Liposomal Drug Delivery Systems Research Articles

Development of Biomembrane-mimetic Nanoparticles for the Treatment of Ischemic Stroke

Increase in vascular permeability of the blood-brain barrier (BBB) is a distinct pathology following ischemic stroke. In previous studies, we demonstrated that liposomal drug delivery system (DDS)-based delivery of neuroprotectants is useful for treating cerebral ischemia/reperfusion injury. Additionally, our previous studies reported that combination therapy with liposomal fasudil plus tissue plasminogen activator (t-PA), a thrombolytic agent, brings about decrease in the risk of t-PA-derived cerebral hemorrhage and prolong the therapeutic time window of t-PA for treating acute ischemic stroke. However, accumulation of systemically administered liposomes into the brain parenchyma is still limited, and new technologies are needed that can overcome the BBB. The unique properties of leukocytes and exosomes, one of the extracellular vesicles, make them promising candidates for overcoming biological barriers (including the BBB) for drug delivery, as leukocytes and certain exosomes were reported to be able to permeate through the inflamed BBB in the ischemic stroke area. We prepared leukocyte-mimetic liposomes (LM-Lipo) via transfer of leukocyte membrane proteins by employing a phenomenon called intermembrane protein transfer, and demonstrated that LM-Lipo could pass through the layer of inflamed endothelial cells via regulation of intercellular junctions, like leukocytes. Additionally, we showed that LM-Lipo efficiently penetrated into spheroids of cancer cells, and inhibited their growth by entrapped doxorubicin. Taken together, it was suggested that imparting leukocyte-like characteristics to liposomes may be an effective approach to overcoming biological barriers. Herein, we summarize our findings regarding liposomal DDS for ischemic stroke therapy and recent approaches to develop biomembrane-mimetic DDS using leukocytes and exosomes.

Formulation and Evaluation of Liposomal Drug Delivery System for Sulfasalazine

Aim: Aim of the current study is to prepare and characterize sulfasalazine-loaded liposomes to improve the bioavailability of the drug and to lessen the adverse effects of the drug. Background: Diseases like inflammatory bowel disease can be treated by anti-inflammatory agents like “Sulfasalazine,” It can also be used to treat ulcerative colitis and Crohn’s disease. The biological half-life of sulfasalazine is 5-10hr; as in the case of conventional therapy, there is a chance of missing the dose. Therefore, frequent administration of drugs is essential to maintain the desired steady-state level. The side effects are thrombocytopenia, megaloblastic anemia, bone marrow depression, folic acid deficiency, impairment of male fertility (Oligospermia), intestinal nephritis due to 5-ASA, diarrhoea, headache, and skin rashes. The bioavailability of sulfasalazine is 15%. This work was undertaken to enhance bioavailability and decrease the side effects. Objective: The main objective of the study is to improve the solubility of sulfasalazine by formulating a liposomal drug delivery system. The major objective is to develop a liposomal formulation with good stability and the highest entrapment efficiency. Methods: Liposomes were produced by the thin-film hydration method. Nine formulations of liposomes were prepared by varying the concentrations of soya lecithin and cholesterol and changing the drug ratio. The obtained liposomes were characterized for surface morphology, FTIR, particle size, zeta potential, drug content, entrapment efficiency, and in-vitro diffusion studies. Results: Among the nine formulations of liposomes, F3 was found to be the best formulation with an entrapment efficiency of 97.8% and a zeta potential value of -37.2mV. Liposomes followed first-order kinetics with a non-fickian diffusion pathway. Conclusions: Sulfasalazine loaded liposomes were prepared with good stability and the highest entrapment efficiency.

Recent Advances in Liposomal Drug Product Development

Liposomes are spherical vesicles composed of a bilayer (uni-lamellar) and/or a concentric series of multiple bilayer (multi-lamellar) separated by aqueous compartments formed by amphipathic molecules, such as phospholipids. Liposomes deliver drugs via encapsulation in inner aqueous or lipid compartments and have advantages such as control of drug release and distribution, alleviation of toxicity, and drug targeting. Since the launch of the first liposomal drug Doxil？？, a variety of products using a liposomal drug delivery system have been developed and commercialized. Recently, several drug candidates developed with sophisticated and diverse technologies have been undergoing clinical trials. In this review, the pharmaceutical characteristics of approved liposomal drugs are overviewed, and the recent advances in liposome technology through candidates in clinical trials are highlighted.

Challenges of Current Anticancer Treatment Approaches with Focus on Liposomal Drug Delivery Systems.

