasticity of the vesicles enhances the delivery of herbal remedies across the skin and accelerates the rate of absorption during the healing process [192]. ...
... Ethanol in ethosomes increases membrane fluidity and permeability by interacting with the lipid molecules of the hydrophilic head regions of the bilayer. This synergy permits the efficient transdermal delivery of herbal medicines for medicinal purposes [192]. For instance, curcumin in ethosomal formulation might be used as a cutaneous delivery for improved wound healing and antimicrobial activity. ...
The treatment of wounds is a serious problem all over the world and imposes a huge financial burden on each and every nation. For a long time, researchers have explored wound dressing that speeds up wound healing. Traditional wound dressing does not respond effectively to the wound-healing process as expected. Therapeutic active derived from plant extracts and extracted bioactive components have been employed in various regions of the globe since ancient times for the purpose of illness, prevention, and therapy. About 200 years ago, most medical treatments were based on herbal remedies. Especially in the West, the usage of herbal treatments began to wane in the 1960s as a result of the rise of allopathic medicine. In recent years, however, there has been a resurgence of interest in and demand for herbal medicines for a number of reasons, including claims about their efficacy, shifting consumer preferences toward natural medicines, high costs and negative side effects of modern medicines, and advancements in herbal medicines brought about by scientific research and technological innovation. The exploration of medicinal plants and their typical uses could potentially result in advanced pharmaceuticals that exhibit reduced adverse effects. This review aims to present an overview of the utilization of nanocarriers in plant-based therapeutics, including its current status, recent advancements, challenges, and future prospects. The objective is to equip researchers with a comprehensive understanding of the historical background, current state, and potential future developments in this emerging field. In light of this, the advantages of nanocarriers based delivery of natural wound healing treatments have been discussed, with a focus on nanofibers, nanoparticles, nano-emulsion, and nanogels.
... Liposomes with a higher EE% are capable of retaining elevated levels of the beneficial medicinal ingredient, leading to a reduction in production expenses. This improves pharmacokinetics and patient compliance [75]. ...
... The process of identifying CQAs and CPPs involves utilizing an experimental design that can effectively evaluate their impact on the CQAs [62]. The purpose of DS is to guarantee a superior product by exhibiting various formulation and/or process parameters [62,75]. DS includes product and process components. ...
Nanomedicine is a developing discipline that is constantly evolving and differentiating. Liposomal preparation has an important role in nanomedicine as a novel platform. QbD involves drug formulation and advancement of a pharmaceutical medicament, including understanding of product quality and formulation steps, processing, and implementing controls to establish the product quality maintained by QbD. Primarily, drug and medicament governing bodies, including the USA and FDA, enhance product quality. Liposomal formulations and optimisation involve dependent and independent variables, requiring experience in optimisation. QbD is a risk-based approach used early in the pharmaceutical process to improve product quality and efficacy. Please shorten the given text so that it is more concise. QbD speeds up product development and ensures consistent, safe drug formulation in complex systems. In QbD, steps flow as adding variables related to CMAs, CPPs, and design places responsible for quality attributes for the final liposomal product preparation. QbD has recently been proposed as a tool for obtaining higher-quality liposomal nanocarriers. The broader structure of this research discusses the involvement of QbD as recent approach including their different parameters. Overall, lastly, the current practices that employ QbD in the optimisation and formulation of doxorubicin (DOX), by the using thin film-hydration extrusion technique primarily. DOX is antitumor class drug with a brand (Doxil®) loaded liposomal with TNF receptor as nanocarrier optimisation and formulation.
... Liposomes, consisting of a lipid layer and a core for encapsulating drugs, are among the first nano-scale materials for drug delivery. By modifying the lipid layer, liposomes can fulfill multiple functions, enabling effective drug delivery [9]. Polymer-based nanoparticles offer specific structures tailored for various applications, including gene/drug delivery [10,11]. ...
A diverse array of organic and inorganic materials, including nanomaterials, has been extensively employed in multifunctional biomedical applications. These applications encompass drug/gene delivery, tissue engineering, biosensors, photodynamic and photothermal therapy, and combinatorial sciences. Surface and bulk engineering of these materials, by incorporating biomolecules and aptamers, offers several advantages such as decreased cytotoxicity, improved stability, enhanced selectivity/sensitivity toward specific targets, and expanded multifunctional capabilities. In this comprehensive review, we specifically focus on aptamer-modified engineered materials for diverse biomedical applications. We delve into their mechanisms, advantages, and challenges, and provide an in-depth analysis of relevant literature references. This critical evaluation aims to enhance the scientific community's understanding of this field and inspire new ideas for future research endeavors.
... Changes in the structure of lipid bilayer lead to improved stability or skin permeability compared to traditional liposomes [68]. They enhance solubility, protect encapsulated molecules, and provide the controlled release of drugs [69]. For this reason, liposomes have become extremely popular as drug delivery systems for bioactive compounds. ...
As secondary plant metabolites, polyphenols are abundant in fruits and vegetables. They are in high demand because of their many health benefits. However, their low bioavailability makes them complex compounds to use for therapeutic purposes. Due to the limited solubility of phytocompounds, dietary supplements made from them may only be partially effective. Such molecules include fisetin, found in strawberries, and have shown great promise in treating Alzheimer’s disease and cancer. Unfortunately, because of their limited water solubility, low absorption, and poor bioavailability, the assistance of nanotechnology is required to allow them to fulfil their potential fully. Here, we provide evidence that nanodelivery methods and structure modifications can improve fisetin bioavailability, which is linked to improvements in therapeutic efficacy. An open question remains as to which nanocarrier should be chosen to meet the abovementioned requirements and be able to enhance fisetin’s therapeutic potential to treat a particular disease.
... Another strategy involves using a novel delivery system comprised of the M13 phage displaying a target-specific peptide or antibody conjugated to another vehicle (such as a liposome or an inorganic nanoparticle) (Fig. 5c). Liposomes are the most common and interesting lipid-based nanoparticles that have been approved by the FDA for drug delivery (Zylberberg and Matosevic, 2016;Dizaj et al., 2014). They have great characteristics such as good biocompatibility, easy biodegradation, little or no side effects, and a large loading capacity. ...
... Various nanocarriers including carbon nanotubes [15], liposomes [16], dendrimers [17], solid lipid nanoparticles (SLNs) [18], archaeosome [19], ethosomes, transferosomes [20], polymeric NPs [21], nanoemulsions [22], niosomes [23], and nanogels [24] were developed for drug delivery in recent decades. ...
This review highlights the potential benefits and drawbacks of using nanocarriers as drug delivery systems. Nanocarriers have been widely utilized to enhance drug efficiency, overcome drug resistance, and reduce adverse effects. However, the interaction between nanocarriers and biological systems can lead to toxic responses. Therefore, it is crucial to carefully select optimized nanocarriers to minimize toxicity and maximize efficiency. Every type of nanocarrier has its own advantages and disadvantages. Hybrid nanocarriers have been engineered to address the limitations of existing nanocarriers and are considered more suitable for developing new formulations. The article discusses various aspects of nanocarriers, including their applicability, potential toxicity, and strategies for utilizing appropriate nanocarriers in nanoformulations. To mitigate the toxicity of nanocarriers, several approaches can be employed, such as PEGylation, coating, charge coating, and injections of free PEG; moreover, by modifying the preparation method or utilizing hybrid nanocarriers, the efficiency of drug delivery systems can be improved. Overall, the article emphasizes the importance of selecting appropriate nanocarriers and employing strategies to reduce toxicity while enhancing drug delivery efficiency.
... Since then, the liposome technology has provided intelligent solutions to solve challenges in pharmacology, such as increasing drug solubility, reducing drug toxicity, and improving targeted drug release [1,2]. Liposomes have three distinct compartments that can be used to carry various compounds such as, e.g., drugs: the interior aqueous compartment; the hydrophobic bilayer; and the polar inter-phase of the inner and outer leaflet [3][4][5]. ...
This study aims to highlight the impact of physicochemical properties on the behaviour of nanopharmaceuticals and how much carrier structure and physiochemical characteristics weigh on the effects of a formulation. For this purpose, two commercially available nanosimilar formulations of Doxil and their respective carriers were compared as a case study. Although the two formulations were “similar”, we detected different toxicological effects (profiles) in terms of in vitro toxicity and immunological responses at the level of cytokines release and complement activation (iC3b fragment), that could be correlated with the differences in the physicochemical properties of the formulations. Shedding light on nanosimilar key quality attributes of liposome-based materials and the need for an accurate characterization, including investigation of the immunological effects, is of fundamental importance considering their great potential as delivery system for drugs, genes, or vaccines and the growing market demand.
... They represent a peculiar class of nanomedicines in which a limited number of drug molecules are conjugated per antibody unit and whose approval is based on the biological license applications (BLA) process. [3] Liposomes have been the first nanomedicine approved for clinical use and are still considered a useful and versatile approach that can be tailored to specific needs by tuning their size, morphology, composition, surface modification, etc. [4,5] To obtain a selective delivery to solid cancers, the approved liposomes loaded with cytotoxic drugs can rely only on passive tumor accumulation by exploiting the enhanced vascular permeability and retention (EPR) effect, due to their size. [6] However, the real benefits of EPR effects for significant tumor selectivity are still under debate [7][8][9] and some evidence suggest that only a minor fraction of the injected dose of a nanomedicine can reach the cancer site by exploiting the EPR effect. ...
Liposomes play an important role in the field of drug delivery by virtue of their biocompatibility and versatility as carriers. Stealth liposomes, obtained by surface decoration with hydrophilic polyethylene glycol (PEG) molecules, represented an important turning point in liposome technology, leading to significant improvements in the pharmacokinetic profile compared to naked liposomes. Nevertheless, the generation of effective targeted liposomes – a central issue for cancer therapy – has faced several difficulties and clinical phase failures. Active targeting remains a challenge for liposomes. In this direction, we designed a new Super Stealth Immunoliposomes (SSIL2) composed of a PEG‐bi‐phospholipids derivative that stabilizes the polymer shielding over the liposomes. Furthermore, its counterpart, conjugated to the fragment antigen‐binding of trastuzumab (Fab’ TRZ ‐PEG‐bi‐phospholipids), is firmly anchored on the liposomes surface and correctly orients outward the targeting moiety. Throughout this study, the performances of SSIL2 are evaluated and compared to classic stealth liposomes and stealth immunoliposomes in vitro in a panel of cell lines and in vivo studies in zebrafish larvae and rodent models. Overall, SSIL2 shows superior in vitro and in vivo outcomes, both in terms of safety and anticancer efficacy, thus representing a step forward in targeted cancer therapy, and valuable for future development.
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... Organic NPs are biodegradable, non-toxic, and sensitive to heat and light. Examples include polymers [100][101][102][103], liposomes [104,105], micelles [106]. and dendrimers [107,108]. ...
