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Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape
Drug Delivery
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.
... Due to these effects, the cGAS-STING pathway is considered to be a promising therapeutic target for advancing cancer immunotherapy strategies [60][61][62]. STING is widely expressed across various cell types, including cancer cells, and performs multiple functions, such as activating type I interferons, inducing autophagy, and triggering apoptosis [16,58,63]. The increase in IFN-γ levels in STING-LNP leads to an increase in NK expression [59]. ...
... The developed targeted cGAMP liposomes effectively activated NK cells, enhanced CD8+ T cell infiltration, and demonstrated a significant anti-tumor effect in a breast cancer mouse model. Drug delivery systems for the treatment of tumors such as breast cancer still face many challenges [58,62,63]. In the case of solid tumors, the effectiveness of anti-cancer drugs depends on overcoming several challenges in drug transport, including targeting the tumor site while minimizing accumulation in healthy organs and traversing a dense layer of blood vessel walls to reach the cancerous tissue, as some cancer cells are located far from blood vessels [22][23][24]. ...
... Currently, there is no effective method to proactively transport drugs to these areas. The efficient and targeted delivery of anti-tumor drugs into human tumor tissues, which enables controlled drug release and improves drug bioavailability and cellular uptake, is a prominent research topic [35,63]. Ultrasound-mediated liposomal drug delivery systems are widely used currently in both clinical and experimental settings and have demonstrated remarkable results [42][43][44]63]. ...
Background: Pharmacologically targeting the STING pathway offers a novel approach to cancer immunotherapy. However, small-molecule STING agonists face challenges such as poor tumor accumulation, rapid clearance, and short-lived effects within the tumor microenvironment, thus limiting their therapeutic potential. To address the challenges of poor specificity and inadequate targeting of STING in breast cancer treatment, herein, we report the design and development of a targeted liposomal delivery system modified with the tumor-targeting peptide iRGD (iRGD-STING-PFP@liposomes). With LIFU irradiation, the liposomal system exploits acoustic cavitation, where gas nuclei form and collapse within the hydrophobic region of the liposome lipid bilayer (transient pore formation), which leads to significantly enhanced drug release. Methods: Transmission electron microscopy (TEM) was used to investigate the physicochemical properties of the targeted liposomes. Encapsulation efficiency and in vitro release were assessed using the dialysis bag method, while the effects of iRGD on liposome targeting were evaluated through laser confocal microscopy. The CCK-8 assay was used to investigate the toxicity and cell growth effects of this system on 4T1 breast cancer cells and HUVEC vascular endothelial cells. A subcutaneous breast cancer tumor model was established to evaluate the tumor-killing effects and therapeutic mechanism of the newly developed liposomes. Results: The liposome carrier exhibited a regular morphology, with a particle size of 232.16 ± 19.82 nm, as indicated by dynamic light scattering (DLS), and demonstrated low toxicity to both HUVEC and 4T1 cells. With an encapsulation efficiency of 41.82 ± 5.67%, the carrier exhibited a slow release pattern in vitro after STING loading. Targeting results indicated that iRGD modification enhanced the system’s ability to target 4T1 cells. The iRGD-STING-PFP@liposomes group demonstrated significant tumor growth inhibition in the subcutaneous breast cancer mouse model with effective activation of the immune system, resulting in the highest populations of matured dendritic cells (71.2 ± 5.4%), increased presentation of tumor-related antigens, promoted CD8+ T cell infiltration at the tumor site, and enhanced NK cell activity. Conclusions: The iRGD-STING-PFP@liposomes targeted drug delivery system effectively targets breast cancer cells, providing a new strategy for breast cancer immunotherapy. These findings indicate that iRGD-STING-PFP@liposomes could successfully deliver STING agonists to tumor tissue, trigger the innate immune response, and may serve as a potential platform for targeted immunotherapy.
... Нанолипосомы представляют собой сферические везикулы, состоящие из фосфолипидных бислоёв, в которых могут быть инкапсулированы как гидрофильные, так и липофильные соединения, что определяет универсальность данной системы доставки лекарственных веществ [54,[61][62][63][64]. По сравнению с другими системами доставки, нанолипосомы имеют свои преимущества, а именно они гипоаллергенны, более биосовместимы и биоразлагаемы, менее иммуногенны и токсичны [47,54,55]. ...
... Нанолипосомы представляют собой сферические везикулы, состоящие из фосфолипидных бислоёв, в которых могут быть инкапсулированы как гидрофильные, так и липофильные соединения, что определяет универсальность данной системы доставки лекарственных веществ [54,[61][62][63][64]. По сравнению с другими системами доставки, нанолипосомы имеют свои преимущества, а именно они гипоаллергенны, более биосовместимы и биоразлагаемы, менее иммуногенны и токсичны [47,54,55]. В зависимости от размера частиц и числа образующих липидных слоёв липосомальные системы подразделяются на малые моноламеллярные с размером частиц до 50 нм и образованные одиночным липидным бислоем, крупные моноламеллярные с размером от 50 до 200 нм и многослойные или мультиламеллярные с размером до 1×10 4 нм и насчитывающие до нескольких десятков слоёв [54,55,62]. С технологической точки зрения наиболее предпочтительны липосомы с меньшим размером частиц, для которых характерны стабильный поверхностный электрический заряд и более высокая эффективность инкапсуляции [54,63]. ...
... Твёрдые липидные наночастицы, также известные как наноструктурированные липидные носители, представляют собой суспензии наноразмерных твёрдых липидных частиц, диспергированных в водной среде. Твёрдые липидные наночастицы в основном получают из жирных кислот (например, пальмитиновая кислота), триглицеридов (например, трилаурин), стероидов (например, холестерин) и глицеридов (например, глицерилмоностерат) [62]. С технологической точки зрения твёрдые липидные наночастицы очень похожи на эмульсии, но они получены с использованием липида, который при комнатной температуре становится твёрдым с образованием липидной фазы, в результате чего образуются твёрдые дисперсные частицы. ...
The most important direction of modern pharmacology is the study of systems used for controlled and targeted delivery of medications, which is carried out by creating nanoencapsulated forms of different nature and chemical structure. Nanoencapsulation is a promising method for creating innovative dosage forms with prolonged action, which allows expanding the range of medications, as well as changing approaches to various diseases that require long-term therapy. This review provides information highlighting the most promising classes of nanosized drug carriers, describes the processes of their use based on lipids, polymers, and biodegradable mineral substances, as well as provides examples of their use in modern pharmaceutical practice.
... Various potent drugs have been incorporated into liposomes with remarkable clinical success [8,10]. Some FDA-approved liposome formulations include Ambisome (amphotericin B), Dioxil (doxorubicin), and Marquibo (vincristine), thereby emphasizing the advantages of using liposomes as drug delivery systems [11]. ...
... Several studies have described the specific properties and applications of drug-loaded liposomes by controlling and modifying process parameters, methods of formulation, varying drug, and lipid contents, changing the volume of the aqueous phase during formulation, and modifying liposome surface for active or passive drug loading mechanisms [11,16]. A general illustration showing liposome formation and structure capabilities can be seen in Figure 2 [17]. ...