According to a 2020 World Health Organization report (Globocan 2020), cancer was a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. The aim of anticancer therapy is to specifically inhibit the growth of cancer cells while sparing normal dividing cells. Conventional chemotherapy, radiotherapy and surgical treatments have often been plagued by the frequency and severity of side effects as well as severe patient discomfort. Cancer targeting by drug delivery systems, owing to their selective targeting, efficacy, biocompatibility and high drug payload, provides an attractive alternative treatment; however, there are technical, therapeutic, manufacturing and clinical barriers that limit their use. This article provides a brief review of the challenges of conventional anticancer therapies and anticancer drug targeting with a special focus on liposomal drug delivery systems.

Effect of a Low-Level Laser on Liposomal Doxorubicin Efficacy in a Melanoma Cell Line.

Introduction: The cytotoxicity of chemotherapy drugs is a significant challenge in the way of surmounting cancer. Liposomal drug delivery has proven to be efficacious in increasing the function of the drugs. Its potential to accumulate drugs in the target site and enhance the efficiency of anti-cancer agents with lower doses hinders their cytotoxicity on normal healthy cells. Since the release of drugs from liposomes is not generally on a controlled basis, several studies have suggested that external stimuli including lasers could be used to induce controlled release and boost the efficiency of liposomal drug delivery systems (LDDSs). Methods: The A375 cancer cell line was used and exposed to the liposomes containing doxorubicin in the presence of a low-level laser beam to investigate its effect on the liposomal stimuli-responsiveness release and its toxicity on cancer cells. So as to achieve that goal, Annexin V/PI was employed to analyze the number of cells that underwent apoptosis and necrosis. Results: Here, we report the effect of laser irradiation on LDDSs. According to the results obtained from the annexin V/PI assay, the pattern of viability status has shifted, so that the number of pre-apoptotic cells treated with liposomal doxorubicin and a laser beam was more than that of cells treated with only liposomal doxorubicin. Conclusion: The use of stimuli-responsive LDDSs, in this case, laser-responsive, has led to favorable circumstances in the treatment of cancer, offering enhanced cancer cell cytotoxicity.

Liposomes –A Overview

Liposomes are sphere-shaped vesicles made up of one or more bilayers of phospholipids. The ability of delayed vesicles to transport medications, vaccines, diagnostic specialists, and other bioactive operators has accelerated development in the liposomal drug delivery system. The liposomal delivery system's pharmacyelements and pharmacokinetics properties have been altered, resulting in a higher therapeutic index and lower overall toxicity. There are many factors to consider, including size, size distribution, surface electrical potential, lamella count, and encapsulation efficacy. The use of surface modification in the development of liposomes with various mechanisms, kinetic properties, and biodistribution was discovered to be beneficial. Drug delivery, drug targeting, controlled release, and improved solubility have all been studied extensively with liposomes.

Sphingosine 1-Phosphate Liposomes for Targeted Nitric Oxide Delivery to Mediate Anticancer Effects against Brain Glioma Tumors.

Specifically targeting glioblastoma multiforme (GBM) blood vessels and actively enhancing the permeability of the brain-blood-tumor barrier (BBTB) are two extremely difficult challenges currently hindering the development of effective therapies against GBM. Herein, a liposome drug delivery system (S1P/JS-K/Lipo) is described, which delivers the nitric oxide (NO) prodrug JS-K, O2 -(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate, to GBM tumors using sphingosine-1-phosphate (S1P)-signaling molecules as active targeting lipid ligands. It is revealed that S1P/JS-K/Lipo actively penetrates the BBTB, aided by caveolin-1-mediated transcytosis, and it is demonstrated that the system specifically interacts with S1P receptors (S1PRs), which are highly expressed on GBM cells. Nondestructive ultrasound imaging in GBM mouse models is also utilized to observe microsized NO bubble production from JS-K, as catalyzed by the glutathione S-transferases (GSTs) resident in GBM cells. Given that these NO bubbles strongly promote GBM cell death in vivo, the S1PR-targeted liposome delivery system-which successfully achieves BBTB penetration and tumor targeted delivery of a complex multicomponent drug regimen-represents a promising approach for targeted therapies against GBM and other carcinomas characterized by elevated S1PR expression.

Temperature-sensitive liposomes employ ultrasound for chemotherapy use

An ultrasonic transducer can initiate and control a temperature increase in a liposome drug-delivery system.