An emerging multidrug-resistant pathogenic yeast called Candida auris has a high potential to spread quickly among hospitalized patients and immunodeficient patients causing nosocomial outbreaks. It has the potential to cause pandemic outbreaks in about 45 nations with high mortality rates. Additionally, the fungus has become resistant to decontamination techniques and can survive for weeks in a hospital environment. Nanoparticles might be a good substitute to treat illnesses brought on by this newly discovered pathogen. Nanoparticles have become a trend and hot topic in recent years to combat this fatal fungus. This review gives a general insight into the epidemiology of C. auris and infection. It discusses the current conventional therapy and mechanism of resistance development. Furthermore, it focuses on nanoparticles, their different types, and up-to-date trials to evaluate the promising efficacy of nanoparticles with respect to C. auris.
... In addition to the cyclodextrin solution formulation, two liposome formulation systems were also developed. Liposomes have demonstrated, both in research and clinical settings, to be a promising system for delivery of complex payloads via the parenteral route [26]. They are versatile carriers, wherein a lipophilic drug can be encapsulated in the lipid bilayer and a hydrophilic drug can be encapsulated in the aqueous core. ...
Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.
... In hydrophobic drugs, it could also be placed between the lipid bilayer of the cell membrane in a phagosomal form (Kumar et al., 2020). LPs used in biology and medicine display a range of benefits comprising high drug/lipid proportion loading efficacy, simplicity of synthesis in a size-controlled way, great stability, manageable delivery kinetics, and biocompatibility (Zylberberg and Matosevic, 2016). Moreover, LPs can be extra equipped with functional moieties to increase their performances in terms of increased circulation half-life, targeted delivery, and intracellular permeation capability (Kim, 2016). ...
Various nanoparticles are used in the discovery of new nanomedicine to overcome the shortages of conventional drugs. Therefore, this article presents a comprehensive and up-to-date review of the effects of nanoparticle-based drugs in the treatment of respiratory disorders, including both basic and clinical studies. Databases, including PubMed, Web of Knowledge, and Scopus, were searched until the end of August 2022 regarding the effect of nanoparticles on respiratory diseases. As a new tool, nanomedicine offered promising applications for the treatment of pulmonary diseases. The basic composition and intrinsic characteristics of nanomaterials showed their effectiveness in treating pulmonary diseases. The efficiency of different nanomedicines has been demonstrated in experimental animal models of asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), lung cancer, lung infection, and other lung disorders, confirming their function in the improvement of respiratory disorders. Various types of nanomaterials, such as carbon nanotubes, dendrimers, polymeric nanomaterials, liposomes, quantum dots, and metal and metal oxide nanoparticles, have demonstrated therapeutic effects on respiratory disorders, which may lead to new possible remedies for various respiratory illnesses that could increase drug efficacy and decrease side effects.
... Although therapies such as chemotherapy are developed to be commonly used against cancer, their lack of specificity in distinguishing between cancerous and healthy cells, as well as the challenge of multidrug resistance, pose significant obstacles. Moreover, these treatments often leave behind serious side effects, including hair loss and bone marrow suppression [17] . Hence, the discovery of more accurate and target-specific drugs to address tumor cells has recently garnered increased attention. ...
As a pathologically heterogeneous disease, cancer is one of the leading causes of global morbidity. According to the World Health Organization, approximately one in six deaths are caused by cancer. Fortunately, many cancers can be cured if diagnosed at early stages and treated efficiently. Despite the benefits of conventional cancer treatments such as surgery, chemotherapy, hormone therapy, and radiation therapy, they have several drawbacks, including cytotoxicity, inaccurate targeting of tumor cells, and multi-drug resistance, which underscore the importance of developing novel and effective strategies to improve diagnosis, prognosis, therapy, and patient survival. Recently, the advancement of nanotechnology has opened new horizons for cancer treatment thanks to the discovery of nanoparticles (NPs) and the small-sized molecules that revolutionized the drug delivery methods in cancerous tissues. The specific characteristics of NPs, such as reduced toxicity, improved permeability, and accurate targeting of tumor cells, provide a great advantage in cancer treatment and help to overcome the limitations and challenges of conventional cancer treatment methods. Besides, the role of NPs in immunotherapy has created a novel concept for cancer treatment. This review gives a brief overview regarding the importance of NPs and their targeting mechanism, as well as the challenges and limitations associated with their use in cancer treatment.
... Liposomes are thought to be biocompatible as well as biodegradable and due to their structure, they can carry both hydrophilic water-soluble molecules in the aqueous core and hydrophobic compounds in the lipid membrane, as previously shown 9 . Thus, large unilamellar vesicles (LUVs), with sizes of approximately 100 nm in diameter, have been successfully as carriers for antitumor drugs in cancer chemotherapy [10][11][12] and for gene delivery purposes 9,13 . These systems are designed to increase drug bioavailability, control drug delivery, and maintain intact drug delivery to the site of action 8 . ...
Drug delivery systems are frequently used for targeted transport of pharmaceuticals and their controlled release at a destined target site. One of the most commonly used drug carriers are liposomes. Additionally, such drug-liposome system is used as model system for studying interaction processes at cellular or even molecular level. The aim of our work was to improve the understanding of drug carrier uptake mechanisms by applying fluorescence lifetime imaging microscopy (FLIM) and fluorescence correlation spectroscopy (FCS), both combined with two-photon (2P) excitation. We prepared giant unilamellar vesicles (GUVs) representing a simplified model system for cell membrane, labelled with the amphiphilic fluorescent dye 3,3'-dioctadecyloxacarbocyanine (DiOC 18 (3)). Furthermore, large unilamellar vesicles (LUVs) were used as a drug carrier system, containing the spectrally different fluorescent sulforhodamine 101 (SRh101) as drug imitate. Herein, we present results of the varying interaction between GUVs and LUVs depending on the used charged lipids. The exchange kinetics and structural changes of the liposome carriers during the fusion process were investigated. We also observed that the internalisation efficiency was mainly influenced by the vesicle´s lipid composition. We ultimately demonstrated that 2P-FLIM and FCS provide a unique methodological approach to study liposome interactions and use them as a versatile model system.
... Formulation optimization can help to identify the optimal liposome size, composition, and surface properties that are required to achieve the desired pharmacokinetic and pharmacodynamic properties. [117] Limited approval and insurance coverage, as well as high production costs, can reduce accessibility and affordability for patients. These challenges can be overcome by developing efficient production methods and advocating for favorable reimbursement policies. ...
Cardiovascular disease is the leading cause of death worldwide. Blood‐contacting medical devices provide critical support for patients with severe respiratory and/or cardiac failure. High shear stress zones and non‐biocompatible circuit can increase the risk of thrombus formation in patients. These thrombi restrict blood flow through the circuits and travel to the lungs and brain, creating significant consequences. Antithrombotic drugs are used to lower this risk, but they also raise the incidence of bleeding problems. This article explores the delicate balance between thrombosis and bleeding in medical devices by examining platelet activation and thrombosis formation under shear stress. The feasibility of a shear‐responsive nanomedicine‐based drug delivery system has been explored as a potential approach for targeted administration of antithrombotic medications to lower systemic drug levels and reduce the bleeding risk. Furthermore, the lack of in vitro platforms to investigate the biological behavior of antithrombotic nanoparticles is impeding their clinical translation. As a result, microfluidic technology offers a platform for investigating nanoparticle behavior in vitro and linking it to their performance in vivo. Finally, the challenges and factors that affect the functionality, stability, and circulation time of liposomal drugs are investigated to improve their efficacy for targeted drug administration in medical devices.
... They are self-assembled nanoparticles composed of lipid bilayers. 35 Liposomes are spherical vesicles composed of an inner aqueous core and outer chemically active one to several concentric lipid bilayers. The lipid bilayersengage hydrophilic heads and hydrophobic hydrocarbon tails encapsulating the aqueous spaces. ...
Nanotechnology is science, engineering and technology conducted at the nanoscale that deals with the development and application of nanoparticles or nanomaterials. This field is considered as the greatest of all inventions humans have ever made till date. The associated research and applications are diverse, ranging from extensions of conventional technology to new approaches based upon the property of molecular self-assembly. Nanotechnology has been greatly advanced in the past few decades and the role of nanotechnology in field of dentistry and particularly in periodontology has evolved greatly. The use of various nanoparticles and materials has brought a new insight into the prevention, diagnosis and management of periodontal disease. In the near futureinvention of dental nanorobots will help in precise diagnosis and may lead us to new treatment opportunities. This review focuses on the updated applications of nanotechnology in the field of Periodontics.
... Liposomes have been extensively used for the delivery of drugs. Many liposomebased drugs, including the chemotherapeutics doxorubicin, daunorubicin and vincristine, were approved by the FDA and are on the market [48]. As shown in Figure 6, liposomes containing C4a promoted a slow release of this ABCG2 inhibitor. ...
Inhibition of ABC transporters is a promising approach to overcome multidrug resistance in cancer. Herein, we report the characterization of a potent ABCG2 inhibitor, namely, chromone 4a (C4a). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane vesicles of insect cells revealed that C4a interacts with both transporters, while showing selectivity toward ABCG2 using cell-based transport assays. C4a inhibited the ABCG2-mediated efflux of different substrates and molecular dynamic simulations demonstrated that C4a binds in the Ko143-binding pocket. Liposomes and extracellular vesicles (EVs) of Giardia intestinalis and human blood were used to successfully bypass the poor water solubility and delivery of C4a as assessed by inhibition of the ABCG2 function. Human blood EVs also promoted delivery of the well-known P-gp inhibitor, elacridar. Here, for the first time, we demonstrated the potential use of plasma circulating EVs for drug delivery of hydrophobic drugs targeting membrane proteins.
... Organic NPs have indeed been utilized for many years and come in a variety of subclasses. The liposomes are the first introduced nano-sized clinically approved drug carriers, including an inner core that can be used to encapsulate either hydrophilic or hydrophobic medicines and an outside lipid layer [58]. The lipid layer of liposomes can be functionalized to obtain many functions, e.g., modifying the biophysical features (mobility and deformation) of living cells, which is beneficial for effective therapeutic drug delivery. ...
In recent years, the incidence and mortality rate of cancer is raising worldwide. Traditional approaches for cancer patient management including surgery, chemotherapy, radiotherapy, and targeted therapies provide unsatisfactory results and are often associated with adverse reactions. Over the last few decades, nanotechnology has been a rapidly emerging area of theragnostic in clinical research. It plays a vital role as a bridge between the science and technology of miscellaneous nanoparticles (NPs) and nanomedicine. In general, NPs with a range of sizes of 1–100 nm are thought to be acceptable for cancer medications. NPs may enhance the consistency and solubility of therapeutic drugs to obtain site-specific targeting, controlled release, and safe for healthy organs. NPs have the benefit of pathophysiological properties, enhanced permeability and retention (EPR) effects, and an advantage in cancer targeting. Furthermore, theranostic nanoparticles have been established having incorporated diagnostics and therapy in a single system that might provide more personalized treatment with optimal doses and monitoring the distribution, targeting, and response to therapy by using imaging tools. In this review, we have discussed the classes of nanoparticles, targeting approaches, and implications of NPs for cancer theranostics with recent examples.