Drug delivery through Liposomes has shown tremendous potential in terms of the therapeutic application of nanoparticles. There are several drug-loaded liposomal formulations approved for clinical use that help mitigate harmful effects of life-threatening diseases. Developments in the field of liposomal formulations and drug delivery have made it possible for clinicians and researchers to find therapeutic solutions for complicated medical conditions. A key aspect in the development of drug-loaded liposomes is a careful review of optimization techniques to improve the overall formulation stability and efficacy. Optimization studies help in improving/modulating the various properties of drug-loaded liposomes and are vital for the development of this class of delivery systems. A comprehensive overview of the various process variables and factors involved in the optimization of drug-loaded liposomes is presented in this review. The influence of different independent variables on drug release and loading properties with the application of a statistical experimental design is also explained in this article.
... Compared to other NDDSs, studies on liposomes are relatively well established. Due to their excellent biocompatibility, high safety profile, and noteworthy therapeutic efficacy, numerous liposome formulations have received FDA-approval, signifying the progression from laboratory investigation to clinical application [167,168]. Undoubtedly, the successful translation of liposomes from the laboratory to the clinic has garnered considerable attention from researchers across diverse fields, fostering further in-depth investigations macrocyclic magnetic resonance imaging (MRI) contrast agent in early clinical development program. To sum up, the integration of inorganic nanoparticles into ischemic treatment approaches holds great potential for enhancing therapeutic outcomes through the modulation of cellular processes and microenvironmental factors. ...
... Compared to other NDDSs, studies on liposomes are relatively well established. Due to their excellent biocompatibility, high safety profile, and noteworthy therapeutic efficacy, numerous liposome formulations have received FDA-approval, signifying the progression from laboratory investigation to clinical application [167,168]. Undoubtedly, the successful translation of liposomes from the laboratory to the clinic has garnered considerable attention from researchers across diverse fields, fostering further in-depth investigations into liposomes [169,170]. ...
In recent years, the frequency of strokes has been on the rise year by year and has become the second leading cause of death around the world, which is characterized by a high mortality rate, high recurrence rate, and high disability rate. Ischemic strokes account for a large percentage of strokes. A reperfusion injury in ischemic strokes is a complex cascade of oxidative stress, neuroinflammation, immune infiltration, and mitochondrial damage. Conventional treatments are ineffective, and the presence of the blood–brain barrier (BBB) leads to inefficient drug delivery utilization, so researchers are turning their attention to nano-drug delivery systems. Functionalized nano-drug delivery systems have been widely studied and applied to the study of cerebral ischemic diseases due to their favorable biocompatibility, high efficiency, strong specificity, and specific targeting ability. In this paper, we briefly describe the pathological process of reperfusion injuries in strokes and focus on the therapeutic research progress of nano-drug delivery systems in ischemic strokes, aiming to provide certain references to understand the progress of research on nano-drug delivery systems (NDDSs).
... These advancements in nanotechnology hold great promise for improving the treatment and management of HIV/AIDS [24][25][26][27]. Major nanocarriers used in antiretroviral therapy [28] Liposomes, novel DDS, encapsulate drugs within lipid bilayers and have garnered attention for their drug entrapment and transport capabilities [29,30]. Coating liposomal surfaces with hydrophilic polymers such as PEG enhances bioavailability and ensures efficient drug delivery. ...
Antiretroviral Therapy (ART) has revolutionized Human Immunodeficiency Virus (HIV) treatment, yet challenges remain, such as drug toxicity, resistance, and inadequate access to infected tissues. Novel drug delivery systems, such as liposomes and receptor-targeted mechanisms, offer promising solutions to improve ART efficacy and minimize its limitations.
This study aims to evaluate the potential of liposomal and receptor-targeted drug delivery systems (DDS) for enhancing the bioavailability, selectivity, and therapeutic outcomes of ART, with a focus on targeting HIV-infected cells and reducing drug resistance.
A systematic review of published articles was conducted, drawing from electronic databases such as PubMed, Scopus, and Web of Science. Keywords such as “liposomes,” “receptor-targeted drug delivery,” and “HIV” were used to identify preclinical and clinical studies relevant to ART. The studies were evaluated for their design, intervention specifics, and key findings. Data were synthesized narratively to highlight the efficacy, safety, and pharmacokinetics of these drug delivery systems.
Liposomal formulations significantly improved drug bioavailability, with zidovudine (AZT) showing an 85% increase, lamivudine (3TC) 90%, efavirenz (EFV) 80%, and indinavir (IDV) 75%. Galactosylated liposomes were highly effective in targeting infected cells (92%) and showed strong potential in preventing drug-resistant strains (85%). Receptor-targeted approaches, such as those targeting Cluster of Differentiation 4 cells (CD4), Chemokine Receptor Type 5 (CCR5), and Chemokine Receptor Type 4 (CXCR4), enhance the precision of drug delivery and reduce the viral load in HIV reservoirs.
Liposomal and receptor-targeted DDS offer significant potential for improving ART efficacy by increasing drug bioavailability, reducing toxicity, and preventing drug resistance. Further research is needed to optimize these technologies and translate their preclinical success into clinical practice, paving the way for more effective HIV therapies.
... Optimizing these factors can lead to tailored release profiles suitable for various biomedical applications. The optimal vesicle size depends on the specific application and desired release kinetics for curcumin 31 . ...
Due to their small size, flexibility, and adhesive properties, extracellular vesicles (EVs) hold promises as effective drug delivery systems. However, challenges such as the variability in vesicle types and the need to maintain their integrity for medical applications exist. Curcumin, a compound found in turmeric and known for its diverse health benefits, including anti-cancer and anti-inflammatory properties, faces obstacles in clinical use due to issues like low solubility, limited absorption, and rapid breakdown in the body. This study aimed to incorporate large-sized curcumin-loaded extracellular vesicles (lEVs) into fast-dissolving nanofibers made of poly(vinyl alcohol) (PVA) by electrospinning. By using aqueous PVA-based solutions for electrospinning, the presence of curcumin-loaded lEVs in the nanofibers was confirmed by confocal laser scanning microscopy. Furthermore, the release study demonstrated high concentrations of the drug in nanofibers containing lEVs. These findings are significant for advancing the development and utilization of active ingredient-loaded EV systems within nanofibrous formulations, potentially leading to improved patient outcomes.
... This technology also enables scientists to elucidate drug resistance mechanisms, optimize drug combinations, and enhance therapeutic efficacy, thereby expediting the development of new drugs [7][8][9]. In the field of nanotechnology, nano-carriers such as nanoparticles, nano-emulsions, liposomes, and micelles significantly enhance the stability and solubility of drug molecules, thereby improving their bioavailability and playing a crucial role in drug discovery [10][11][12]. ...
Historically, drug discovery and development have proven to be time-consuming and costly, with the process averaging around 15 years and costing approximately USD 2 billion to bring a new small-molecule drug to market [...]
... Many nano-carriers, including emulsions, liposomes, and nanoparticles, have been used to deliver oral drugs. The majority of nano-carriers have shown benefits in protecting drugs from harsh environments in the gastrointestinal tract, increasing the GIT's absorption into the bloodstream, concentrating on certain sites, and guaranteeing controlled release [60][61][62][63][64]. ...