Method Development and Characterization of Liposomal Formulation of Isotretinoin

This study aims to develop a liposomal drug delivery system of isotretinoin, an acne drug-using spray drying, as a cost-effective and time-effective technique. The liposomal formulation was prepared by using spray drying; three different strategies were adopted: suspension spray drying (SSD), thin-film hydration and spray drying (TFHSD), and emulsion spray drying (ESD). Isotretinoin was 99% bound with lipid, so lipids hydrogenated soy phosphatidylcholine (HSPC), distearoyl phosphatidylglycerol (DSPG), and cholesterol were selected for the formulation development. The HSPC, DSPG, cholesterol, and isotretinoin were taken in the ratio 4 : 1 : 0.16 : 3.1 mmol. In vitro drug release studies, microscopy, drug content, and related substance characterizations were done to formulate each strategy of spray drying prepared dry liposomes of isotretinoin. Results were compared with the USP monograph of isotretinoin. It was revealed that isotretinoin's liposomal formulation using ESD was having drug release according to the USP limits. Drug content was also according to the USP requirement; no free drug crystals were found in microscopy, multivesicular vesicles were found in shape, a particle size of up 60 µ was found. The ESD technique was a successful, time-effective, and cost-effective technique for preparing a liposomal drug delivery system for isotretinoin.

Sorting sub-150-nm liposomes of distinct sizes by DNA-brick-assisted centrifugation.

In cells, myriad membrane-interacting proteins generate and maintain curved membrane domains with radii of curvature around or below 50 nm. To understand how such highly curved membranes modulate specific protein functions, and vice versa, it is imperative to use small liposomes with precisely defined attributes as model membranes. Here, we report a versatile and scalable sorting technique that uses cholesterol-modified DNA 'nanobricks' to differentiate hetero-sized liposomes by their buoyant densities. This method separates milligrams of liposomes, regardless of their origins and chemical compositions, into six to eight homogeneous populations with mean diameters of 30-130 nm. We show that these uniform, leak-resistant liposomes serve as ideal substrates to study, with an unprecedented resolution, how membrane curvature influences peripheral (ATG3) and integral (SNARE) membrane protein activities. Compared with conventional methods, our sorting technique represents a streamlined process to achieve superior liposome size uniformity, which benefits research in membrane biology and the development of liposomal drug-delivery systems.

Clodronate-loaded liposomal and fibroblast-derived exosomal hybrid system for enhanced drug delivery to pulmonary fibrosis

Pulmonary fibrosis is a rapidly progressive and fatal fibrotic lung disease with high mortality and morbidity. However, pulmonary fibrosis therapy in the clinic has been limited by poor selectivity and inefficiency of drug delivery to fibroblasts. Herein, a clodronate (CLD)-loaded liposome and fibroblast-derived exosome (EL-CLD) hybrid drug delivery system with non-specific phagocytosis inhibition and fibroblast homing properties, was designed for the treatment of pulmonary fibrosis. EL-CLD effectively depleted Kupffer cells via apoptosis by passive targeting after intravenous injection, and thus significantly reduced accumulation in the liver. Notably, the EL-CLD hybrid system preferentially accumulated in the fibrotic lung, and significantly increased penetration inside pulmonary fibrotic tissue by targeted delivery due to the specific affinity for fibroblasts of the homologous exosome. Nintedanib (NIN), an anti-fibrotic agent used to treat pulmonary fibrosis, was loaded in the EL-CLD system, and achieved a remarkable improvement in curative effects. The enhanced therapeutic efficacy of NIN was a result of enhanced pulmonary fibrotic tissue accumulation and delivery, combined with a diminished macrophage-induced inflammatory response. Hence, the EL-CLD hybrid system acts as an efficient carrier for pulmonary anti-fibrotic drug delivery and should be developed as an efficient fibroblast specific therapy.

Research progress of liposome drug delivery system in stomatology

Liposomes are spherical vesicles with bilayer membrane structure spontaneously formed by phospholipids dispersed in an aqueous medium. Liposomes are excellent drug carrier with amphiphilic properties. Liposomes have good biocompatibility, biodegradability and no immunogenicity. Liposomes can achieve the delivery of the drug, enhance the solubility, improve the stability, reduce the toxic effect of the drug, and improve the therapeutic effect of the loaded drug. In recent years, liposome drug delivery systems have been widely used in dentistry. This article reviews the application of liposome drug delivery systems in caries, dental pulp diseases, periodontitis, implantation, oral anesthesia and oral candidiasis.

