Liposomal Drug Research Articles

Regulated bioanalysis of liposomal amphotericin B to support pharmacokinetic studies of liposomal drugs.

Background: Because of the delicate nature of liposomes, bioanalysis of free and liposomal-encapsulated drugs is among the most challenging assays to perform. Current regulatory guidance for bioanalysis is not sufficient to address the complexity of this particular formulation. Method & results: Three individual LC-MS/MS methods to quantify free amphotericin B (10-3000ng/ml) and encapsulated amphotericin B (100-50,000ng/ml) in pretreated human plasma and total amphotericin B (100-50,000ng/ml) in human plasma were fully validated and applied to a bioequivalence study. The acceptance criteria and experimental design of additional validation tests using cross quality control were carefully deliberated a priori and included in the sample analysis as well. Discussion: Additional validation tests are necessary to demonstrate that the measured concentration of the intended component is accurate and free of interference from other coexisting components in the sample. These practices can be used as guidance for future liposomal drug method validation.

A separate assay of released and liposomal encapsulated eribulin in dog plasma by liquid chromatography with tandem mass spectrometry for its application to a pharmacokinetic study.

Eribulin has been used as a drug for the treatment of metastatic breast cancer and liposomal formulation of eribulin is under development to achieve a wider therapeutic index. It is important to separately determine released and encapsulated drugs in systemic circulation for liposomal drugs. In this study, a separate assay method was developed for the determination of released and total (encapsulated + released) eribulin concentrations in dog plasma by liquid chromatography with tandem mass spectrometry. The released eribulin in dog plasma was separated by ultrafiltration of plasma samples. Obtained plasma ultrafiltrate and untreated plasma samples recognized as released and total eribulin, respectively, were subjected to protein precipitation for extraction of eribulin. Eribulin was quantifiable from 0.1ng/mL. Accuracy and precision of eribulin in both matrices were within±15 and 15%, respectively, indicating a robust assay. Released and total eribulin concentrations in plasma were determined after intravenous administration of the liposomal formulation of eribulin to dogs, resulting in minimal released eribulin in plasma. In conclusion, a robust method for released and total eribulin levels in dog plasma was developed and was successfully applied to a pharmacokinetic study in dogs to characterize the pharmacokinetic profiles.

Imidazole-Based pH-Sensitive Convertible Liposomes for Anticancer Drug Delivery.

In efforts to enhance the activity of liposomal drugs against solid tumors, three novel lipids that carry imidazole-based headgroups of incremental basicity were prepared and incorporated into the membrane of PEGylated liposomes containing doxorubicin (DOX) to render pH-sensitive convertible liposomes (ICL). The imidazole lipids were designed to protonate and cluster with negatively charged phosphatidylethanolamine-polyethylene glycol when pH drops from 7.4 to 6.0, thereby triggering ICL in acidic tumor interstitium. Upon the drop of pH, ICL gained more positive surface charges, displayed lipid phase separation in TEM and DSC, and aggregated with cell membrane-mimetic model liposomes. The drop of pH also enhanced DOX release from ICL consisting of one of the imidazole lipids, sn-2-((2,3-dihexadecyloxypropyl)thio)-5-methyl-1H-imidazole. ICL demonstrated superior activities against monolayer cells and several 3D MCS than the analogous PEGylated, pH-insensitive liposomes containing DOX, which serves as a control and clinical benchmark. The presence of cholesterol in ICL enhanced their colloidal stability but diminished their pH-sensitivity. ICL with the most basic imidazole lipid showed the highest activity in monolayer Hela cells; ICL with the imidazole lipid of medium basicity showed the highest anticancer activity in 3D MCS. ICL that balances the needs of tissue penetration, cell-binding, and drug release would yield optimal activity against solid tumors.

A Nucleus-Targeted Nanosystem Integrated with Photodynamic Therapy and Chemotherapy