The field of nano-drug delivery systems (NDDS) has gotten a lot of attention due to its potential to enhance the effectiveness of therapy and bioavailability of natural products. This review looks at the inclusion of natural products into nano-drug delivery platforms, with an emphasis on nanocarriers including liposomes, nanoparticles, and dendrimers, which have been utilised for bettering drug solubility, stability, and targeted delivery. Natural chemicals, while recognised for their pharmacological properties, frequently face challenges such as poor solubility and bioavailability, limiting their therapeutic utility. These limitations can be overcome by NDDS, resulting in improved therapeutic benefits. The article also explains how nano-drug delivery systems improve natural product bioavailability by using mechanisms such as enhanced permeation and retention (EPR), extended-release, and targeted delivery. Furthermore, it examines current advancements, challenges, and future possibilities in the field, providing a comprehensive understanding of how NDDS can alter the use of natural commodities in medicine.
... Researchers developed several types of lipid carriers, such as liposomes [6], transferosomes [7], ethosomes [8], invasomes [9], novasomes [10], and cubosomes [11], which marked a breakthrough in transdermal drug delivery. Liposomes, however, deposit in the stratum corneum, so their effectiveness in transdermal delivery is limited [12]. To overcome this drawback, surfactants replaced cholesterol in transferosomes, resulting in an ultra-deformable and highly flexible structure [13]. ...
Background: Nimodipine is a vasodilator that is used for the prevention of cerebral vasospasm after subarachnoid hemorrhage. The oral and intravenous administration of the drug is associated with undesirable side effects. So, transdermal delivery using lipid-based nanovesicles, also known as transferosomes, can be thought of as an alternative. Objective: To optimize the formulation of transferosomes using the statistical design of experiments, with the aim of obtaining the most suitable transferosomes for the transdermal delivery of nimodipine. Methods: In the Box-Behenken statistical design, the independent variables were the quantities of nimodipine, phospholipon 90%, and sodium deoxycholate, while the dependent variables were the vesicle size, entrapment efficiency for nimodipine and its flux through the rat's skin. The optimized formulation was characterized through transmission electron microscopy and the deformability index. Results: The optimized formulation of transferosomes suggested by the software consisted of 30 mg nimodipine, 150 mg phospholipon 90% and 15 mg sodium deoxycholate. The resulted values were 248 nm for vesicles size, 81% for entrapment, and 476 μg/cm 2 /h. Under transmission electron microscopy, transferosomes appeared as vesicles, with a 0.98 deformability index for the optimized formula. Conclusions: Nimodipine can be formulated as transferosomes and efficiently applied for transdermal delivery.
... Liposomes were chosen because they have been extensively utilized for their safety and adaptability in delivering both water-soluble and lipid-soluble drugs. Drug delivery via liposomes protects encapsulated drugs by shielding them from catabolic processes, preventing interaction with metabolizing enzymes while in the bloodstream 16,17 Liposomes composed of sphingomyelin/cholesterol (1:1, M/M) and loaded with Pimasertib or PROPIMA were prepared by ethanol-injection technique. 18 Their characterization ( Figure 8A) showed a narrow particle size distribution (PDI < 0.2) with a <200 nm diameter, and an optimal size for passive targeting of liposomes in the tumour through the fenestrations of the endothelium while avoiding excessive phagocytosis by the reticuloendothelial system. ...
Pimasertib, a potent antiproliferative drug, has been extensively studied for the treatment of cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would...
... streamline the approval process. [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] ...
Liposome-based nanoparticles have become a cornerstone in modern drug delivery, offering significant advantages in the encapsulation and targeted delivery of therapeutic agents. These spherical vesicles, composed of lipid bilayers, enhance the bioavailability and reduce the toxicity of drugs, particularly in the treatment of cancer and infectious diseases. This review provides a comprehensive overview of the design, formulation, and clinical applications of liposome-based nanoparticle systems. It discusses the advantages of these systems, the challenges in their development, and recent innovations such as stealth liposomes, stimuli-responsive liposomes, and hybrid liposomes. Furthermore, the review highlights the potential of these nanoparticles in overcoming the limitations of traditional drug delivery methods, particularly in oncology.
... Researchers developed several types of lipid carriers, such as liposomes [6], transferosomes [7], ethosomes [8], invasomes [9], novasomes [10], and cubosomes [11], which marked a breakthrough in transdermal drug delivery. Liposomes, however, deposit in the stratum corneum, so their effectiveness in transdermal delivery is limited [12]. To overcome this drawback, surfactants replaced cholesterol in transferosomes, resulting in an ultra-deformable and highly flexible structure [13]. ...
Background: Nimodipine is a vasodilator that is used for the prevention of cerebral vasospasm after subarachnoid hemorrhage. The oral and intravenous administration of the drug is associated with undesirable side effects. So, transdermal delivery using lipid-based nanovesicles, also known as transferosomes, can be thought of as an alternative. Objective: To optimize the formulation of transferosomes using the statistical design of experiments, with the aim of obtaining the most suitable transferosomes for the transdermal delivery of nimodipine. Methods: In the Box-Behenken statistical design, the independent variables were the quantities of nimodipine, phospholipon 90%, and sodium deoxycholate, while the dependent variables were the vesicle size, entrapment efficiency for nimodipine and its flux through the rat's skin. The optimized formulation was characterized through transmission electron microscopy and the deformability index. Results: The optimized formulation of transferosomes suggested by the software consisted of 30 mg nimodipine, 150 mg phospholipon 90% and 15 mg sodium deoxycholate. The resulted values were 248 nm for vesicles size, 81% for entrapment, and 476 μg/cm2/h. Under transmission electron microscopy, transferosomes appeared as vesicles, with a 0.98 deformability index for the optimized formula. Conclusions: Nimodipine can be formulated as transferosomes and efficiently applied for transdermal delivery.
... The liposomal drug delivery system was the first-ever approved nanoscale pharmaceutical product for clinical use in 1995 [36]. Liposomes are micelle structures made up of phospholipid bilayers with hydrophilic heads exposed to outer and inner surfaces and hydrophobic tails tucked inside the shell. ...
Improving the apparent solubility of poorly soluble therapeutic molecules with poor absorption into the circulatory system is a significant research question in drug discovery. This enhancement is achieved by delivering drugs through nano-carriers that provide apparent solubility with its surfactant. The effectiveness of a nano-carrier is relied majorly on its loading efficiency which is determined by the extent of interaction between the drug and the surfactants of the carriers. The loading effectiveness can be reckoned with a better understanding of the drug-surfactant conjugation mechanism. Hence this review comprehends the different nano-carriers, their appropriate surfactant systems, and the loading mechanism of drugs with surfactants through different bonds. Further, the current status and prospects of the nano-carriers are briefly summarized at last to expound on the significance of these nano-carriers in drug delivery.
... Thus, liposomal drug delivery systems had significant advantages relative to free drugs by reducing the side effects and their passive accumulation at the sites of increased vasculature permeability. [34,46] Compared to unentrapped drugs, liposomal drugs have reduced extravasation into tissues with stretched endothelial junctions and significantly reduced side effects. With all these advantages, liposomal drug delivery has evolved as a conventional technology platform and has gained considerable clinical acceptance. ...