Abstract P800: Liposomal Delivery of PICK1 Inhibitor, FSC231, Prevents Ischemic/Reperfusion-Induced Degradation of GluA2 AMPA Receptor Subunit

Stroke remains to be a leading cause of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity, eventually leading to delayed neuronal death. The hippocampus is particularly susceptible to AMPA receptor-mediated delayed neuronal death. AMPA receptors (AMPARs) are homo- or hetero-tetramers composed of GluA1-4 subunits. The majority of AMPARs are impermeable to calcium due to a post-transcriptional modification in the channel pore of the GluA2 AMPAR subunit. Calcium-permeable AMPARs lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C Kinase-1 (PICK1). We hypothesize that disrupting the PICK1—GluA2 interaction will prevent the degradation of GluA2, thereby protecting neurons within the hippocampus from AMPAR-mediated delayed neuronal death. Pretreatment with liposome-encapsulated FSC231, an inhibitor of PICK1, in acute rodent hippocampal slices prevents the OGD/R-induced association of PICK1—GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This work is the first to utilize a liposomal drug delivery system for the delivery of a small molecule in ex vivo acute rodent hippocampal slices exposed to ischemia/reperfusion injury. These results suggest that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels and is a potential therapeutic target for the treatment of ischemic stroke.

Anti-Tumor Efficacy of Pyrvinium Pamoate Nanoliposomes in an Experimental Model of Melanoma.

Pyrvinium Pamoate (PP) is an old drug approved by the FDA for the treatment of pinworm infections. Recently, it has been introduced as an anti-tumor agent, however, low aqueous solubility severely limits its potential effects. In this study, we developed a liposomal formulation of pyrvinium pamoate to investigate its in vitro cytotoxicity and in vivo efficacy against melanoma cells. As drug carriers, liposomes were fabricated using the thin-film method. PP was encapsulated within the liposomes using a remote loading method. We evaluated the morphology, particle size, and Zeta potential of the liposomes. Additionally, High-Performance Liquid Chromatography (HPLC) was employed for qualitative and quantitative analysis. Then we investigated our liposomal PP for its in vitro cytotoxicity as well as the tumor growth inhibition in C57BL/6 mice bearing B16F0 melanoma tumors. Based on the analytical result, the liposomal drug delivery system is a homogeneous and stable colloidal suspension of PP particles. The images of Atomic force microscopy and particle size data showed that all the prepared nanocarriers were spherical with a diameter of approximately 101 nm. According to both in vitro and in vivo studies, nanoliposomal PP exhibited an improved anti-proliferative potential against B16F10 melanoma tumor compared to free PP. Liposomal encapsulation improves the water solubility of PP and enhances its anti-cancer activity.

Integrin αvβ3-targeted liposomal drug delivery system for enhanced lung cancer therapy

Conventional chemotherapy for tumor treatment remains flawed because it fails to limit cytotoxicity to a small set of selectable tissues. Active targeting techniques for the delivery of drugs to specific sites are increasingly used to enhance drug accumulation at tumor sites with the aim of reducing side effects in vivo. Liposomes, modified with different targeting ligands, are considered to be one of the most promising targeted drug carriers. Herein, novel linear and cyclic arginine-glycine-aspartate (RGD) peptide-based lipids were synthesized to develop modified liposomal drug delivery systems with active targeting and pH-sensitivity. The RGD-modified liposomes showed excellent active targeting ability for integrin αvβ3 receptors, resulting in improved cellular uptake. The modified liposomes also enhanced intracellular doxorubicin (DOX) release because of their degradation in an acidic environment. Consequently, the RGD-modified, DOX-loaded liposomes exhibited significant antitumor efficacy and low toxicity in vitro and in vivo. In particular, 5% cRGD-lipid modified DOX-loaded liposome showed the greatest inhibition of tumor growth in mice among the tested formulations, and much less toxicity than free DOX. In conclusion, the DOX-loaded pH-sensitive liposome modified with 5% cRGD-lipid developed in the current study provides a potential approach for improved tumor therapy.

Liposome mediated pulmonary drug delivery system: An updated review

Liposomes are the sphere-shaped vesicles consisting of one or more phospholipid bilayers. Structurally the liposomal vesicles are the bilayered vesicles that consist of a core of aqueous solution and a lipid spheres that contain no aqueous material. They are generally made up of phospholipids. Liposomal drug delivery systems have been widely used in pulmonary drug delivery for multiple applications which includes optimum solubilization of active pharmaceutical agents, prolonged period of drug release. Moreover, the site avoidance and site-specific drug targeting therapy could be achieved by the liposomal drug delivery system, to inhibit the tissue toxicity of many potent drug substances. In this present review, formulation aspects of liposomes, various aerosolization methods and the characterization methods of liposome formulation and an extensive overview of the use of liposomes as a pulmonary drug delivery system for the treatment of diseases like tuberculosis and lung cancer and are discussed. Liposomes can be used as a successful drug carrier in the fields like lung infection, tumor targeting, genetic transfer, immunomodulation, skin, and topical therapy.