Minimally invasive photodynamic therapy, destroying lesions with a light-activated photosensitizer, has been increasingly performed since it is highly efficiency, safe, synergistically compatible, repeatable, and minimally-invasive, with few adverse reactions. However, the most present photosensitizer or nanodrug delivery system containing a photosensitizer can target tumor cells but rarely cell nuclei. In this regard, the nucleus-targeting drug delivery system has been developed aiming impair tumor cells in an efficient and direct manner. In this study, the cationic liposome (Clip) drug delivery system integrated with low dose nucleus-targeting chemotherapeutic drug Doxorubicin (DOX) and photosensitizer AlPcS4 (Clip-AlPcS4@DOX) was synthesized. Among them, Clip was used to efficiently load drugs into cells almost at the same time, low dose DOX was used to open the channel for the materials to enter the nucleus on the premise of ensuring low cytotoxicity and then introduced photosensitizer into the nucleus, AlPcS4 photosensitizer was used to damage directly and efficiently through the photodynamic therapy (PDT) effect after entering the nucleus. In summary, a nucleus-targeting nanodrug delivery system (Clip-AlPcS4@DOX) was designed and synthesized and could be induced cell apoptosis more quickly and efficiently. Therefore, it could be a promising nucleus-targeting nanosized reagent integrating the PDT and chemotherapy for gastric therapy.

A comprehensive review on liposomes: A vesicular system for drug delivery

In the last few years, many techniques have been utilized to enhance the pharmacological activity of any Active Pharmaceutical Drug [API] resulting in better bioavailability and lesser side effects. Liposomal drug delivery has evolved in this manner to increase the drug effect and reduce side effects. This review article focuses on all the aspects of liposomes with formulation methodology and characterization. Liposomes seem the first choice for designing a drug delivery system.

A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives.

Liposomes have been considered promising and versatile drug vesicles. Compared with traditional drug delivery systems, liposomes exhibit better properties, including site-targeting, sustained or controlled release, protection of drugs from degradation and clearance, superior therapeutic effects, and lower toxic side effects. Given these merits, several liposomal drug products have been successfully approved and used in clinics over the last couple of decades. In this review, the liposomal drug products approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are discussed. Based on the published approval package in the FDA and European public assessment report (EPAR) in EMA, the critical chemistry information and mature pharmaceutical technologies applied in the marketed liposomal products, including the lipid excipient, manufacturing methods, nanosizing technique, drug loading methods, as well as critical quality attributions (CQAs) of products, are introduced. Additionally, the current regulatory guidance and future perspectives related to liposomal products are summarized. This knowledge can be used for research and development of the liposomal drug candidates under various pipelines, including the laboratory bench, pilot plant, and commercial manufacturing.

A novel, rapid and cost-effective method for separating drug-loaded liposomes prepared from egg yolk phospholipids

Liposomal drug formulations often utilize passive drug-loading methods to encapsulate drugs into the liposome. These formulations require an additional processing step to remove the unencapsulated drug, using techniques like ultracentrifugation, ultrafiltration, column chromatography, dialysis, etc. However, these methods suffer from downsides like high costs, high time consumption, low scalability, etc. In this study, we have employed solvents of varying dielectric constants to carry out this separation. Using phospholipids isolated from chicken eggs, we synthesized doxorubicin hydrochloride loaded liposomes. Utilizing solvents such as acetone and ethanol along with low-speed centrifugation, we were able to efficiently recover up to 94% of the drug-loaded liposomes, which was much higher than that achieved with conventional techniques like ultracentrifugation (11%) and ultrafiltration (89%). The morphology and size of acetone-treated liposomes, monitored using TEM and DLS analysis, were found to be intact and only slightly altered. The bilayer morphology was determined to be unaltered by solvents through XRD analysis. The absence of residual solvents was confirmed through 1H NMR analysis. In vitro release study using doxorubicin confirmed that the release profile was similar irrespective of the separation technique. Thus, we have established a novel approach for cheaply and quickly separating egg phospholipid-based liposomes from unencapsulated drugs.

WITHDRAWN: Smart Trends: Liposome-Based Nanocarriers for Cancer Treatment and its Applications

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Effect of cholesterol on nano-structural alteration of light-activatable liposomes via laser irradiation: Small angle neutron scattering study

Although the light-activated liposomes have been extensively studied for drug delivery applications, the fundamental mechanism of the drug release based on lipid compositions has not been fully understood. Especially, despite the extensive use of cholesterol in the lipid composition, the role of cholesterol in the light-activated drug release has not been studied. In this study, the influence of cholesterol on drug release from light-responsive drug-encapsulated liposomes after activated by near infrared (NIR) laser was investigated. We prepared methotrexate (MTX)-encapsulated DSPC liposomes consisting of 0 mol% (Chol) or 35 mol% cholesterol (+Chol), with (+Au) or without gold nanorods (Au) on the lipid bilayer to compare drug release, morphological changes, and nanostructures after laser irradiations. Transmission electron microscopy (TEM) and small angel neutron scattering (SANS) data revealed that only +Chol +Au liposomes showed partial aggregation of the liposomes after laser irradiation. Similar trends on the drug release and structural change were observed when the liposomes were heated to above chain-transition temperature. Overall, we have found that (1) inclusion of 35 mol% cholesterol enhanced the permeability of lipid bilayers above Tc; (2) the mechanism of laser-activated liposomal drug delivery is disrupting lipid bilayer membranes by the photothermal effect in the presence of plasmonic materials. By understanding the fundamentals of the technology, precise controlled drug release at a targeted site with great stability and repeatability is anticipated.