... Liposomes are the first nanoscale drug that have been clinically approved for therapeutic applications. 182 These nanospheres comprise of naturally occurring or artificially ...
Nanotechnology has gained immense appraisal owing to its multidimensional advantages in the scientific world. Recent progress has confirmed nanostructured architectures to possess promising medicinal applications which have triggered its investigation as Nano-drug delivery vehicles. These engineered vehicles offer an unprecedented platform for controlled release of encapsulated drug to targeted site with higher effectuality and reduced toxicity by overcoming the loopholes allied with the conventional drug delivery systems. This review provides a systematic overview of specific properties of nanostructured materials viz., inorganic nanoparticles, polymeric micelles, chitosan, liposomes, dendrimers, carbon nanotubes, quantum dots, niosomes etc. and consolidates their therapeutic approaches in the diagnosis and treatment of chronic diseases like Cancer, COVID-19, HIV/AIDS. Factors including interactions of nanomaterials with physiological environment, mode of drug administration, stability of the therapeutic agents and mechanism of action etc. have been summarized for attaining efficacious drug delivery. In addition to opportunities, the challenges of nanomedicines in drug delivery have also been insighted. In the futuristic perspective further advancement is necessitated in the domain of Nanotechnology mediated advanced drug delivery system by combining newer treatment approaches such as gene therapy, immunotherapy etc. with the existing nanotechnology to improve the performance of the drugs and maximize the efficiency of targeted drug distribution.
... Liposomes have been widely used as a carrier to deliver both hydrophilic and hydrophobic drugs, antibacterial and antifungal agents, vaccines, Enzs, and genetic cargo [99]. This popularity refers to high drug/lipid ratio loading efficiency, ease of fabrication in a size-controlled manner, long-circulating by polyethylene glycol (PEG) coating, excellent stability, controllable release kinetics, and biocompatibility [100]. Liposomal formulations have shown an ability to enhance the PK and PD of active pharmaceutical ingredients (API), while hindering their associated off-target toxicity [101]. ...
Enzyme (Enz)-mediated therapy indicated a remarkable effect in the treatment of many human cancers and diseases with an insight into clinical phases. Because of insufficient immobilization (Imb) approach and ineffective carrier, Enz therapeutic exhibits low biological efficacy and bio-physicochemical stability. Although efforts have been made to remove the limitations mentioned in clinical trials, efficient Imb-destabilization and modification of nanoparticles (NPs) remain challenging. NP internalization through insufficient membrane permeability, precise endosomal escape, and endonuclease protection following release are the primary development approaches. In recent years, innovative manipulation of the material for Enz immobilization (EI) fabrication and NP preparation has enabled nanomaterial platforms to improve Enz therapeutic outcomes and provide low-diverse clinical applications. In this review article, we examine recent advances in EI approaches and emerging views and explore the impact of Enz-mediated NPs on clinical therapeutic outcomes with at least diverse effects.
Graphical abstract
... In 1995, liposomes became the first nanoscale medicine to receive FDA approval for clinical use. Since then, the technology has advanced significantly, and pioneering recent work in liposome-based delivery systems has resulted in major advances with important therapeutic applications [82]. Liposomes have been investigated extensively for many years as a drug carrier and have demonstrated to have promising potential for curcumin delivery to in-vivo [83][84][85][86]. ...
Curcumin is a polyphenol molecule derived from Curcuma longa Linn's rhizomes. Curcumin appears to have been the target of substantial research, with cancer, viral, fungal infections, bacterial, arthritis, antioxidant, anti-inflammatory, allergies, Alzheimer's disease, and other chronic diseases and disorders all being explored. Curcumin has undesirable features such as inadequate intake and low aqueous solubility. To resolve these challenges, research has taken numerous attempts to improve its absorption, solubility, and bioavailability. Nanotechnology plays a critical role in the creation of nanostructured devices, nanomedicines, targeted therapy, and nanocarriers. Curcumin nano formulation has alleviated some of the major disadvantages of curcumin-based medication delivery. The emphasis of the study is on nano-based techniques to address therapeutic activity, efficacy, bioavailability, and solubility. Curcumin was localized to a certain cellular and molecular level by combining nano-curcumin with a specific molecule to enhance activity at the target site. A detailed description of solubility and bioavailability enhancement technique using protein carriers, solid dispersions, nanofiber, carbon dots, liposomes, and polymer carrier drug delivery systems is provided in this review.
... Both inorganic and organic nanoparticles have been proposed for cancer therapy [29]. Among organic nanoparticles, liposomes are the very first nanosystem approved for the treatment of cancer, and still are the best-investigated platform in clinical trials and academic research [30][31][32][33]. They offer numerous advantages over therapies with free drugs: increased solubility and bioavailability of the loaded drug, controlled/constant rate of drug released over the desired timescale, protection of the loaded drug, selectivity against cancer targets, thus increased efficacy, and reduced dose of the administered drug, thus lower systemic toxicity [34][35][36]. ...
Liver cancer is one of the most common causes of cancer death worldwide. In recent years, substantial progress has been made in the development of systemic therapies, but there is still the need for new drugs and technologies that can increase the survival and quality of life of patients. The present investigation reports the development of a liposomal formulation of a carbamate molecule, reported as ANP0903, previously tested as an inhibitor of HIV-1 protease and now evaluated for its ability to induce cytotoxicity in hepatocellular carcinoma cell lines. PEGylated liposomes were prepared and characterized. Small, oligolamellar vesicles were produced, as demonstrated by light scattering results and TEM images. The physical stability of the vesicles in biological fluids was demonstrated in vitro, alongside the stability during storage. An enhanced cellular uptake was verified in HepG2 cells treated with liposomal ANP0903, resulting in a greater cytotoxicity. Several biological assays were performed to elucidate the molecular mechanisms explaining the proapoptotic effect of ANP0903. Our results allow us to hypothesize that the cytotoxic action in tumor cells is probably due to the inhibition of the proteasome, resulting in an increase in the amount of ubiquitinated proteins within the cells, which in turn triggers activation of autophagy and apoptosis processes, resulting in cell death. The proposed liposomal formulation represents a promising approach to deliver a novel antitumor agent to cancer cells and enhance its activity.
... They can also transport hydrophilic and hydrophobic compounds as well as larger molecules. The improved pharmacological activity and efficacy should also be attributed to skin adhesion and the proximity of the nanosystems to the target cells [277][278][279]. The application of lipid nanosystems for transdermal drug delivery is discussed herein. ...
Skin delivery is an exciting and challenging field. It is a promising approach for effective drug delivery due to its ease of administration, ease of handling, high flexibility, controlled release, prolonged therapeutic effect, adaptability, and many other advantages. The main associated challenge, however, is low skin permeability. The skin is a healthy barrier that serves as the body's primary defence mechanism against foreign particles. New advances in skin delivery (both topical and transdermal) depend on overcoming the challenges associated with drug molecule permeation and skin irritation. These limitations can be overcome by employing new approaches such as lipid nanosystems. Due to their advantages (such as easy scaling, low cost, and remarkable stability) these systems have attracted interest from the scientific community. However, for a successful formulation, several factors including particle size, surface charge, components, etc. have to be understood and controlled. This review provided a brief overview of the structure of the skin as well as the different pathways of nanoparticle penetration. In addition, the main factors influencing the penetration of nanoparticles have been highlighted. Applications of lipid nanosystems for dermal and transdermal delivery, as well as regulatory aspects, were critically discussed.
... Both organic and inorganic nanoparticles [6] have been studied to improve tolerability, pharmacologic specificity, biodegradability, and targeting for oral drugs [7,8]. Numerous nanocarriers including nanoparticles [9,10], liposomes [11,12], emulsions [13] etc., have been applied for oral drugs. Most nanocarriers showed advantages in protecting drugs from harsh conditions in the GIT, increasing the drugs can be metabolized by the gut microflora which effects the release characters of drugs. ...
The oral route is the most preferred route for systemic and local drug delivery. However, the oral drug delivery system faces the harsh physiological and physicochemical environment of the gastrointestinal tract, which limits the bioavailability and targeted design of oral drug delivery system. Innovative pharmaceutical approaches including nanoparticulate formulations, biomimetic drug formulations, and microfabricated devices have been explored to optimize drug targeting and bioavailability. In this review, the anatomical factors, biochemical factors, and physiology factors that influence delivering drug via oral route are discussed and recent advance in conventional and novel oral drug delivery approaches for improving drug bioavailability and targeting ability are highlighted. We also address the challenges and opportunities of oral drug delivery systems in future.
... Organic NPs have been extensively studied over the recent years and contain a variety of types. The first nano-scale medication licensed for medical use is called a liposome [100]. Liposomes are biocompatible, biodegradable, and nontoxic vesicles. ...
The wide spread of antibiotic resistance has been alarming in recent years and poses a serious global hazard to public health as it leads to millions of deaths all over the world. The wide spread of resistance and sharing resistance genes between different types of bacteria led to emergence of multidrug resistant (MDR) microorganisms. This problem is exacerbated when microorganisms create biofilms, which can boost bacterial resistance by up to 1000-fold and increase the emergence of MDR infections. The absence of novel and potent antimicrobial compounds is linked to the rise of multidrug resistance. This has sparked international efforts to develop new and improved antimicrobial agents as well as innovative and efficient techniques for antibiotic administration and targeting. There is an evolution in nanotechnology in recent years in treatment and prevention of the biofilm formation and MDR infection. The development of nanomaterial-based therapeutics, which could overcome current pathways linked to acquired drug resistance, is a hopeful strategy for treating difficult-to-treat bacterial infections. Additionally, nanoparticles’ distinct size and physical characteristics enable them to target biofilms and treat resistant pathogens. This review highlights the current advances in nanotechnology to combat MDR and biofilm infection. In addition, it provides insight on development and mechanisms of antibiotic resistance, spread of MDR and XDR infection, and development of nanoparticles and mechanisms of their antibacterial activity. Moreover, this review considers the difference between free antibiotics and nanoantibiotics, and the synergistic effect of nanoantibiotics to combat planktonic bacteria, intracellular bacteria and biofilm. Finally, we will discuss the strength and limitations of the application of nanotechnology against bacterial infection and future perspectives.
... Because of enhanced penetration and endurance, organic nanocarriers, such as micelles and liposomes, can aggregate at the appropriate location [71]. Because they are simple compounds, liposome-mediated drug delivery and polymeric nanocarriers are first-generation nanocarriers [72]. ...
... Summary of the liposomal drugs approved by the FDA and/or EMA for cancer treatment[28][29][30][31][32][33][34][35][36][37][38][39][40]. ...