Hybrid lipopolymer vesicle drug delivery and release systems.

Hybrid lipopolymer vesicles are membrane vesicles that can be self-assembled on both the micro- and nano-scale. On the nanoscale, they are potential novel smart materials for drug delivery systems that could combine the relative strengths of liposome and polymersome drug delivery systems without their respective weaknesses. However, little is known about their properties and how they could be tailored. Currently, most methods of investigation are limited to the microscale. Here we provide a brief review on hybrid vesicle systems with a specific focus on recent developments demonstrating that nanoscale hybrid vesicles have different properties from their macroscale counterparts.

Formulation Development and evaluation of Liposomal Drug Delivery System Containing Etoposide

Formulation Development and evaluation of Liposomal Drug Delivery System Containing Etoposide

Fabrication of A Folic Acid-Modified Arsenic Trioxide Prodrug Liposome and Assessment of its Anti-Hepatocellular Carcinoma Activity

ObjectiveTo reduce the toxicity and side effects of arsenic trioxide (ATO) and provide a new approach for the treatment of primary liver cancer, a folic acid-modified calcium arsenite liposomal “target-controlled” drug delivery system (FA-LP-CaAs) was fabricated using the reverse microemulsion method. MethodsA Malvern particle size analyzer and a transmission electron microscope were employed to determine the particle size, distribution, zeta potential and morphology of FA-LP-CaAs. Further, inductively coupled plasma emission spectrometry was employed to determine the drug loading capacity, entrapment efficiency, and in vitro release behavior of FA-LP-CaAs. To determine its toxicity in human hepatoma cells (HepG2) and human normal hepatocytes (LO2) and its effect on HepG2 cell cycle and apoptosis, the MTT method was used. Laser confocal and flow cytometry were also employed to determine the uptake of FA-LP-CaAs by cells. After establishing a mouse liver cancer model, the in vivo distribution of the drug included in the formulation was investigated using in vivo fluorescence. To evaluate the liver cancer targeting and anti-tumor effects of FA-LP-CaAs in vivo, the distribution of ATO in tissues and changes in tumor volume and body weight after liposomal administration were investigated using hematoxylin-eosin (HE)-stained tumor sections. ResultsThe particle size, zeta potential and PDI of FA-LP-CaAs were (122.67 ± 2.18) nm, (12.81 ± 0.75) mV and 0.22 ± 0.01, respectively, while its drug loading capacity was 18.49% ± 1.14%. In vitro experimental results revealed that FA-LP-CaAs had a strong killing effect on HepG2 cells. Further, the cell uptake capacity of this formulation was found to improve. Based on in vivo assessments, FA-LP-CaAs could significantly increase the distribution of ATO in tumor sites and inhibit tumor growth. ConclusionsHerein, an FA-LP-CaAs formulation was successfully fabricated. This liposomal drug delivery system had a round appearance, uniform particle size, good polydispersity coeffi-cient, evident “core-shell” structure, high drug loading capacity and pH response, tumor targeted drug delivery and sustained drug release. These findings support further research and the application of ATO as an anti-liver cancer prodrug and provide a new method for the treatment of liver cancer.

Compositional inhomogeneity of drug delivery liposomes quantified at the single liposome level

Liposomes are the most used drug delivery vehicle and their therapeutic function is closely linked to their lipid composition. Since most liposome characterization is done using bulk techniques, providing only ensemble averages, the lipid composition of all liposomes within the same formulation are typically assumed to be identical. Here we image individual liposomes using confocal microscopy to quantify that liposomal drug delivery formulations, including multiple component mixtures mimicking Doxil, display more than 10-fold variation in their relative lipid composition. Since liposome function is tightly regulated by the physicochemical properties bestowed by the lipid composition, such significant variations could render only a fraction of liposomes therapeutically active. Additionally, we quantified how this degree of compositional inhomogeneity was modulated by liposome preparation method, the saturation state of the membrane lipid, and whether anti-fouling polyethylene glycol (PEG) conjugated lipids were added to the initial lipid mix or inserted after liposome formation. We believe the insights into the factors governing the degree of inhomogeneity offers the possibility for producing more uniform liposomal drug delivery systems, potentially increasing their therapeutic efficacy.