Recent Advancements of Stimuli-Responsive Targeted Liposomal Formulations for Cancer Drug Delivery

Liposomes have gained attention as a well-accepted nanocarrier for several chemotherapeutic drugs and are considered a drug delivery system of choice for a wide range of products. These amphipathic spherical vesicles primarily consist of one or more phospholipid bilayers, showing promise for drug delivery of both hydrophilic and hydrophobic components in addition to unique properties, such as biocompatibility, biodegradability, low toxicity, and nonimmunogenicity. Recent advances in liposomes are mainly centered on chemical and structural modification with the multifunctional approach to target the cancer cells activating the offensive mechanisms within the proximity of the tumors. Stimuli-responsive liposomes are a precisive approach to deliver and release chemotherapeutic drugs in the tumor site in a controlled fashion, thus reducing damage to normal tissues and preventing the side effects of the conventional chemotherapy regimen. The unique characteristics of the tumor microenvironment facilitate applying an endogenous stimulus (pH, redox potential, or enzymatic activity) to trigger the release of the drug or the application of an external stimulus (heat or light) to tailor the drug release from liposomes. This review focuses on newer developments in stimuli-sensitive liposomal drug delivery systems designed to implement either exogenous (temperature, light, and magnetic field) or endogenous (pH changes, enzymatic triggers, or redox potential) approaches.

Investigation of miscibility transitions in hybrid biomembranes with fluorescence spectroscopy

The combination of lipids and amphiphilic block copolymers to form hybrid biomembranes has been an area of recent scientific interest, with the goal of blending the biocompatibility of lipids with the enhanced mechanical durability and chemical diversity of block copolymers. Such hybrid membranes may have applications toward the continued development of liposomal drug delivery vehicles. Like various lipid mixtures, membranes containing both lipids and block copolymers display composition- and temperature-dependent phase behavior.

A review on: liposomes

Liposomes, spherical shaped vesicles consisting of one or more phospholipid bilayers, were first described in the mid60s. Today, they are a very useful reproduction, reagent, and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. Among several talented new drug delivery systems, liposomes characterize an advanced technology to deliver active molecules to the site of action. Research on liposome technology has progressed from conventional vesicles to ‘second-generation liposomes’, in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids. They are of 0.05- 5.0 micrometer in diameter. Liposomes are used for the treatment of various diseases like tumors or cancer. In this review article provides a Liposomal Drug Delivery System and various aspects related to liposome that can be studied.

Using peptides to promote delivery and improve anti-tumour efficacy of liposomal drug

Liposomal drugs exhibit advantages for cancer therapy, but efficacy is often limited by their rapid clearance from the blood by the reticuloendothelial system, and an inability to target and penetrate tumours. Interestingly, a 21-amino acid SIRP-α- (signal regulatory protein-α) interacting ‘self’ peptide is reported to inhibit uptake by phagocytes. Also, ‘iRGD’ a 9-amino acid cyclic peptide that binds αvβ3 integrins and neuropilin-1 (NRP-1), promotes targeting and penetration of the drug into tumours. Here we explore the potential of nitrilotriacetic acid-ditetra-decylamine (NTA3-DTDA)-containing liposomes (NTA-liposomes) engrafted with His-tagged forms of ‘self’ peptide (pCD47) to prolong circulation time in blood after iv administration, and of iRGD peptide (piRGD) to enhance treatment efficacy of doxorubicin-containing liposomes (Caelyx). Our results show that pre-incubation of murine phagocytic DC2.4 and RAW246.7 cells with pCD47 inhibits the uptake of NTA-liposomes in vitro, but engraftment of pCD47 surprisingly reduces liposome lifetime in blood. Engraftment of piRGD promoted binding of NTA-liposomes to murine B16 melanoma and CT26 colorectal carcinoma cells in vitro. Importantly, iv administration of piRGD-engrafted Caelyx was found to significantly inhibit tumour growth and prolong survival in both B16 and CT26 murine tumour models. Our results show that engraftment of piRGD onto Caelyx is a convenient strategy to enhance treatment efficacy.