To improve currently available cancer treatments, nanomaterials are employed as smart drug delivery vehicles that can be engineered to locally target cancer cells and respond to stimuli. Nanocarriers can entrap chemotherapeutic drugs and deliver them to the diseased site, reducing the side effects associated with the systemic administration of conventional anticancer drugs. Upon accumulation in the tumor cells, the nanocarriers need to be potentiated to release their therapeutic cargo. Stimulation can be through endogenous or exogenous modalities, such as temperature, electromagnetic irradiation, ultrasound (US), pH, or enzymes. This review discusses the acoustic stimulation of different sonosensitive liposomal formulations. Emulsion liposomes, or eLiposomes, are liposomes encapsulating phase-changing nanoemulsion droplets, which promote acoustic droplet vaporization (ADV) upon sonication. This gives eLiposomes the advantage of delivering the encapsulated drug at low intensities and short exposure times relative to liposomes. Other formulations integrating microbubbles and nanobubbles are also discussed.
... Besides, lipid penetration and permeation occur due to the fusion of the ethosomes with skin lipids, called the ethosome effect. Because of the two effects, ethosomes show improved skin penetration.46 ...
The incidence rate of melanoma is dramatically increasing worldwide, raising it to the fifth most common cancer in men and the sixth in women currently. Resistance generally occurs to the agents used in chemotherapy; besides their high toxicity destroys the normal cells. This study reviewed a detailed summary of the structure, advantages, and disadvantages of nanotechnology-based drug delivery systems in treatment of melanoma, as well as some nanocarrier applications in animal models or clinical studies. Respective databases were searched for the target keywords and 93 articles were reviewed and discussed. A close study of the liposomes, niosomes, transferosome, ethosomes, transethosomes, cubosomes, dendrimers, cyclodextrins, solid lipid nanoparticles, and carbon nanotubes was conducted. It was found that these nanocarriers could inhibit metastasis and migration of melanoma cells and decrease cell viability. Conclusively, some nanocarriers like liposomes, niosomes, and transferosomes have been discussed as superior to conventional therapies for melanoma treatment.
Liposomes are considered among the most versatile and advanced nanoparticle delivery systems used to target drugs to specific cells and tissues. Structurally, liposomes are sphere-like vesicles of phospholipid molecules that are surrounded by equal number of aqueous compartments. The spherical shell encapsulates an aqueous interior which contains substances such as peptides and proteins, hormones, enzymes, antibiotics, antifungal and anticancer agents. This structural property of liposomes makes it an important nano-carrier for drug delivery. Extrusion is one of the most frequently used technique for preparing monodisperse uni-lamellar liposomes as the technique is used to control vesicle size. The process involves passage of lipid suspension through polycarbonate membrane with a fixed pore size to produce vesicles with a diameter near the pore size of the membrane used in preparing them. An advantage of this technique is that there is no need to remove the organic solvent or detergent from the final preparation. This review focuses on composition of liposome formulation with special emphasis on factors affecting drug release and drug-loading. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA, it has been the most prescribed drug for symptomatic relief in PD, whose prolonged use, however, causes undesirable motor fluctuations like dyskinesia and dystonia. Further, therapeutics targeting the pathological hallmarks of PD including α-synuclein aggregation, oxidative stress, neuroinflammation, and autophagy impairment have also been developed, yet PD treatment is a largely unmet success. The inception of the nanovesicle-based drug delivery approach over the past few decades brings add-on advantages to the therapeutic strategies for PD treatment in which nanovesicles (basically phospholipid-containing artificial structures) are used to load and deliver drugs to the target site of the body. The present review narrates the characteristic features of nanovesicles including their blood-brain barrier permeability and ability to reach dopaminergic neurons of the brain and finally discusses the current status of this technology in the treatment of PD. From the review, it becomes evident that with the assistance of nanovesicle technology, the therapeutic efficacy of anti-PD pharmaceuticals, phyto-compounds, as well as that of nucleic acids targeting α-synuclein aggregation gained a significant increment. Furthermore, owing to the multiple drug-carrying abilities of nanovesicles, combination therapy targeting multiple pathogenic events of PD has also found success in preclinical studies and will plausibly lead to effective treatment strategies in the near future.
An emerging but less explored shared pathophysiology across microbiota-gut-brain axis disorders is aberrant miRNA expression, which may represent novel therapeutic targets. miRNAs are small, endogenous non-coding RNAs that are important transcriptional repressors of gene expression. Most importantly, they regulate the integrity of the intestinal epithelial and blood-brain barriers and serve as an important communication channel between the gut microbiome and the host. A well-defined understanding of the mode of action, therapeutic strategies and delivery mechanisms of miRNAs is pivotal in translating the clinical applications of miRNA-based therapeutics. Accumulating evidence links disorders of the microbiota-gut-brain axis with a compromised gut-blood-brain-barrier, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. This has the potential to affect all organs, including the brain, causing central inflammation and the development of neurodegenerative and neuropsychiatric diseases. In this review, we have examined in detail miRNA biogenesis, strategies for therapeutic application, delivery mechanisms, as well as their pathophysiology and clinical applications in inflammatory gut-brain disorders. The research data in this review was drawn from the following databases: PubMed, Google Scholar, and Clinicaltrials.gov. With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research.
Spherical structures built from uni- and multilamellar lipid bilayers (LUV and MLV) are nowadays considered not just as nanocarriers of various kinds of therapeutics, but also as the vehicles that, when coupled with gold (Au) nanoparticles (NPs), can also serve as a tool for imaging and discriminating healthy and diseased tissues. Since the presence of Au NPs or their aggregates may affect the properties of the drug delivery vehicle, we investigated how the shape and position of Au NP aggregates adsorbed on the surface of MLV affect the arrangement and conformation of lipid molecules. By preparing MLVs constituted from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in the presence of uncoated Au NP aggregates found i) both within liposome core and on the surface of the outer lipid bilayer, or ii) adsorbed on the outer lipid bilayer surface only, we demonstrated the maintenance of lipid bilayer integrity by microscopic techniques (cryo-TEM, and AFM). The employment of SERS and FTIR-ATR tehniques enabled us not only to elucidate the lipid interaction pattern and their orientation in regards to Au NP aggregates, but also unequivocally confirmed the impact of Au NP aggregates on persistence/breaking of van der Waals interactions between hydrocarbon chains of DPPC.
Lipid vesicles or more precisely liposome, is a term that is derived from two Greek words, 'Lipos' means fat and 'Soma' which means body. These spherical, self-contained structures have an inner core that is enclosed by one or more concentric lipid bilayers. Their size generally ranges from 20 nm to few microns and the thickness of lipid bilayer usually lies in nanoscale range. Since their inception in 1960s as conventional vesicles, they have witnessed tremendous technolgical development that has led to formation of 'second generation liposomes which possess long circulating time in body. Liposomes exhibits superior properties like better solubility , enhanced bioavailability, lower dose size, biodegradable nature of lipid bilayer etc, over the conventional drug delivery systems. Different methods are being employed for liposomes preparation like ether injection, hydration method, sonication, microemulsification, reverse evaporation, freeze thawed technique etc. The method of preparation depends on various parameters like lipid bilayer composition, route of administration, disease in which liposomal formulation is required etc. Liposomes are generally characterized for shape, size, surface properties, lamellarity, phase behaviour and drug release profile etc. This article briefly summarises the classification, methods of preparation, characterization and application of liposomes.
One of the major limitations for the treatment of many diseases is an inability of drugs to cross the cell membrane barrier. Different kinds of carriers are being investigated to improve drug bioavailability. Among them, lipid or polymer-based systems are of special interest due to their biocompatibility. In our study, we combined dendritic and liposomal carriers and analysed the biochemical and biophysical properties of these formulations. Two preparation methods of Liposomal Locked-in Dendrimers (LLDs) systems have been established and compared. Carbosilane ruthenium metallodendrimer was complexed with an anti-cancer drug (doxorubicin) and locked in a liposomal structure, using both techniques. The LLDs systems formed by hydrophilic locking had more efficient transfection profiles and interacted with the erythrocyte membrane better than systems using the hydrophobic method. The results indicate these systems have improved transfection properties when compared to non-complexed components. The coating of dendrimers with lipids significantly reduced their hemotoxicity and cytotoxicity. The nanometric size, low polydispersity index and reduced positive zeta potential of such complexes made them attractive for future application in drug delivery. The formulations prepared by the hydrophobic locking protocol were not effective and will not be considered furthermore as prospective drug delivery systems. In contrast, the formulations formed by the hydrophilic loading method have shown promising results where the cytotoxicity of LLD systems with doxorubicin was more effective against cancer than normal cells.
Mitochondrial dysfunction in Parkinson’s Disease (PD) is implicated through both environmental exposure and genetic factors (Grünewald et al. 2016; Tzoulis et al. 2013; Flønes et al. 2018; Fonseca-Fonseca et al. 2021). The first evidence reported of mitochondrial dysfunction associated with PD was in 1983 when 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure caused parkinsonian-like symptoms (Langston et al. 1983; Langston and Ballard 1983). Currently, there are limited approved drugs for the treatment of PD and these drugs only offer treatment for symptomatic purposes (Zhen and Chu 2020). However, as research advancements emerge in this field, organ-specific targeted therapies are receiving high priority as future therapeutic approaches hence nano-drug carriers like liposomes came into the valuable options for the treatment of PD. Around 30 years ago, researchers found a new way of delivering medicinal substances to specific areas of the brain—by injecting them into a certain part, in this case, the rat’s striatum. Liposomes loaded with dopamine partially ameliorated the cognitive and motor deficits in a PD rat model, as well as demonstrated the importance of targeted delivery to the brain (During et al. 1992).
Tamoxifen as an antiestrogen is successfully applied for the clinical treatment of breast cancer in pre- and post-menopausal women. Due to the side effects related to the oral administration of Tamoxifen (such as deep vein thrombosis, pulmonary embolism, hot flushes, ocular disturbances and some types of cancer), liposomal drug delivery is recommended for taking this drug. Drug encapsulation in a liposomal or lipid drug delivery system improves the pharmacokinetic and pharmacodynamic properties. In this regard, we carried out 200-ns molecular dynamics (MD) simulations for three systems (pure DPPC and neutral and protonated Tamoxifen-loaded DPPC). Here, DPPC is a model lipid bilayer to provide us with conditions like liposomal drug delivery systems to investigate the interactions between Tamoxifen and DPPC lipid bilayers and to estimate the preferred location and orientation of the drug molecule inside the bilayer membrane. Properties such as area per lipid, membrane thickness, lateral diffusion coefficient, order parameters and mass density, were surveyed. With insertion of neutral and protonated Tamoxifen inside the DPPC lipid bilayers, area per lipid and membrane thickness increased slightly. Also, Tamoxifen induce ordering of the hydrocarbon chains in DPPC bilayer. Analysis of MD trajectories shows that neutral Tamoxifen is predominantly found in the hydrophobic tail region, whereas protonated Tamoxifen is located at the lipid-water interface (polar region of DPPC lipid bilayers).