Objectives: Several innovations are being developed and marketed in the drug delivery systems for treating various disorders. Novel drug delivery techniques, such as bioengineered liposomes, nanoparticles, and exosomes, can selectively target the placenta or fetus. This allows for the administration of 'fetal-friendly' drugs during pregnancy with minimal risk of off-target effects. Due to their unique size and drug-encapsulating properties, they will be prominent in treating pregnancy-related disorders. This review's objective was to summarize currently developed innovative and alternative drug delivery systems for pregnancy-related disorders, along with their advantages and clinical relevance. Methods: This process used a defined search strategy of indexed publications from databases like Google Scholar, PubMed, Embase, Medline, Scopus, and UTMB library from 2000 to 2020 and included methods to assess the quality of the evidence retrieved. Results: Pregnancy is a unique physiological condition where some of the drugs will be lifesaving to the mother, but they can be toxic to fetal tissue. It is mandatory to research on the novel drug delivery systems. Although there was a substantial quantity of research has been carried out on maternal-placental-fetal drug uptake, transfer, and toxicity, therapeutic evaluations of innovative and alternative drug delivery systems in pregnancy remain in their infancy. Conclusions: In this review, we highlighted the physiological considerations of the placenta and summarized recent research work on alternative drug delivery systems used in pregnancy and their potential applications in clinical reality.
... This is followed by the "ETH effect", during which the phospholipids within the SC fuse with ETH vesicles, enhancing drug delivery. 161,162 In previous investigations, 30% alcohol plasmids loaded with tacrolimus (TAC) exhibited significantly heightened permeability in the epidermis and superior epidermal accumulation compared to traditional formulations. 163 In recent research, hyaluronic acid-based tacrolimus ETH (HA-TAC-ETH) demonstrated nanometric vesicle sizes (315.7 ± 2.2 nm), a polydispersity index (PDI) of 0.472 ± 0.07, and high entrapment efficiency (88.3 ± 2.52%). ...
Psoriasis is an immune-mediated inflammatory skin disease where topical therapy is crucial. While various dosage forms have enhanced the efficacy of current treatments, their limited permeability and lack of targeted delivery to the dermis and epidermis remain challenges. We reviewed the evolution of topical therapies for psoriasis and conducted a bibliometric analysis from 1993 to 2023 using a predictive linear regression model. This included a comprehensive statistical and visual evaluation of each model’s validity, literature profiles, citation patterns, and collaborations, assessing R variance and mean squared error (MSE). Furthermore, we detailed the structural features and penetration pathways of emerging drug delivery systems for topical treatment, such as lipid-based, polymer-based, metallic nanocarriers, and nanocrystals, highlighting their advantages. This systematic overview indicates that future research should focus on developing novel drug delivery systems characterized by enhanced stability, biocompatibility, and drug-carrying capacity.
... Liposomes are lipid-based spherical vesicles with a lipophilic bilayer surrounded by two hydrophilic layers [ 86 ], which comprise several components, such as lipids, sterols, polysaccharides, and surfactants. As they can accumulate at an in ammatory site, they are used to effectively treat IBD with reduced toxicity [ 87 ]. Determining the liposome type is crucial for selecting the synthesis method. ...
Inflammatory bowel diseases (IBD) significantly contribute to high mortality globally and negatively affect patients' qualifications of life. The gastrointestinal tract has unique anatomical characteristics and physiological environment limitations. Moreover, certain natural or synthetic anti-inflammatory drugs are associated with poor targeting, low drug accumulation at the lesion site, and other side effects, hindering them from exerting their therapeutic effects. Colon-targeted drug delivery systems represent attractive alternatives as novel carriers for IBD treatment. This review mainly discusses the treatment status of IBD, obstacles to drug delivery, design strategies of colon-targeted delivery systems, and perspectives on the existing complementary therapies. Moreover, based on recent reports, we summarized the therapeutic mechanism of colon-targeted drug delivery. Finally, we addressed the challenges and future directions to facilitate the exploitation of advanced nanomedicine for IBD therapy.
... Liposomes are an established drug delivery platform [1][2][3][4][5][6]. However, once injected into the blood circulation, their performance is affected by the layer of plasma proteins named protein or biomolecular corona, which quickly forms on the surface of all nanoparticles [7,8]. ...
Background
Plasma protein binding is inevitable for nanomaterials injected into blood circulation. For liposomes, this process is affected by the lipid composition of the bilayer. Membrane constituents and their ratio define liposome characteristics, namely, surface charge and hydrophobicity, which drive protein adsorption. Roughly 30 years ago, the correlation between the amount of bound proteins and the resulting circulation time of liposomes was established by S. Semple, A. Chonn, and P. Cullis. Here, we have estimated ex vivo plasma protein binding, primarily to determine the impact of melphalan prodrug inclusion into bilayer on bare, PEGylated (stealth), and Sialyl Lewis X (SiaLeX)-decorated liposomes.
Experimental
Liposomes were allowed to bind plasma proteins for 15 minutes, then liposome-protein complexes were isolated, and protein and lipid quantities were assessed in the complexes. In addition, the uptake by activated HUVEC cells was evaluated for SiaLeX-decorated liposomes.
Results:
Melphalan moieties on the bilayer surface enrich protein adsorption compared to pure phosphatidylcholine sample. Although PEG-lipid had facilitated a significant decrease in protein adsorption in the control sample, when prodrug was added to the composition, the degree of pro-tein binding was restored to the level of melphalan liposomes without a stealth barrier. A similar effect was observed for SiaLeX-decorated liposomes.
Conclusion
None of the compositions reported here should suffer from quick elimination from circulation, according to the cut-off values introduced by Cullis and colleagues. Nevertheless, the amount of bound proteins is sufficient to affect biodistribution, namely, to impair receptor recog-nition of SiaLeX and reduce liposome uptake by endothelial cells.
... Table 1lists the liposome formulations that are commercially available[24,25] Table 1. Marketed Formulation of Liposomes. ...
The first nanomedicine to be approved for use in clinical settings was liposomes. These are the spherical vesicles with a bilayer of phospholipids enclosing a middle empty aqueous region. Because of their extraordinary potential to stop medication deterioration and lessen unwanted effects, liposomes are being utilized more and more for targeted drug distribution. For targeted drug delivery, the pharmaceuticals can be integrated into the liposomes' aqueous space or phospholipid bilayer. In order to target a medication or substance to the active site at a predetermined rate and time range without impacting other body parts in the process, liposomes are available in a range of sizes to treat different sorts of diseases. Vesicular systems, as they are often called, are colloidal spheres composed of cholesterol, sphingolipids, glycolipids, long-chain unsaturated fats, layer proteins, and active atoms. They are also constituted of non-poisonous surfactants. Liposomes are one of the most often utilized methods in biological, pharmaceutical, medical, and nutritional research for the encapsulation and transport of a wide range of different compounds, including bioactive substances., benefits and drawbacks, as well as different approaches to preparation, assessment etc. This paper examines the liposomal vesicles' classification, manufacturing and encapsulating techniques, and uses in the food, cosmetics, and pharmaceutical industries. Furthermore, this section presents the primary analytical techniques utilized to investigate the properties of liposomes, including their size, stability, fluidity, lamellarity, surface charge, and encapsulation efficiency.
... Table 1lists the liposome formulations that are commercially available[24,25] Table 1. Marketed Formulation of Liposomes. ...