Prednosti lipozomalnih nesteroidnih antiinflamatornih lekova

Introduction: Liposomes are small, spherical artificial vesicles that can be created from cholesterol and natural non-toxic phospholipids. Due to their size, hydrophobic and hydrophilic character (besides biocompatibility), liposomes are promising drug delivery systems. Topic: Liposomal formulations of non-steroidal anti-inflammatory drugs (NSAIDs) can be used in all population groups (children, adults, and the elderly) which gives them a wide range of applications. NSAIDs oral administration is associated with severe adverse effects in the gastrointestinal tract such as epigastric pain, heartburn, nausea, diarrhea, vomiting, peptic ulcer, and hepatic impairment. It has been observed in clinical trials, that liposomal formulations enhanced the drug permeability and the percentage of accumulated dose in the skin compared to control conventional gel formulations. Liposomal gel controls ibuprofen release and drug permeability in vitro and has shown a permeability pattern conducive to maintaining constant drug levels. Application: So far, liposomes containing sodium diclofenac, indomethacin, aceclofenac, and related NSAIDs have been produced in laboratory conditions. Liposomal technology is most commonly applied in cosmetology, cancer therapy and yet unexplored application possibilities for liposomes, such as therapy for Alzheimer's disease. Although varying in size and structure, they all possess certain common advantages - increased dermal availability of lipophilic drugs and their targeted delivery onto the required location. Liposomes have been proven highly effective in terms of retaining the NSAIDs in the synovial cavity, mostly because of their size and chemical composition. Undesirable therapy effects, fast clearance, and exposure to nontargeted sites could be minimized by administering NSAIDs using liposomes as carriers. Side effects and complications associated with the long-term oral and intramuscular applications of NSAIDs could especially be avoided using their liposomal formulations. Liposomes can be seen as ideal carriers for anti-inflammatory drugs as their ability to (passively) target sites of inflammation and release their content to inflammatory target cells enables them to increase local efficacy with only limited systemic exposure and adverse effects, improving bioavailability and patient compliance. A few NSAIDs are experimentally formulated in liposomes having improved pharmacokinetic characteristics. Further clinical investigations will show their pharmaco-dynamic effects. The in vitro release and ex vivo permeation (permeability) study showed a prolonged diclofenac release with high permeation flux. Conclusion: The use of liposomes as drug carriers becomes a notable positive step in the treatment of inflammatory, pain-causing, and rheumatic diseases. Liposomes present an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address the different delivery considerations. The main objectives for the development of NSAIDs in liposomal carriers are deeper penetration of the active substance, fewer side effects, better and longer effect, the ability to change the characteristics of both the drug and the carrier, and adequate dose adjustment. Despite several challenges that accordingly still need to be addressed, liposomal drug formulations have significant health-promoting potential. Despite the encouragement of NSAID development and research studies, it still takes a long time for liposomal NSAID formulations to become available for everyday use.

Formulation, ex-vivo and in-vitro characterization of liposomal drug delivery system of Fexofenadine

Formulation, ex-vivo and in-vitro characterization of liposomal drug delivery system of Fexofenadine

Development of growth factor-incorporating liposomes for integration into scaffolds as a method to improve tissue regeneration.

This review is an update with regard to the efforts to develop liposomal carriers for growth factor delivery. It is well known that growth factors have the potential to enhance/accelerate tissue regeneration; however, their poor stability, which results in rapid loss of their activity, together with their rapid clearance from defected tissues (when applied as free molecules) is a serious drawback for their use; their highly hydrophilic nature and low capability to permeate through biological barriers (cell membranes) are additional factors that limit their applicability. In recent years, the advantages of liposomal drug delivery systems have motivated efforts to deliver growth factors (GFs) in liposomal form. Herein, after briefly introducing the basic structural characteristics of liposome types and their advantages when used as drug carriers, as well as the basic problems encountered when GFs are applied for tissue regeneration, we focus on recent reports on the development and potential regenerative effects of liposomal GFs, towards defects of various tissues. The methodologies used for incorporation, attachment or immobilization of liposomal GFs in order to sustain their retention at the defected tissues are also highlighted.