Nanomedicine is a branch of medicine using nanotechnology to prevent and treat diseases. Nanotechnology represents one of the most effective approaches in elevating a drug‘s treatment efficacy and reducing toxicity by improving drug solubility, altering biodistribution, and controlling the release. The development of nanotechnology and materials has brought a profound revolution to medicine, significantly affecting the treatment of various major diseases such as cancer, injection, and cardiovascular diseases. Nanomedicine has experienced explosive growth in the past few years. Although the clinical transition of nanomedicine is not very satisfactory, traditional drugs still occupy a dominant position in formulation development, but increasingly active drugs have adopted nanoscale forms to limit side effects and improve efficacy. The review summarized the approved nanomedicine, its indications, and the properties of commonly used nanocarriers and nanotechnology.
Numerous drugs have emerged to treat various diseases, such as COVID-19, cancer, and protect human health. Approximately 40% of them are lipophilic and are used for treating diseases through various delivery routes, including skin absorption, oral administration, and injection. However, as lipophilic drugs have a low solubility in the human body, drug delivery systems (DDSs) are being actively developed to increase drug bioavailability. Liposomes, micro-sponges, and polymer-based nanoparticles have been proposed as DDS carriers for lipophilic drugs. However, their instability, cytotoxicity, and lack of targeting ability limit their commercialization. Lipid nanoparticles (LNPs) have fewer side effects, excellent biocompatibility, and high physical stability. LNPs are considered efficient vehicles of lipophilic drugs owing to their lipid-based internal structure. In addition, recent LNP studies suggest that the bioavailability of LNP can be increased through surface modifications, such as PEGylation, chitosan, and surfactant protein coating. Thus, their combinations have an abundant utilization potential in the fields of DDSs for carrying lipophilic drugs. In this review, the functions and efficiencies of various types of LNPs and surface modifications developed to optimize lipophilic drug delivery are discussed.
Liposomes with enhanced elasticity have been proven to increase the efficiency of drug transport across the skin. The understanding of the background physicochemical processes driving the liposome viscoelastic properties is an essential feature for the design of effective formulations involving different lipids and additive molecules. In this work we use field-cycled nuclear magnetic resonance relaxometry to analyze both the mechanical properties of liposome membranes, and their relationship with the involved molecular dynamics. Different liposomal formulations were considered. We show a correlation between the molecular dynamical regime and mesoscopic physical parameters that define the expected deformability of the vesicles. Results strongly suggest that the purity of the used lipids may influence the elastic properties of the membranes in an appreciable way. Common features in the behaviour of the involved dynamic variables were identified by comparing formulations with surfactants of similar molecular weight.
Taurine, or 2-aminoethanesulfonic acid, is one of the most abundant sulfur-containing amino acids in the human body. It is found in the heart, brain, retina, and skeletal muscles, and is synthesized in the pancreas. Studies have revealed that taurine is of high physiological importance: it protects against pathologies associated with mitochondrial diseases, and linked processes like aging, metabolic syndrome, cancer, cardiovascular diseases, and neurological disorders. It is also used as a nutritional supplement. Taurine and the Mitochondrion: Applications in the Pharmacotherapy of Human Diseases explores the significance of taurine in the biology of mitochondria. It also explains its role as a pharmacological agent for treating different diseases. Readers will gain an insight into the crucial role it plays in human physiology and the benefits of taurine supplements. Topics covered in this reference include - Synthesis of taurine and its dietary sources - The Role of taurine in mitochondrial health - Taurine as a neurotransmitter - Beneficial effects of taurine in physiological systems such as the reproductive system, renal system, and the gastrointestinal tract - Hepatoprotective and anti-inflammatory properties of taurine - The anti-aging promise of taurine supplementation - Role of taurine supplementation in obesity
As repeatedly mentioned in the current book, taurine (TAU) is a very hydrophilic molecule. Hence, the passage of this amino acid through the physiological barriers (e.g., blood-brain barrier; BBB) is weak. In this context, experimental and clinical studies that mentioned the positive effects of TAU on CNS disorders administered a high dose of this amino acid (e.g., 12 g/day). For example, in an animal model of hepatic encephalopathy, we administered 1 g/kg of TAU to hyperammonemic rats to preserve their brain energy status and normalize their locomotor activity. In some cases, where anticonvulsant effects of TAU were evaluated; also, a high dose of this amino acid was used (150 mg/kg). In other circumstances, such as investigations on the reproductive system, the blood-testis barrier (BTB) could act as an obstacle to the bioavailability of TAU. On the other hand, recent studies mentioned the importance of targeted delivery of molecules to organelles such as mitochondria. These data mention the importance of appropriate formulations of this amino acid to target brain tissue as well as cellular mitochondria. Perhaps, TAU failed to show significant and optimum therapeutic effects against human disease (e.g., neurological disorders) because of its inappropriate drug delivery system. Therefore, targeting tissues such as the brain with appropriate TAU-containing formulations is critical. The current chapter discusses possible formulations for bypassing physiological barriers (e.g., blood-brain barrier; BBB or BTB) and effectively targeting subcellular compartments with TAU. These data could help develop effective formulations for managing human diseases (e.g., CNS disorders or infertility issues in men).
Solid lipid nanoparticlesSolid lipid nanoparticles (SLNs) are promising carriers that allow for the delivery of poorly water-soluble drugs and have the potential to achieve sustained drug release or targetedTargeted delivery to the site of interest. Here we describe the preparation of solid lipid nanoparticlesSolid lipid nanoparticles (SLNs) by forming a microemulsionMicroemulsions at an elevated temperature which, upon cooling, yields a suspension of solid nanoparticlesNanoparticles. This nanotemplate engineering method is inexpensive, reproducible, and easy to scale up.
Atomic force microscopyAtomic force microscopy is a high-resolution and nonoptical technique used to visualize and characterize biological samples and surfaces. In pharmaceutical research and development (R&D) and quality control (QC), drug deliveryDrug delivery systems, like liposomesLiposomes with sizes in a nanometer range, are preferred samples to be studied through atomic force microscopy. The instrument can determine the sample’s topography (e.g., height), morphology, and material properties (e.g., hardness, adhesiveness). Various measuring modes, e.g., intermittent contact (AC mode), can generate height (measured), lock-in amplitude, and lock-in phase data, revealing interesting details about the drug deliveryDrug delivery system. In this study, empty and drug-loaded liposomesLiposomes with various lipidLipids compositions and sizes (50–800 nm) were visualized and characterized with state-of-the-art atomic force microscope (AFM)Atomic force microscopy (AFM). The main focus here was the preparation methods of the samples, instrumental settings, and pitfalls that can occur during the whole imagingImaging process. Moreover, troubleshooting and postdata processing are essential for a high-quality outcome.
Nanotechnology is an emerging field in the drug delivery using the nanoparticles 5 to 200 nanometers in size. The drug is protected against chemical and enzymatic degradation by dissolving and entrapping the drug into biodegradable nanoparticles. The nanomaterials may be composed of proteins, polymers, polysaccharides, lipids, metals, etc. It is highly specific and target oriented. They have very low side effects, protects the drug from degradation, and a smaller number of doses required. The ultimate goal of nanodrug delivery system is to develop clinically useful formulation for treating diseases in patients. In this review article, we have discussed about the different types of nanotechnology‐based materials used in the drug delivery like liposomes, dendrimers, micelles their properties and applications. But the toxicity of the nanoparticles is of much health concern, which should be resolved.
Since the progression of osteoarthritis (OA) is closely associated with synovitis and cartilage destruction, the inhibition of inflammatory responses in synovial macrophages and reactive oxygen species (ROS) induced apoptosis in chondrocytes is crucial for OA amelioration. However, most of the current anti-inflammatory and antioxidant drugs are small molecules apt to be eliminated in vivo. Herein, mesoporous polydopamine nanoparticles (DAMM NPs) doped with arginine and manganese (Mn) ions were prepared to load dexamethasone (DEX) for OA intervention. A series of in vitro studies showed that the sustained release of DEX from DAMM NPs suppressed synovial inflammation and simultaneously inhibited toll-like receptor 3 (TLR-3) production in chondrocytes, contributing to prevention of chondrocyte apoptosis through the inflammatory factor-dependent TLR-3/NF-κB signaling pathway via modulation of macrophage-chondrocyte crosstalk. In addition, DAMM NPs exerted a predominant role in removal of ROS generated in chondrocytes. Therefore, the DEX-loaded DAMM NPs significantly attenuated OA development in mice model. Importantly, the T1-T2 magnetic contrast capabilities of DAMM NPs allowed an MRI-trackable delivery, manifesting a distinct feature widely regarded to boost the potential of nanomedicines for clinical applications. Together, our developed antioxidant-enhanced DAMM NPs with MRI-visible signals may serve as a novel multifunctional nanocarriers for prevention of OA progression.
The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo. This enables effective delivery of encapsulated compounds to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of positive results in preclinical studies, the clinical translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biological challenges that still remain, and current clinical and experimental use of liposomes for biomedical applications. The translational obstacles of liposomal technology will also be presented.
This single-arm Phase II trial was designed to assess the safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer.
Patients with a histological diagnosis of epithelial ovarian, fallopian tube or primary peritoneal carcinoma, who were relapse-free at least 6 months after completion of first-line platinum-based chemotherapy, and who had measurable disease and gave consent to participate in this study received infusions of pegylated liposomal doxorubicin (30 mg/m(2)) at 1 mg/min, followed by carboplatin (AUC 5 mg min/ml) over 30 min every 28 days.
Thirty-three of 35 enrolled patients were eligible for efficacy analysis. One patient (3.0%) achieved a complete response, while 16 (48.5%) achieved a partial response, with an overall objective response rate of 51.5% (95% confidence interval, 34.5-68.6%). Among the 22 patients who had evaluable CA125 levels at entry, responses were observed in 18 patients, with a response rate of 81.8% (95% confidence interval, 65.3-98.3%). The median progression-free survival and overall survival rates for all 35 patients were 10.7 months (95% confidence interval, 8.1-13.2 months) and 38.8 months (95% confidence interval, 31.0-46.7 months), respectively. The most frequent Grade 3-4 toxicities, regardless of cause, were neutropenia (82.9%), thrombocytopenia (51.4%), leukopenia (45.7%) and anemia (17.1%).
The safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer were confirmed. Although there were concerns of severe hematological toxicity with this therapy, this potential complication was safely managed through adequate monitoring of bone marrow function.