The first nanomedicine to be approved for use in clinical settings was liposomes. These are the spherical vesicles with a bilayer of phospholipids enclosing a middle empty aqueous region. Because of their extraordinary potential to stop medication deterioration and lessen unwanted effects, liposomes are being utilized more and more for targeted drug distribution. For targeted drug delivery, the pharmaceuticals can be integrated into the liposomes' aqueous space or phospholipid bilayer. In order to target a medication or substance to the active site at a predetermined rate and time range without impacting other body parts in the process, liposomes are available in a range of sizes to treat different sorts of diseases. Vesicular systems, as they are often called, are colloidal spheres composed of cholesterol, sphingolipids, glycolipids, long-chain unsaturated fats, layer proteins, and active atoms. They are also constituted of non-poisonous surfactants. Liposomes are one of the most often utilized methods in biological, pharmaceutical, medical, and nutritional research for the encapsulation and transport of a wide range of different compounds, including bioactive substances., benefits and drawbacks, as well as different approaches to preparation, assessment etc. This paper examines the liposomal vesicles' classification, manufacturing and encapsulating techniques, and uses in the food, cosmetics, and pharmaceutical industries. Furthermore, this section presents the primary analytical techniques utilized to investigate the properties of liposomes, including their size, stability, fluidity, lamellarity, surface charge, and encapsulation efficiency.
... In addition to storage instabilities, targeted liposome manufacturers also face the challenge of very limited guidance from the FDA. The rate of the lab-scale development of targeted liposomes has drastically outpaced the FDA's reaction time to the new technology [159]. While there is some guidance provided for liposomal products in general [160], these documents do not adequately cover the novel targeting strategies discussed in this review. ...
In drug development, it is not uncommon that an active substance exhibits efficacy in vitro but lacks the ability to specifically reach its target in vivo. As a result, targeted drug delivery has become a primary focus in the pharmaceutical sciences. Since the approval of Doxil® in 1995, liposomes have emerged as a leading nanoparticle in targeted drug delivery. Their low immunogenicity, high versatility, and well-documented efficacy have led to their clinical use against a wide variety of diseases. That being said, every disease is accompanied by a unique set of physiological conditions, and each liposomal product must be formulated with this consideration. There are a multitude of different targeting techniques for liposomes that can be employed depending on the application. Passive techniques such as PEGylation or the enhanced permeation and retention effect can improve general pharmacokinetics, while active techniques such as conjugating targeting molecules to the liposome surface may bring even further specificity. This review aims to summarize the current strategies for targeted liposomes in the treatment of diseases.
... Clinical trials have shown the effectiveness of liposome based vaccines, and additional human trials are currently underway. Hepatitis A virus that has been rendered inactive and is anchored to a phospholipid bilayer can be discovered in Epaxal, a liposomal based hepatitis A vaccine [92,93]. In healthy human volunteers, the liposome based malaria vaccine has been shown to increase levels of anti malarial antibody [94]. ...
Liposomes have been the delivery of choice for the cancer targeting therapy for the last few decades. Since the 1990s, the development of sterically stabilized (stealth) liposomes has garnered interest for their long circulating half-life. PEGylated (Polyethylene Glycol) liposomes are most extensively studied for delivering cancer therapeutics in a sustained manner. Stealth liposomes are having a less intrinsic toxicity with higher efficacy in cancer treatment. There are numerous clinical trials on the liposomes in tackling cancer is evident for the better outcome of the delivery system. Stealth liposomes are extensively studied for their improved circulation time and better pharmacokinetic profile in cancer treatment. The steric hindrance of the stealth liposomes bypasses the reticuloendothelial system clearance. Further the ligands conjugation in the surface of the liposomes able to achieve better target to the cancer cells. The vascularization nature of the cancerous cells is readily making the liposomal delivery of the cancer drugs accumulate in the cancerous cells rather than healthy cells. There is an utmost need to understand the possible mechanism of stealth liposomes and the basic science behind the development of liposomal delivery system in advancing the cancer treatment with less toxicity. The present review addresses the various modalities of the liposomal development, liposome characterization, mechanism of PEGylated liposomes, the advancements and results of the liposomes in the treatment of various diseases, and the clinical trials and regulatory considerations of liposomal drug delivery system.
... The Stealth effect enables the nanosytem to pass through the blood vessels with less immunogenic reaction and less uptake by macrophages of RES. This results in a longer circulating time and better kinetic Table 1. 2 Some of the FDA-approved liposome-based pharmaceutical products available in the market [28]. ...
The science and technology has emerged in pharmaceutical research with focus on developing novel drug delivery systems for oral administration. Conventional dosage forms like tablets and capsules are associated with a low bioavailability, frequent application, side effects and hence patient noncompliance. By developing novel strategies for drug delivery, researchers embraced an alternative to traditional drug delivery systems. Out of those, fast dissolving drug delivery systems are very eminent among pediatrics and geriatrics. Orally disintegrating films are superior over fast dissolving tablets as the latter are assigned with the risk of suffocation. Due to their ability of bypassing the dissolution and the first pass effect after oral administration, self-emulsifying formulations have also become increasingly popular in improving oral bioavailability of hydrophobic drugs. Osmotic devices enable a controlled drug delivery independent upon gastrointestinal conditions using osmosis as driving force. The advances in nanotechnology and the variety of possible materials and formulation factors enable a targeted delivery and triggered release. Vesicular systems can be easily modified as required and provide a controlled and sustained drug delivery to a specific site. Today's drug delivery technologies enable the embodiment of the drug into novel delivery devices and hence facilitate various therapeutic and commercial benefits. Ranging from fast dissolving to Nano particulate drug delivery systems, a variety of novel delivery systems have been developed and evaluated and numerous strategies for a controlled drug delivery to a specific target-site have been researched. However, there are several challenges remaining. One of the permanent features of drug delivery technologies, is the important part that polymers play in navigating the drug liberation as well as in manufacturing drug carriers. Progress, especially in the field of nanotechnology, is limited by the availability of suitable biocompatible polymers. An ongoing interest in new polymer synthesis has occurred due to the demand for polymers with aimed physical and biological features. For this reason, a wide array of biodegradable polymers form natural or synthetic origin has been studied for their ability of an extended drug liberation and targeted drug delivery. So far, only a small number of them are found to be biocompatible. From the manufacturing perspective, conventional methods have the merit of easy scale-up but are likely to lose conciseness in monitoring over particle characteristics. Although top-down techniques would allow to regulate size and shape, they are only applicable to a few drug delivery systems. Several other approaches have been made including in the treatment of diabetes mellitus to address the limitations with the administration of insulin. By using the glucose modulation, the insulin delivery rates can be regulated enabling a self-regulated drug delivery. The major challenge is to develop a delivery system that exhibits the natural pattern of insulin release in vivo. Critically concluded, the need for new materials for their quality of being biodegradable, biocompatible and low toxicity will be met in future and in combination with novel fabrication techniques will provide significant advantages in drug delivery.
... These cell lines comprised A549, a lung carcinoma line; HEK293, a human embryonic kidney line; and DC 2.4, which is a dendritic cell line. Our rationale for selecting the A549 line was based on its epithelial origin, closely resembling the pulmonary epithelium, and, hence, it provided an excellent model for studying respiratory pathogens' interactions within the nasal epithelium [31,32]. The incorporation of the HEK293 line in our assay portfolio was two-fold: first, it was selected as a representative of healthy human tissues to assess the vaccine's general cytotoxicity; second, due to its transfectability, it allows for the high-efficiency expression of recombinant genes, which could be instrumental in understanding a potential response to vaccination [32,33]. ...