Liposomal drug delivery: Recent developments and challenges

The spherical vesicles known as liposomes may contain one or many phospholipid bilayers. The first liposomes were found in the 1960s. One of the many distinctive drug delivery methods is the liposome, which offers a complex way to transfer active molecules to the site of action. Clinical trials are now testing a variety of formulations. Long-lasting second-generation liposomes are created by altering the vesicle’s lipid composition, size, and charge. Superficial vesicles have given way to liposome growth. Glycolipids and other substances have been used to make liposomes for the modification of outer surfaces through various types of targeting ligands and detecting agents or moiety. Now, the liposomes developed for the different market and it is flooded with cosmetics and, more crucially, medications. Three of the main applications of liposome technology include steric and environmental stabilization of loaded molecules, remote drug loading through pH and ion gradients approach, and simultaneously lipoplexes which is the complexes forms of cationic liposomes with anionic nucleic acids or proteins for the gene delivery or siRNA technology. The scope of liposome research was expanded, allowing for the production of various goods. The present review focuses on the different aspects of liposomal drug delivery concerning types, preparation, pros, and cons.

Liposome: A Novel Drug Delivery System

Liposome was derived from two Greek words “Lipos meaning fat and Soma meaning body”. Liposome were spherical shaped vesicles consist of phospholipids and cholesterol. Due to their size hydrophobic and lipophilic character they are very promising system for drug delivery. This novel drug delivery system aims to target the drug directly to the site of action. Liposomes are very biocompatible and stable and have unique property to entrap both hydrophilic drug and lipophilic drug to its compartment and lead to controlled release effect. They are of 0.05- 5.0 micrometer in diameter. Liposomes are used for the treatment of various diseases like tumors or cancer. Liposomal Drug Delivery System and various aspects related to liposome that can be studied Compared with traditional drug delivery systems, liposomes exhibit better properties, including site-targeting, sustained or controlled release, protection of drugs from degradation and clearance, superior therapeutic effects, and lower toxic side effects. This review describes liposomes structure, composition, preparation methods, and evaluation clinical applications

Mild hyperthermia accelerates doxorubicin clearance from tumour-extravasated temperature-sensitive liposomes.

Mild hyperthermia (HT) (40-43 °C) has been combined with temperature-sensitive liposomes (TSL), offering on-demand drug release for increased drug bioavailability and reduced systemic toxicity. Different HT regimens have been applied to trigger liposome drug release in the blood vessels (intravascular) of heated tumours or following tumour extravasation (interstitial). The present study systematically assessed the in vivo doxorubicin (Dox) release and therapeutic efficacy of Dox-loaded TSL with different release profiles. Low temperature-sensitive liposomes (LTSL-Dox), traditional-temperature-sensitive liposomes (TTSL-Dox), and non-temperature-sensitive liposomes (NTSL-Dox) were combined with a single or two HT in different tumour models (murine melanoma B16F10 tumour and human breast MDA-MB-435). The efficacy of each treatment was assessed by monitor tumour growth and mice survival. The level of Dox in tumour tissues was quantified using 14C-Dox and liquid scintillation while Dox release was assessed using live imaging and confocal laser scanning microscopy. Applying a second HT to release Dox from extravasated TTSL-Dox was not therapeutically superior to single HT application due to Dox clearance from the extravasated TTSL-Dox. Our findings revealed that enhanced blood perfusion in heated tumours during the second water bath HT could be seen as a hurdle for TTSL-Dox's anticancer efficacy, where the systemic toxicity of the redistributed Dox from the tumour tissues could be potentiated.

Accelerated blood clearance and hypersensitivity by PEGylated liposomes containing TLR agonists

Systemic administration of toll-like receptor (TLR) agonists have demonstrated impressive preclinical results as an anti-cancer therapy due to their potent innate immune-stimulatory properties. The clinical advancement has, however, been hindered by severe adverse effects due to systemic activation of the immune system. Liposomal drug delivery systems may modify biodistribution, cellular uptake, and extend blood circulation, and thus, potentially enable systemic administration of TLR agonists at therapeutic doses.In this study, we investigated potential barriers for the administration of TLR agonists formulated in polyethylene glycosylated (PEGylated) liposomes with regards to liposome formulation, TLR agonist, administration route, administration schedule, biodistribution, blood clearance, and anti-PEG antibodies. We found that administration of TLR agonists formulated in PEGylated liposomes led to high anti-PEG antibody titers, which upon multiple intravenous administrations, resulted in accelerated blood clearance and acute hypersensitivity reactions. The latter was found to be associated with anti-PEG IgG antibody and not anti-PEG IgM antibody opsonization. This study highlights the need to carefully design and evaluate nanoparticle delivery systems for immunotherapy as anti-nanoparticle immune responses may challenge the therapeutic application.