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Pegylation of nanoparticles has been widely implemented in the field of drug delivery to prevent macrophage clearance and increase drug accumulation at a target site. However, the shielding effect of polyethylene glycol (PEG) is usually incomplete and transient, due to loss of nanoparticle integrity upon systemic injection. Here, we have synthesized unique PEG-dendron-phospholipid constructs that form super stealth liposomes (SSLs). A β-glutamic acid dendron anchor was used to attach a PEG chain to several distearoyl phosphoethanolamine lipids, thereby differing from conventional stealth liposomes where a PEG chain is attached to a single phospholipid. This composition was shown to increase liposomal stability, prolong the circulation half-life, improve the biodistribution profile and enhance the anticancer potency of a drug payload (doxorubicin hydrochloride).
Copyright © 2014. Published by Elsevier B.V.
To evaluate the safety and efficacy of ketoprofen in Transfersome® gel (IDEA-033) in comparison with a ketoprofen-free vehicle (TDT 064) for the treatment of osteoarthritis (OA) of the knee.
Patients with knee OA (N = 866) were randomly assigned to receive topical IDEA-033 containing 100, 50, or 25 mg ketoprofen, or TDT 064 twice daily for 12 weeks, in a double-blind trial. The primary efficacy endpoint was the change in the Western Ontario and McMaster Universities (WOMAC®) Osteoarthritis Index pain subscale score. The coprimary efficacy endpoints were the WOMAC function subscale score and the patient global assessment of response to therapy. The secondary endpoints included the numeric pain rating for the first 14 days of treatment and the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder rates.
The WOMAC pain scores were reduced by approximately 50% or more in all four groups. The 100 and 50 mg ketoprofen groups, but not the 25 mg group, showed a superior reduction in the WOMAC pain score versus the TDT 064 group (100 mg: -57.4% [P = 0.0383]; 50 mg: -57.1% [P = 0.0204]; and 25 mg: -53.4% [P = 0.3616] versus TDT 064: -49.5%). The superiority of the ketoprofen-containing formulations was not demonstrated for the WOMAC function subscale score, whereas the patient global assessment of 50 mg ketoprofen group, but not the 100 or 25 mg group, was superior to that of the TDT 064 group (P = 0.0283). Responder rates were significantly higher for all the IDEA-033 groups versus the TDT 064 group, but were high in all groups (100 mg: 88.6%; 50 mg: 86.8%; 25 mg: 88.6%; and TDT 064: 77.5%). Dermal reactions were the only relevant drug-related adverse events in all four groups.
The 50 and 100 mg ketoprofen doses of IDEA-033 were only marginally superior to TDT 064 for reducing pain associated with knee OA. The study indicates a high treatment response to the topical ketoprofen-free vehicle TDT 064.
The field of cancer nanomedicine is considered a promising area for improved delivery of bioactive molecules including drugs, pharmaceutical agents and nucleic acids. Among these, drug delivery technology has made discernible progress in recent years and the areas that warrant further focus and consideration towards technological developments have also been recognized. Development of viable methods for on-demand spatial and temporal release of entrapped drugs from the nanocarriers is an arena that is likely to enhance the clinical suitability of drug-loaded nanocarriers. One such approach, which utilizes light as the external stimulus to disrupt and/or destabilize drug-loaded nanoparticles, will be the discussion platform of this article. Although several phototriggerable nanocarriers are currently under development, I will limit this review to the phototriggerable liposomes that have demonstrated promise in the cell culture systems at least (but not the last). The topics covered in this review include (i) a brief summary of various phototriggerable nanocarriers; (ii) an overview of the application of liposomes to deliver payload of photosensitizers and associated technologies; (iii) the design considerations of photoactivable lipid molecules and the chemical considerations and mechanisms of phototriggering of liposomal lipids; (iv) limitations and future directions for in vivo, clinically viable triggered drug delivery approaches and potential novel photoactivation strategies will be discussed.
To describe the preparation of nano emodin transfersome (NET) and investigate its effect on mRNA expression of adipose triglyceride lipase (ATGL) and G0/G1 switch gene 2 (G0S2) in adipose tissue of diet-induced obese rats.
NET was prepared by film-ultrasonic dispersion method. The effects of emodin components at different ratios on encapsulation efficiency were investigated.The NET envelopment rate was determined by ultraviolet spectrophotometry. The particle size and Zeta potential of NET were evaluated by Zetasizer analyzer. Sixty male SD rats were assigned to groups randomly. After 8-week treatment, body weight, wet weight of visceral fat and the percentage of body fat (PBF) were measured. Fasting blood glucose and serum lipid levels were determined. The adipose tissue section was HE stained, and the cellular diameter and quantity of adipocytes were evaluated by light microscopy. The mRNA expression of ATGL and G0S2 from the peri-renal fat tissue was assayed by RT-PCR.
The appropriate formulation was deoxycholic acid sodium salt vs. phospholipids 1:8, cholesterol vs. phospholipids 1:3, vitamin Evs. phospholipids 1:20, and emodin vs. phospholipid 1:6. Zeta potential was -15.11 mV, and the particle size was 292.2 nm. The mean encapsulation efficiency was (69.35 +/- 0.25)%. Compared with the obese model group, body weight, wet weight of visceral fat, PBF and mRNA expression of G0S2 from peri-renal fat tissue were decreased significantly after NET treatment (all P < 0.05), while high-density lipoprotein cholesterol (HDL-C), the diameter of adipocytes and mRNA expression of ATGL from peri-renal fat tissue were increased significantly (all P < 0.05).
The preparation method is simple and reasonable. NET with negative electricity was small and uniform in particle size, with high encapsulation efficiency and stability. NET could reduce body weight and adipocyte size, and this effect was associated with the up-regulation of ATGL, down-regulation of G0S2 expression in the adipose tissue, and improved insulin sensitivity.
Sustained delivery of analgesic agents at target sites remains a critical issue for effective pain management. The use of nanocarriers has been reported to facilitate effective delivery of these agents to target sites while minimizing systemic toxicity. These include the use of biodegradable liposomal or polymeric carriers. Of these, liposomes present as an attractive delivery system due to their flexible physicochemical properties which allow easy manipulation in order to address different delivery considerations. Their favorable toxicity profiles and ease of large scale production also make their clinical use feasible. In this review, we will discuss the concept of using liposomes as a drug delivery carrier, their in vitro characteristics as well as in vivo behavior. Current advances in the targeted liposomal delivery of analgesic agents and their impacts on the field of pain management will be presented.
The aim of this study was to prepare and investigate the potential use of liposomes in the
transdermal drug delivery of meloxicam (MX). The vesicles containing a constant amount of MX,
phosphatidylcholine (PC), cholesterol (Chol) and cetylpyridinium chloride (CPC) (1:5:1:1
MX/PC/Chol/CPC molar ratio) to obtain liposomes. MX loaded liposomes were investigated for
particle size, zeta potential, entrapment efficiency (%EE) and in vitro skin permeation. The results
indicated that the liposomes were spherical in structure, 77 to 100 nm in size and charged. The %EE
of MX in the vesicles ranged from 55 to 56%. The elastic liposomes consisting of
MX/PC/Chol/CPC provided a significantly higher skin permeation of MX compared to the other
formulations. Fourier Transform Infrared Spectroscopy (FT-IR) and Differential Scanning
Calorimetry (DSC) analysis indicated that the application of liposomes may disrupt the stratum
corneum lipid. Our research suggests that MX loaded elastic liposomes can be potentially used as a
transdermal drug delivery system.
Abstract Liposomes are well known lipid carriers for drug delivery of bioactive molecules encapsulated inside their membrane. Liposomes as skin drug delivery systems were initially promoted primarily for localized effects with minimal systemic delivery. Subsequently, a novel vesicular system, transferosomes was reported for transdermal delivery with efficiency similar to subcutaneous injection. The multiple bilayered organizations of lipids applied in these vesicles structure are somewhat similar to complex nature of stratum corneal intercellular lipids domains. The incorporation of novel agents into these lipid vesicles results in the loss of entrapped markers but it is similar to fluidization of stratum corneum lipids on treatment with a penetration enhancer. This approach generated the utility of penetration enhancers/fluidizing agents in lipids vesicular systems for skin delivery. For the transdermal and topical applications of liposomes, fluidity of bilayer lipid membrane is rate limiting which governs the permeation. This article critically reviews the relevance of using different types of vesicles as a model for skin in permeation enhancement studies. This study has also been designed to encompass all enhancement measurements and analytical tools for characterization of permeability in liposomal vesicular system.
Liposomes are used as a delivery vehicle for drug molecules and imaging agents. The major impetus in their biomedical applications comes from the ability to prolong their circulation half-life after administration. Conventional liposomes are easily recognized by the mononuclear phagocyte system and are rapidly cleared from the blood stream. Modification of the liposomal surface with hydrophilic polymers delays the elimination process by endowing them with stealth properties. In recent times, the development of various materials for surface engineering of liposomes and other nanomaterials has made remarkable progress. Poly(ethylene glycol)-linked phospholipids (PEG-PLs) are the best representatives of such materials. Although PEG-PLs have served the formulation scientists amazingly well, closer scrutiny has uncovered a few shortcomings, especially pertaining to immunogenicity and pharmaceutical characteristics (drug loading, targeting, etc.) of PEG. On the other hand, researchers have also begun questioning the biological behavior of the phospholipid portion in PEG-PLs. Consequently, stealth lipopolymers consisting of non-phospholipids and PEG-alternatives are being developed. These novel lipopolymers offer the potential advantages of structural versatility, reduced complement activation, greater stability, flexible handling and storage procedures and low cost. In this article, we review the materials available as alternatives to PEG and PEG-lipopolymers for effective surface modification of liposomes.
The purpose of this work was to explore the feasibility of ethosomes for improving the antiarthritic efficacy of tetrandrine by topical application. It was found that tetrandrine was a weak base (pK a = 7.06) with pH-dependent partition coefficient. The spherical-shaped ethosomes were prepared by pH gradient loading method. Ex vivo permeation and deposition behavior demonstrated that the drug flux across rat skin and deposition of the drug in rat skin for ethosomes was 2.1- and 1.7-fold higher than that of liposomes, respectively. Confocal laser scanning microscopy confirmed that ethosomes could enhance the topical delivery of the drug in terms of depth and quantity compared with liposomes. The ethosomes were shown to generate substantial enhancement of therapeutic efficacy of tetrandrine on Freund's complete adjuvant-induced arthritis with regard to liposomes. These results indicated that ethosomes would be a promising carrier for topical delivery of tetrandrine into and across the skin.