Chitosan, a natural polysaccharide derived from chitin, possesses biocompatibility, biodegradability, and mucoadhesive characteristics, making it an attractive material for the delivery of mRNA payloads to the nasal mucosa and promoting their uptake by target cells such as epithelial and immune cells (e.g., dendritic cells and macrophages). In this project, we aimed at developing novel lipid-based nanoformulations for mRNA delivery to counteract the pandemic caused by SARS-CoV-2 virus. The formulations achieved a mRNA encapsulation efficiency of ~80.2% with chitosan-lipid nanoparticles, as measured by the RiboGreen assay. Furthermore, the evaluation of SARS-CoV-2 Spike (S) receptor-binding domain (RBD) expression via ELISA for our vaccine formulations showed transfection levels in human embryonic kidney cells (HEK 293), lung carcinoma cells (A549), and dendritic cells (DC 2.4) equal to 9.9 ± 0.1 ng/mL (174.7 ± 1.1 fold change from untreated cells (UT)), 7.0 ± 0.2 ng/mL (128.1 ± 4.9 fold change from UT), and 0.9 ± 0.0 ng/mL (18.0 ± 0.1 fold change from UT), respectively. Our most promising vaccine formulation was also demonstrated to be amenable to lyophilization with minimal degradation of loaded mRNA, paving the way towards a more accessible and stable vaccine. Preliminary in vivo studies in mice were performed to assess the systemic and local immune responses. Nasal bronchoalveolar lavage fluid (BALF) wash showed that utilizing the optimized formulation resulted in local antibody concentrations and did not trigger any systemic antibody response. However, if further improved and developed, it could potentially contribute to the management of COVID-19 through nasopharyngeal immunization strategies.
... Lipid-based nanoparticles offer remarkable benefits in formulating, targeting, and preserving small molecules. These nanoparticles possess self-emulsifying properties that allow for the encapsulation of both hydrophilic and hydrophobic drugs, thereby improving the solubility of poorly water-soluble drugs and enhancing bioavailability [3]. Furthermore, lipid-based nanoparticles can be customized to specific molecules based on their physicochemical characteristics [4]. ...
Lipid-based nanoparticles hold great potential for drug delivery, providing biocompatibility and the ability to encapsulate both hydrophilic and hydrophobic drugs. However, there are certain challenges associated with small molecules, such as leakage and premature release, which can compromise their effectiveness. Despite these challenges, lipid nanoparticles offer advantages in terms of solubility, stability, and targeted delivery, thereby reducing side effects. Additionally, they can be customized for specific molecules, ensuring biocompatibility and biodegradability. While complications may arise, lipid nanoparticles offer numerous benefits for loading biomolecules, improving pharmacokinetics, and enhancing therapeutic effects. It is important to address stability and loading challenges when encapsulating biomolecules and consider potential immunogenic responses that may impact biocompatibility and safety.
... Liposomal drugs encapsulating low molecular weight compounds are recognized as beneficial pharmaceuticals that improve solubility, circulating half-life, and drug delivery efficiency to the target site [1][2][3][4][5]. In cancer treatment, the accumulation of liposomes in tumor tissues, known as enhanced permeabilization and retention (EPR), is facilitated by leaky tumor blood vessels and impaired lymphatic drainage. ...
Purpose
Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen.
Methods
We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration–time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model.
Results
FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage.
Conclusions
Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens.
... Liposomes are mainly consisted of phospholipids and cholesterol; thus, among the various nanoparticle types, they are usually preferred as drug carriers because they are structurally versatile, highly biocompatible, and non-toxic [30,31]. Liposome pegylation, which refers to the coating of the vesicle surface with polyethylene glycol molecules, can efficiently reduce the rapid clearance of liposomes by macrophages and prolong their circulation time in the blood [32,33]. Thus, the synthesis of cross-linked nanoliposomes, by the reaction of type 4 molecules with nanoliposomes bearing maleimide groups on their surface, was considered to be a method to synthesize novel and stable liposome scaffolds for sustained release of drugs. ...
With the aim to develop novel scaffolds for the sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably S-4-methoxytrityl (Mmt)-protected mercapto acids, followed by the removal of the acid labile S-Mmt group. This method allowed for the efficient synthesis of the title compounds in high yield and purity, which were further used in the development of a thioether cross-linked liposome scaffold, by thia–Michael reaction of the terminal thiol groups with pre-formed nano-sized liposomes bearing maleimide groups on their surface. The reaction process was followed by 1H-NMR, using a Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion NMR experiment (1H-NMR CPMG), which allowed for real-time monitoring and optimization of the reaction process. The thioether cross-linked liposomal scaffold that was synthesized was proven to preserve the nano-sized characteristics of the initial liposomes and allowed for the sustained release of calcein (which was used as a hydrophilic dye and a hydrophilic drug model), providing evidence for the efficient synthesis of a novel drug release scaffold consisting of nanoliposome building blocks.
Objectives
Glaucoma is a leading cause of permanent blindness. Despite therapeutic advancements, glaucoma management remains challenging due to limitations of conventional drug delivery, primarily topical eye drops, resulting in suboptimal outcomes and a global surge in cases. To address these issues, liposomal drug delivery has emerged as a promising approach.
Key findings
This review explores the potential of liposomal-based medications, with a particular focus on topical administration as a superior alternative to enhance therapeutic efficacy and improve patient compliance compared to existing treatments. This writing delves into the therapeutic prospects of liposomal formulations across different administration routes, as evidenced by ongoing clinical trials. Additionally, critical aspects of liposomal production and market strategies are discussed herein.
Summary
By overcoming ocular barriers and optimizing drug delivery, liposomal topical administration holds the key to significantly improving glaucoma treatment outcomes.
Herbal medicines, integral to human history, remain vital in developing countries owing to the high costs of synthetic drugs, with 80% of the population relying on traditional practices. There has been an escalating focus within the scientific community on the exploration of phytoconstituents. This growing interest is due to the diverse benefits offered by herbal or plant- based ingredients. Despite the dominance of allopathic treatments, medicinal plants are still widely used but face challenges like poor absorption and low bioavailability. Many plant-derived pharmacologically active compounds, such as tannins, flavonoids, and terpenoids, show poor solubility in water. This low solubility, amalgamated with their inability to efficiently cross lipid-cell membranes due to their large molecular size, considerably hinders their absorption. These factors lead to declined efficacy and lower bioavailability of these compounds. Nanotechnology enhances the effectiveness of medicinal plants through strategies such as polymeric nanoparticles (NPs), solid lipid nanoparticles (SLNPs) and liposomes, improving solubility, protection and controlled release. These advances revolutionize drug delivery, surging the bioavailability and therapeutic value of herbal formulations. Nanomedicine employs NPs and nanorobots for enhanced bioavailability, solubility and targeted delivery, despite challenges like understanding working principles, potential toxicity and production scalability. Innovations in biopolymer-based systems, including chitosan and alginate NPs and advanced delivery systems like dendrimers and inorganic NPs, show significant potential. NPs have been effectively utilized to improve the pharmacokinetic and pharmacodynamic properties of various drugs. By integrating biotechnological systems and phytosomes, the bioavailability and bioactivity of herbal drug formulations can be significantly enhanced. The future of nanomedicine is promising, with ongoing research enhancing therapy precision and effectiveness and reducing adverse effects, making continued exploration in this field highly worthwhile.
Aim: The study explores glycerosomes as effective vesicular systems for transdermal delivery of atorvastatin (ATO) to overcome drawbacks related to its oral administration.Methodology: The objectives of this study were to formulate, by thin-film hydration method, optimize using definitive screening design and evaluate ATO-loaded glycerosomes (ATOG) which were then incorporated into patch followed by the evaluation of glycerosomes containing different concentration of glycerol.Results & discussion: Vesicle size, Polydispersity index (PDI), zeta potential, entrapment efficiency and loading capacity of spherical ATOG (0-30%w/w) showed 137.3-192d.nm, 0.292-0.403, -3.81 to-6.76mV, 80.03-92.77% and 5.80-6.40%, respectively. In-vitro release study showed sustained release, increased skin permeability and better cell viability than pure drug. ATOG patches showed greater skin permeability than pure drug and ATO-liposomal patches.Conclusion: The study concludes that ATOGs are promising for effective transdermal delivery.
The finding of new vesicular systems is a challenging process that depends on different factors such as the components used, the interactions between them or the dispersant media. Our objective was to develop a new vesicular delivery system formed by self-assembly of β-Sitosterol (Sit), Lauryl Glucoside (LGL) and Lauryl Glucose Carboxylate (LGC) molecules, all plant-based, biodegradable and biocompatible components. Nanovesicles (NVs) with different molar ratios of Sit, LGL and LGC were prepared using a single step method named DELOS, and characterized by dynamic light scattering, cryo-electron microscopy and small-angle X-ray scattering. Antioxidant compound α-tocopherol (TCP) was integrated in the NVs showing their potential to nanoformulate hydrophobic payloads. Finally, in vitro biocompatibility assays with reconstructed human epidermis and ex vivo skin retention studies using multiphoton microscopy and NVs labelled with Nile Red (NR) were carried out. As a result of this work, a new platform of NVs has been obtained by the self-assembly of Sit, LGL and LGC, obtaining vesicular systems with tunable physicochemical properties in terms of size (130 – 220 nm), surface charge ((-70) – (-40) mV) and lamellarity (unilamellar and multilamellar vesicles), when the carbon chain of the alkyl polyglucoside was >12. The vesicles could efficiently integrate TCP, proving their potential role as delivery systems and maintaining its antioxidant activity after loading. Finally, they also showed biocompatibility with the skin and improved the permeability of the poorly water-soluble molecule NR in terms of time and depth through the epidermis. Overall, the results of this work point to the successful development of an attractive platform based on stable and homogeneous nanovesicles composed of plant-derived ingredients for topical delivery.
Addressing infectious conditions presents a formidable challenge, primarily due to the escalating issue of bacterial resistance. This, coupled with limited financial resources and stagnant antibiotic research, compounds the antibiotic crisis. Innovative strategies, including novel antibiotic development and alternative solutions, are crucial to combat microbial resistance. Nanotherapeutics offers a promising approach to enhance drug delivery systems. Integration into lipid-based nanoscale delivery systems, particularly through therapeutic substance encapsulation in liposomal carriers, significantly prolongs drug presence at infection sites. This not only reduces toxicity but also shields antibiotics from degradation. Lipidic carriers, particularly liposomes, exhibit remarkable specificity in targeting infectious cells. This holds great promise in combating antimicrobial resistance and potentially transforming treatment for multi-drug resistant infections. Leveraging liposomal carriers may lead to breakthroughs in addressing drugresistant bacterial infections. This review emphasizes the potential of antimicrobial-loaded liposomes as a novel delivery system for bacterial infections. Encapsulating antimicrobial agents within liposomes enhances treatment efficiency. Moreover, liposomal systems counteract challenges posed by antimicrobial resistance, offering hope in managing persistent multidrug-resistant infections. In the battle against bacterial resistance and the antibiotics crisis, the use of antimicrobial-loaded liposomes as delivery vehicles shows great promise. This innovative approach not only extends drug effectiveness and reduces toxicity but also provides a path to address highly resistant infectious conditions. As research advances, liposomal nanotherapeutics may emerge as a transformative solution in the fight against bacterial infections.
The global outbreak of infectious diseases in recent decades has caused serious health problems worldwide. Key factors that contribute to the lack of a complete therapeutic strategy against viral infections include biomimetic architecture, ability to manipulate the antibody, continuous antigen transfer, covert system of injecting inappropriate doses of drugs at target sites, resulting in drug resistance. Reasons include low water solubility, poor permeability, plasma protein a high self-similarity, short gene half-life, and rapid system elimination. To combat these challenges, nanoparticle-based drug delivery has emerged as a revolutionary approach, applying nanoengineering tools to nanoparticle synthesis to achieve optimal drug concentrations at targeted sites over time nanoparticles with nano dimensional structure enhanced permeability and retention effects, increasing surface area volume ratios, in surface-functioning capacity, prove effective in antiviral therapeutic delivery but size, shape, charge, and surface topology of nanoparticles allow target specific drug delivery, cellular uptake, opsonization by host immune cells, drug retention time, transcytosis, extended biological half -life, in vivo stability, and significantly affect cytotoxicity. This review provides an in-depth analysis of the critical role of nanotechnology-based drugs while addressing important aspects of clinical safety and efficacy.
Introduction:
Wounds, resulting from traumas, surgery, burns or diabetes, are important medical problems due to the complexity of wound healing process regarding healing times and healthcare costs. Nanosystems have emerged as promising candidates in this field thank to their properties and versatile applications in drugs delivery.
Areas covered:
Lipid-based nanosystems (LBN) are described for wound treatment, highlighting their different behaviors when interacting with the cutaneous tissue. The role of nanosystems in delivering mostly natural compounds on skin as well as the technological and engineering strategies to increase their efficiency in wound healing effect are reviewed. Finally, in vitro, ex-vivo and in vivo studies are reported.
Expert opinion:
LBN have shown promise in addressing the challenges of wound healing as they can improve the stability of drugs used in wound therapy, leading to higher efficacy and fewer adverse effects as compared to traditional formulations. LBNs being involved in the inflammatory and proliferation stages of the wound healing process, enable the modification of wound healing through multiple ways. In addition, the use of new technologies, including 3D bioprinting and photobiomodulation, may lead to potential breakthroughs in wound healing. This would provide clinicians with more potent forms of therapy for wound healing.
This study focused on developing an optimal formulation of liposomes loaded with bee venom (BV) and coated with PEG (BV-Lipo-PEG). The liposomes were characterized using dynamic light scattering, transmission electron microscopy, and Fourier transform infrared spectroscopy. Among the liposomal formulations, F3 exhibited the narrowest size distribution with a low PDI value of 193.72 ± 7.35, indicating minimal agglomeration-related issues and a more uniform size distribution. BV-Lipo-PEG demonstrated remarkable stability over 3 months when stored at 4 °C. Furthermore, the release of the drug from the liposomal formulations was found to be pH-dependent. Moreover, BV-Lipo-PEG exhibited favorable entrapment efficiencies, with values reaching 96.74 ± 1.49. The anticancer potential of the liposomal nanocarriers was evaluated through MTT assay, flow cytometry, cell cycle analysis, and real-time experiments. The functionalization of the liposomal system enhanced endocytosis. The IC50 value of BV-Lipo-PEG showed a notable decrease compared to both the free drug and BV-Lipo alone, signifying that BV-Lipo-PEG is more effective in inducing cell death in A549 cell lines. BV-Lipo-PEG exhibited a higher apoptotic rate in A549 cell lines compared to other samples. In A549 cell lines treated with BV-Lipo-PEG, the expression levels of MMP-2, MMP-9, and Cyclin E genes decreased, whereas the expression levels of Caspase3 and Caspase9 increased. These findings suggest that delivering BV via PEGylated liposomes holds significant promise for the treatment of lung cancer.