The current investigation aimed to evaluate the transdermal potential of novel testosterone propionate (TP) ethosomes and liposomes prepared by surfactant modification. The effect of hexadecyl trimethyl ammonium bromide and cremophor EL-35 on the particle size and zeta potential of the prepared vesicles was investigated. The entrapment efficiency and stability, as well as in vitro and in vivo skin permeation, were studied with the various techniques, such as differential scanning calorimetry, confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, and so on. The results indicated that the ethosomes were defined as spherical, unilamellar structures with low polydispersity (0.100 ± 0.015) and nanometric size (156.5 ± 3.5 nm). The entrapment efficiency of TP in ethosomal and liposomal carriers was 92.7% ± 3.7% and 64.7% ± 2.1%, respectively. The stability profile of the prepared TP ethosomal system assessed for 120 days revealed very low aggregation and very low growth in vesicular size. TP ethosomes also provided an enhanced transdermal flux of 37.85 ± 2.8 μg/cm(2)/hour and a decreased lag time of 0.18 hours across mouse skin. The skin permeation efficiency of the TP ethosomes as further assessed by confocal laser scanning microscopy revealed enhanced permeation of rhodamine red-loaded formulations to the deeper layers of the skin (260 μm) than that of the liposomal formation (120 μm).
Failure of clinical trials of nonviral vector-mediated gene therapy arises primarily from either an insufficient transgene expression level or immunostimulation concerns caused by the genetic information carrier (e.g., bacteria-generated, double-stranded DNA (dsDNA)). Neither of these issues could be addressed through engineering-sophisticated gene delivery vehicles. Therefore, we propose a systemic delivery of chemically modified messenger RNA (mRNA) as an alternative to plasmid DNA (pDNA) in cancer gene therapy. Modified mRNA evaded recognition by the innate immune system and was less immunostimulating than dsDNA or regular mRNA. Moreover, the cytoplasmic delivery of mRNA circumvented the nuclear envelope, which resulted in a higher gene expression level. When formulated in the nanoparticle formulation liposome-protamine-RNA (LPR), modified mRNA showed increased nuclease tolerance and was more effectively taken up by tumor cells after systemic administration. The use of LPR resulted in a substantial increase of the gene expression level compared with the equivalent pDNA in the human lung cancer NCI-H460 carcinoma. In a therapeutic model, when modified mRNA encoding herpes simplex virus 1-thymidine kinase (HSV1-tk) was systemically delivered to H460 xenograft-bearing nude mice, it was significantly more effective in suppressing tumor growth than pDNA.Molecular Therapy (2012); doi:10.1038/mt.2012.250.
Liposomes, phospholipid vesicles with a bilayered membrane structure, have been widely used as pharmaceutical carriers for drugs and genes, in particular for treatment of cancer. To enhance the efficacy of the liposomal drugs, drug-loaded liposomes are targeted to the tumors by means of passive (enhanced permeability and retention mediated) targeting, based on the longevity of liposomes in blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the liposomal surface to bind certain antigens on the target cells. Antibody-targeted liposomes loaded with anticancer drugs demonstrate high potential for clinical applications. This review highlights evolution of liposomes for both passive and active targeting and challenges in development of targeted liposomal therapeutics specifically antibody-targeted liposomes.
TDT 067 is a novel, carrier-based dosage form of terbinafine in Transfersome (1.5%) formulated for topical delivery of terbinafine to the nail, nail bed, and surrounding tissue. We examined the effects of TDT 067 and conventional terbinafine on the morphology of dermatophytes. Trichophyton rubrum hyphae were exposed to TDT 067 or terbinafine (15 mg/ml) and examined under white light, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Subungual debris from patients treated with TDT 067 in a clinical trial was also examined. Exposure of T. rubrum hyphae to TDT 067 led to rapid and extensive ultrastructural changes. Hyphal distortion was evident as early as 4 h after exposure to TDT 067. After 24 h, there was complete disruption of hyphal structure with few intact hyphae remaining. Exposure to terbinafine resulted in morphological alterations similar to those seen with TDT 067; however, the effects of TDT 067 were more extensive, whereas a portion of hyphae remained intact after 24 h of exposure to terbinafine. Lipid droplets were observed under TEM following 30 min of exposure to TDT 067, which after 24 h had filled the intracellular space. These effects were confirmed in vivo in subungual debris from patients with onychomycosis who received topical treatment with TDT 067. The Transfersome in TDT 067 may potentiate the action of terbinafine by delivering terbinafine more effectively to its site of action inside the fungus. Our in vivo data confirm that TDT 067 can enter fungus in the nail bed of patients with onychomycosis and exert its antifungal effects.
The main disadvantage of transdermal drug delivery is the poor penetration of most compounds into the human skin. The main barrier of the skin is located within its uppermost layer, the stratum corneum (SC). Several approaches have been developed to weaken this skin barrier. One of the approaches for increasing the skin penetration of drugs and many cosmetic chemicals is the use of vesicular systems, such as, liposomes and ethosomes. Ethosomes are phospholipid-based elastic nanovesicles containing a high content of ethanol (20-45%). Ethanol is known as an efficient permeation enhancer and has been added in the vesicular systems to prepare elastic nanovesicles. It can interact with the polar head group region of the lipid molecules, resulting in the reduction of the melting point of the stratum corneum lipid, thereby increasing lipid fluidity and cell membrane permeability. The high flexibility of vesicular membranes from the added ethanol permits the elastic vesicles to squeeze themselves through the pores, which are much smaller than their diameters. Ethosomal systems are much more efficient in delivering substances to the skin in the terms of quantity and depth, than either conventional liposomes or hydroalcoholic solutions. The scope of this small review is to introduce the novel concept of ethosomes and to describe some approaches and mechanisms of stimulating topical and transdermal products with ethosomes.
The physical properties of the lamellar lipid-bilayer component of biological membranes are controlled by a host of thermodynamic forces leading to overall tensionless bilayers with a conspicuous lateral pressure profile and build-in curvature-stress instabilities that may be released locally or globally in terms of morphological changes. In particular, the average molecular shape and the propensity of the different lipid and protein species for forming non-lamellar and curved structures are a source of structural transitions and control of biological function. The effects of different lipids, sterols, and proteins on membrane structure are discussed and it is shown how one can take advantage of the curvature-stress modulations brought about by specific molecular agents, such as fatty acids, lysolipids, and other amphiphilic solutes, to construct intelligent drug-delivery systems that function by enzymatic triggering via curvature.
Practical applications: The simple concept of lipid molecular shape and how it impacts on the structure of lipid aggregates, in particular the curvature and curvature stress in lipid bilayers and liposomes, can be exploited to construct liposome-based drug-delivery systems, e.g., for use as nano-medicine in cancer therapy. Non-lamellar-forming lysolipids and fatty acids, some of which may be designed to be prodrugs, can be created by phospholipase action in diseased tissues thereby providing for targeted drug release and proliferation of molecular entities with conical shape that break down the permeability barrier of the target cells and may hence enhance efficacy.
TB is an infectious disease that is far from being eradicated and controlled. The treatment for TB is associated with noncompliance to therapy because it consists of a long-term treatment with a multidrug combination and is associated with the appearance of several side effects. Liposomal formulations are being developed with first- and second-line antibiotics, and might be an extremely useful alternative to current therapies. This article will thus focus on the role of liposomes as nanodelivery systems for the treatment of TB. Among several advantages, these nanocarriers allow an increase in the bioavailability of antibiotics, which may lead to a reduction in the time of treatment. Results obtained with such nanosystems, although preliminary, are promising and are perspective of the use of inhalation for TB treatment.
Pharmacosomes are amphiphilic lipid vesicular systems containing phospholipid complexes with a potential to improve bioavailability of poorly water soluble as well as poorly lipophilic drugs. To improve the water solubility, bioavailability and minimize the gastrointestinal toxicity of aceclofenac, its pharmacosomes were prepared. Aceclofenac was complexed with phosphatidylcholine (80%) in two different ratios (1:1 and 2:1) using conventional solvent evaporation technique. Pharmacosomes thus prepared were subjected to solubility and drug content evaluation, scanning electron microscopy, differential scanning calorimetry, X ray powder diffraction and in vitro dissolution study. Pharmacosomes of aceclofenac were found to be disc shaped with rough surface in scanning electron microscopy. Drug content was found to be 91.88% (w/w) for aceclofenac phospholipid complex (1:1) and 89.03% (w/w) aceclofenac-phospholipid complex (2:1). Differential scanning calorimetric thermograms and X ray powder diffraction datas confirmed the formation of phospholipid complex. Solubility and dissolution profile of the prepared complex was found to be much better than aceclofenac.
A novel mitochondrial-targeted liposomal drug-delivery system was prepared by modification of the liposomal surface with a newly synthesized polymer, rhodamine-123 (Rh123)-PEG-DOPE inserted into the liposomal lipid bilayer. This novel polymer was synthesized by conjugating the mitochondriotropic dye Rh123, with the amphiphilic polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate. The modified liposomes showed better uptake by cells (HeLa, B16F10) estimated by fluorescence microscopy and FACS analysis. The co-localization study with stained mitochondria as well as with the isolation of mitochondria of the cultured cells after their treatment with Rh123 liposomes showed a high degree of accumulation of the modified liposomes in the mitochondria. We also prepared mitochondrial-targeted and nontargeted paclitaxel (PCL)-loaded liposomes. Mitochondrial-targeted PCL-loaded liposomes demonstrated enhanced cytotoxicity toward cancer cells compared with nontargeted drug-loaded liposomes or free PCL. Thus, Rh123-modified liposomes target mitochondria efficiently and can facilitate the delivery of a therapeutic payload to mitochondria.
Mesenchymal stem cells (MSCs) hold a great promise for application in several therapies due to their unique biological characteristics. In order to harness their full potential in cell-or gene-based therapies it might be advantageous to enhance some of their features through gene delivery strategies. Accordingly, we are interested in developing an efficient and safe methodology to genetically engineer human bone marrow MSC (BM MSC), enhancing their therapeutic efficacy in Regenerative Medicine. The plasmid DNA delivery was optimized using a cationic liposome-based reagent. Transfection efficiencies ranged from approximately 2% to approximately 35%, resulting from using a Lipid/DNA ratio of 1.25 with a transgene expression of 7 days. Importantly, the number of plasmid copies in different cell passages was quantified for the first time and approximately 20,000 plasmid copies/cell were obtained independently of cell passage. As transfected MSC have shown high viabilities (>90%) and recoveries (>52%) while maintaining their multipotency, this might be an advantageous transfection strategy when the goal is to express a therapeutic gene in a safe and transient way.
The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia.
Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy.
Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%).
Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.
Neomycin sulphate (a hydrophilic drug) is extensively used topically in treatment if various skin infections. The objective of the present research was to investigate the dermal delivery of neomycin sulphate through elastic liposomes for effective treatment of deep skin infections. Elastic liposomes containing neomycin sulphate were prepared using Phospholipon®90 G and Tween 80/Span 80. Elastic liposomal-gel was prepared by incorporating prepared EL in corbopol resins. Extent of skin penetration of NS from EL and its gel was studied. EL was characterized for vesicular shape, size, zeta potential, entrapment efficiency, stability, in vitro skin penetration and in vivo antibacterial study in rats. TEM and Zeta Seizer defined EL as spherical, unilamellar structures with low polydispersity and nanometric size range (145 ± 5.85nm). Drug entrapment efficiency of EL carrier was found to be (34.6% ± 0.15%). EL suspension was found to be stable for 14 d when stored at 2-80C where as its gel was stable for 2 months. CLSM studies revealed that vesicles facilitated the co-penetration of NS to the deeper layers of the rat skin up to 180μm. In vitro penetration studies showed enhanced deposition of NS (25.92% ± 3.48%) in rat skin after 24 hours. Histological findings after deep dermal S. aureus infection in rats indicated that EL were efficient carriers for delivery of NS to bacteria localized within deep skin strata and showed complete eradication of staphylococcal infections within 7 d. The results showed that effective treatment of deep dermal infection is possible with neomycin through elastic liposomes.
Sophisticated drug delivery systems (DDS) are required for delivering drugs, especially macromolecules such as nucleic acids or proteins, to their sites of action. Therefore it is a prerequisite that future DDS are designed to selectively target a tissue. In this review, we focus on systems that actively target the vasculature in tumors or adipose tissues. For targeting tumor vasculatur, a new strategy referred to as dual-targeting is proposed that uses a combination of a receptor specific ligand and a cell penetrating peptide, which can induce the synergistic enhancement of tissue selectivity under in vivo conditions. A novel pH-sensitive cationic lipid was designed to enhance the endosomal release of encapsulated compounds such as siRNA as well as to improve the stability in blood circulation after intravenous administration. A cyclic RGD peptide is used as an active targeting ligand. For targeting adipose vasculature, prohibitin, which is expressed on the surface of adipose endothelial cells, was targeted with KGGRAKD peptides on the surface of PEGylated nanoparticles. Prohibitin targeted nanoparticles (PTNP) encapsulating Cytochrome c (CytC) can selectively target adipose vasculature by optimizing the lengths of the PEG linkers and can deliver CytC to adipose endothelial cells. PTNP can successfully induce anti-obese effects as well as apoptosis by delivering CytC to the cytosol in endothelial cells. Unexpectedly, the EPR (enhanced permeability and retention) effect, which is usually observed in tumor tissue, was also observed in the adipose vasculature, especially in obese mice, where PEGylated nanoparticles can pass through the endothelial barriers in adipose tissue. We believe that these achievements in active targeting will allow a greatly expanded use of DDS for nanomedicines.
Cells move and change shape by dynamically reorganizing their cytoskeleton next to the plasma membrane. In particular, actin assembly generates forces and stresses that deform the cell membrane. Cell-sized liposomes are designed to mimic this function. The activation of actin polymerization at their membrane is able to push the membrane forward, thus reproducing the mechanism of lamellipodium extension at the cell front. Moreover, the cell cortex, a submicrometer-thick actin shell right beneath the cell membrane can be reproduced; it contributes to cell tension with the action of molecular motors. We will describe experimental methods to prepare liposomes that mimic the inside geometry of a cell, and that reproduce actin-based propulsion of the liposome using an outside geometry. Such systems allow to study how actin-related proteins control and affect actin cortex assembly and can produce forces that drive cell shape changes.
Copyright © 2015 Elsevier Inc. All rights reserved.
Background: CPX-351 is a liposomal formulation that co-encapsulates Cyt and Daun enabling delivery of both drugs at a synergistic 5:1 molar ratio. A Phase I study in advanced AML patients demonstrated substantial efficacy with complete remissions (CRs) and acceptable safety. The MTD was 101 units/m2. One unit of CPX-351 contains 1 mg Cyt and 0.44mg of Daun. Here we examine the PK of CPX-351 as a function of dose, inter-patient variability and patient characteristics in order to identify potential PD relationships. Methods: 35 male and female patients with advanced hematologic malignancies were included in the PK portion of this Phase I trial and received 24, 32, 43, 57, 76, 101, or 134 units/m2 of CPX-351 by IV infusion over 90 minutes on Days 1, 3, and 5. Validated LC/MS/MS assays were used for determination of total plasma Cyt and Daun. PK parameters [Cmax, AUC, t1/2, Vss, CL, Cmax/Dose, AUC/Dose] were determined on Days 1 and 5. Results: Mean Cyt and Daun PK parameters are presented in the table below. No significant differences were observed in t1/2, Vss, CL, Cmax/Dose, or AUC/Dose among dose groups on either study day, although some drug accumulation was observed from day 1 to day 5. Cyt and Daun PK parameters were not correlated with patient gender, age or race. Incidence of non-hematologic toxicity increased with dose and systemic exposure. CRs were observed in patients receiving doses of 32-134 units/m2 of CPX-351. The responses at 101 units/m2 and above appear to be more durable. The Cyt:Daun molar ratio remained near 5:1 for up to 48 hours on both study days for all dose levels. Conclusions: Cyt and Daun delivered in CPX-351 exhibited linear single dose and multiple dose PK and low inter-patient variability in plasma concentrations within dose groups. CPX-351 provides predictable, extended systemic exposure of elevated Cyt:Daun concentrations near a 5:1 molar ratio. The 100 unit/m2 dose is undergoing testing in Phase II studies.
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Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1292. doi:10.1158/1538-7445.AM2011-1292
The Silences of the Archives, the Reknown of the Story.
The Martin Guerre affair has been told many times since Jean de Coras and Guillaume Lesueur published their stories in 1561. It is in many ways a perfect intrigue with uncanny resemblance, persuasive deception and a surprizing end when the two Martin stood face to face, memory to memory, before captivated judges and a guilty feeling Bertrande de Rols. The historian wanted to go beyond the known story in order to discover the world of the heroes. This research led to disappointments and surprizes as documents were discovered concerning the environment of Artigat’s inhabitants and bearing directly on the main characters thanks to notarial contracts. Along the way, study of the works of Coras and Lesueur took a new direction. Coming back to the affair a quarter century later did not result in finding new documents (some are perhaps still buried in Spanish archives), but by going back over her tracks, the historian could only be struck by the silences of the archives that refuse to reveal their secrets and, at the same time, by the possible openings they suggest, by the intuition that almost invisible threads link here and there characters and events.
A brain drug delivery system for glioma chemotherapy based on transferrin and cell-penetrating peptide dual-functioned liposome, Tf/TAT-lip, was made and evaluated with doxorubicin (DOX) as a model drug. TAT conjugated liposome (TAT-lip) loaded with doxorubicin (DOX) were prepared by the thin film hydration methods (lip-DOX) and then conjugated with transferrin (Tf) to yield Tf/TAT-lip-DOX which was characterized for their various physicochemical and pharmaceutical properties. Cellular uptakes were explored in both brain capillary endothelial cells (BCECs) of rats and U87 cells. The blood brain barrier model in vitro was established to evaluate the trans-endothelial ability crossing the BBB. The biodistribution of each formulation was further identified. The Tf/TAT-lip-DOX presents the best anti-proliferative activity against U87 cells. The orthotropic glioma model was established for the evaluation of anti-glioma effect. In conclusion, the experimental data in vitro and in vivo indicated that the Tf/TAT-lip was a promising brain drug delivery system due to its high delivery efficiency across the BBB.
The goal of this study was to develop and evaluate the potential use of transfersome vesicles in the transdermal drug delivery of Ibuprofen. It was investigated by encapsulating the drug in various formulations of composed of various ratios of soya phosphatidylcholine, span 80 and tween 80, prepared by lipid film hydration by rotatary evaporation method and evaluated for particle shape, size, zeta potential, entrapment efficiency (%EE),elasticity, stability, and in vitro skin permeation. The vesicles were spherical in structure as confirmed by Scanning Electron Microscopy and TEM, the vesicle size of best formulation for Span 80 and Tween 80 was 962 nm and 2250 nm respectively, and zeta potential (negatively charged) for Span 80 and Tween 80 was found to be -16.1 and -17.5 respectively. The %EE of ibuprofen in the vesicles was 47.8(plus or minus)2.2 and the elasticity of both increases with increase in surfactant conc. and were found to be 34.4(plus or minus)1.4 and 26.5(plus or minus)1.6. Stability studies for Transferosome were carried out for 5 weeks at 450C. In vitro skin permeation studies were carried by human cadaver skin using franz diffusion cell, and drug release after 24 hrs and flux was found 2.5824 and 1.9672 ug/cm2/hr respectively. Fourier Transform Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC) analysis indicated that the application of transfersomes significantly disrupted the stratum corneum lipid. It is evident from this study that transfersomes are a promising prolonged delivery system for Ibuprofen and have reasonably good stability characteristics. This research suggests that ibuprofen loaded transfersomes can be potentially used as a transdermal drug delivery system.
Liposome co-encapsulation of synergistic anti-cancer drug combination is an emerging area that has demonstrated therapeutic benefit in clinical trials. Remote loading of two or more drugs into a single liposome constitutes a new challenge that calls for a re-examination of drug loading strategies to allow the loading of the drug combination efficiently and with high drug content. In this study, the Mn(2+) gradient coupled with A23187 ionophore was applied in the sequential co-encapsulation of doxorubicin and irinotecan, as this drug loading method is capable of remotely loading drugs by apparently two different mechanisms, namely, coordination complexation and pH gradient. Doxorubicin and irinotecan could be co-encapsulated into liposomes in a wide range of drug-to-drug ratios, with encapsulation efficiencies of > 80%. The total encapsulated drug content was non-linearly correlated with increases in the intraliposomal Mn(2+) concentration, with a maximum total drug-to-lipid molar ratio of 0.8:1 achieved with 600 mM Mn(2+). This high encapsulated drug content did not affect the stability of the co-encapsulated liposomes upon storage for six months. Regardless of the encapsulated drug amount, the liposomes did not exhibit the fiber bundle precipitate morphology but rather an undefined structural organization in the aqueous core. The co-encapsulated liposome formulation was further tested in an intraperitoneally grown, human ovarian tumor xenograft model, and was shown to significantly improve the survival of the tumor-bearing animals. The improvement in therapeutic efficacy was possibly due to the increase in systemic drug exposure, with the maintenance of the synergistic molar drug ratio of 1:1 in circulation.
Eukaryotic subcellular membrane systems, such as the nuclear envelope or endoplasmic reticulum, present a rich array of architecturally and compositionally complex supramolecular targets that are as yet inaccessible. Here we describe layer-by-layer phospholipid membrane assembly on microfluidic droplets, a route to structures with defined compositional asymmetry and lamellarity. Starting with phospholipid-stabilized water-in-oil droplets trapped in a static droplet array, lipid monolayer deposition proceeds as oil/water-phase boundaries pass over the droplets. Unilamellar vesicles assembled layer-by-layer support functional insertion both of purified and of in situ expressed membrane proteins. Synthesis and chemical probing of asymmetric unilamellar and double-bilayer vesicles demonstrate the programmability of both membrane lamellarity and lipid-leaflet composition during assembly. The immobilized vesicle arrays are a pragmatic experimental platform for biophysical studies of membranes and their associated proteins, particularly complexes that assemble and function in multilamellar contexts in vivo.