Skin carcinoma remains one of the most widespread forms of cancer, and its global impact continues to increase. Basal cell carcinoma, melanoma, and squamous cell carcinoma are three kinds of cutaneous carcinomas depending upon occurrence and severity. The invasive nature of skin cancer, the limited effectiveness of current therapy techniques, and constraints to efficient systems for drug delivery are difficulties linked with the treatment of skin carcinoma. In the present era, the delivery of drugs has found a new and exciting horizon in the realm of nanotechnology, which presents inventive solutions to the problems posed by traditional therapeutic procedures for skin cancer management. Lipid-based nanocarriers like solid lipid nanoparticles and nanostructured lipid carriers have attracted a substantial focus in recent years owing to their capability to improve the drug's site-specific delivery, enhancing systemic availability, and thus its effectiveness. Due to their distinct structural and functional characteristics, these nanocarriers can deliver a range of medications, such as peptides, nucleic acids, and chemotherapeutics, via different biological barriers, such as the skin. In this review, an effort was made to present the mechanism of lipid nanocarrier permeation via cancerous skin. In addition, recent research advances in lipid nanocarriers have also been discussed with the help of in vitro cell lines and preclinical studies. Being a nano size, their limitations and toxicity aspects in living systems have also been elaborated.
The intricate physiological structure of the inner ear presents challenges for traditional medication treatment strategies, including systemic adverse responses, trouble penetrating the blood–labyrinth barrier, and low local cochlear concentration, resulting in poor therapeutic outcomes. An intriguing tactic that is extensively developed over decades is utilizing drug delivery systems to transport medication molecules to the inner ear. Herein, the challenges associated with inner ear delivery are discussed, cutting‐edge achievements in inner ear drug delivery systems are emphasized, including nano‐, micro‐, and macrocarriers, and finally opportunities to leverage advanced technologies to improve existing drug delivery strategies are highlighted.
Prinsepia utilis seed oil (PUSO) is a natural medication obtained from Prinsepia utilis Rogle seed, which has been used for the treatment of skin diseases. The study aims to prepare ethosomes with high drug loading as a water-soluble transdermal vehicle to enhance the transdermal delivery of PUSO. PUSO-loaded ethosomes (PEs) were prepared using a cold method, and optimized by an orthogonal experimental design with entrapment efficiency (EE) as the dependent variable. The PEs prepared with the optimized formulation showed good stability, with a spherical shape under transmission electron microscopy (TEM), average particle size of 39.12 ± 0.85 nm, PDI of 0.270 ± 0.01, zeta potential of -11.3 ± 0.24 mV, and EE of 95.93 ± 0.43%. PEs significantly increased the skin deposition of PUSO compared to the PUSO suspension (P < 0.001). Moreover, the optimum formula showed significant ameliorative effects on ultraviolet B (UVB) irradiation-associated macroscopic and histopathological changes in mice skin. Therefore, PEs represent a promising therapeutic approach for the treatment of UVB-induced skin inflammation, with the potential for industrialization.
The process of autophagy refers to the intracellular absorption of cytoplasm (such as proteins, nucleic acids, tiny molecules, complete organelles, and so on) into the lysosome, followed by the breakdown of that cytoplasm. The majority of cellular proteins are degraded by a process called autophagy, which is both a naturally occurring activity and one that may be induced by cellular stress. Autophagy is a system that can save cells' integrity in stressful situations by restoring metabolic basics and getting rid of subcellular junk. This happens as a component of an endurance response. This mechanism may have an effect on disease, in addition to its contribution to the homeostasis of individual cells and tissues as well as the control of development in higher species. The main aim of this study is to discuss the guidelines for the role of autophagy in drug delivery vector uptake pathways. In this paper, we discuss the meaning and concept of autophagy, the mechanism of autophagy, the role of autophagy in drug delivery vectors, autophagy-modulating drugs, nanostructures for delivery systems of autophagy modulators, etc. Later in this paper, we talk about how to deliver chemotherapeutics, siRNA, and autophagy inducers and inhibitors. We also talk about how hard it is to make a drug delivery system that takes nanocarriers' roles as autophagy modulators into account.
Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.
Introduction:
Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation.
Areas covered:
We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials.
Expert opinion:
microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.
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.
Objective
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.
Methods
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.
Results
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.
Conclusion
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/cm²/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.
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.
Gene therapy has demonstrated potential for the treatment of both acquired and inherited diseases. During the past decade, liposomal-gene delivery has progressed from the laboratory bench through to clinical trials, although low transfection efficiency continues to limit its application. An understanding of the mechanisms of the fundamental biophysical interactions permits further optimization of delivery strategies. Recent advances in negating cellular transfection barriers include condensation of plasmid into smaller particles, promotion of intracellular DNA-release from endosomes and the facilitation of plasmid nuclei-entry by nuclear localization signal. The extracellular environment, however, remains the major obstacle to in vivo administration, and characterization of the in vivo barriers will help in efforts to design a more efficient formulation that will achieve therapeutic effect.
The penetration of intact particles in the nanometer range (nanoparticles, [NP]) through human skin is a controversial topic, which has attracted much interest from both the pharmaceutical and the personal care industries. Concerns have also been raised about the possible implications that dermal exposure to NP may have for human health, particularly from physical sunblock formulations. Here we use a theoretical approach to determine the feasibility of NP penetration of healthy human skin. The maximum flux of NPs of various dimensions is calculated based on two algorithms that have been developed to model passive diffusion of molecules through skin. The results confirm that NPs are too large to permeate skin by this mechanism. Although components of NPs may dissolve in the skin and measurable amounts have been detected in body fluids, this is not indicative of actual NP transport through the skin. The possible roles for NP formulations in drug permeation enhancement are also considered but are not associated with the penetration of intact NP.
Topical administration of celecoxib proved to be an effective mean of preventing skin cancer development and improving anticancer drugs effectiveness in skin tumors treatment. The aim of this study was the development of an effective topical formulation of celecoxib, able to promote drug skin delivery, providing its in depth penetration through the skin layers. Three kinds of vesicular formulations have been investigated as drug carriers: liposomes containing a surfactant, or transfersomes and ethosomes, containing suitable edge activators. Firstly, the effect of membrane composition variations on the system performance has been evaluated for each vesicle type. Selected formulations were characterized for particle size, polydispersity index and encapsulation efficiency. The best formulations were subjected to ex vivo permeation studies through excised human skin. All vesicular formulations markedly (p < 0.001) improved the drug amount penetrated into the skin with respect to an aqueous suspension, from 2.0 to 6.5, up to 9.0 folds for liposomes, transfersomes and ethosomes, respectively. In particular, ethosomes containing Tween 20 as edge activator not only showed the best vesicle dimensions and homogeneity, and the highest encapsulation efficacy (54.4%), but also enabled the highest increase in drug penetration through the skin, probably due to the simultaneous presence in their composition of ethanol and Tween 20, both acting as permeation enhancers. Therefore, among the various vesicular formulations examined in the study, Tween 20-ethosomes can be considered the most promising one as carrier for topical celecoxib applications aimed to prevent skin cancer development and increase the anticancer dru