Liposomes to target the lymphatics by subcutaneous administration

Liposomes have been proposed as carriers for the delivery of therapeutic and diagnostic agents to the lymphatic system. Subcutaneous (s.c.) injection is the route of administration most extensively studied for this purpose. Decisive factors influencing lymphatic absorption and lymph node uptake of s.c. administered liposomes are liposome size and the anatomical site of injection. Generally, other factors such as lipid composition, charge and the presence of a hydrophilic PEG-coating on the liposome surface do not substantially affect lymphatic absorption and lymph node uptake of s.c. administered liposomes. Studies on the intranodal fate of liposomes demonstrate that phagocytosis by macrophages is the most important mechanism for lymph node uptake of liposomes. The observation of relatively high uptake of liposomes in regional lymph nodes after s.c. administration has stimulated research on lymphatic targeting of liposomes for diagnostic and therapeutic applications.     

Recent advances in tumor vasculature targeting using liposomal drug delivery systems

Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells).     

Liposomal drug delivery systems: an update review

The discovery of liposome or lipid vesicle emerged from self forming enclosed lipid bi-layer upon hydration; liposome drug delivery systems have played a significant role in formulation of potent drug to improve therapeutics. Recently the liposome formulations are targeted to reduce toxicity and increase accumulation at the target site. There are several new methods of liposome preparation based on lipid drug interaction and liposome disposition mechanism including the inhibition of rapid clearance of liposome by controlling particle size, charge and surface hydration. Most clinical applications of liposomal drug delivery are targeting to tissue with or without expression of target recognition molecules on lipid membrane. The liposomes are characterized with respect to physical, chemical and biological parameters. The sizing of liposome is also critical parameter which helps characterize the liposome which is usually performed by sequential extrusion at relatively low pressure through polycarbonate membrane (PCM). This mode of drug delivery lends more safety and efficacy to administration of several classes of drugs like antiviral, antifungal, antimicrobial, vaccines, anti-tubercular drugs and gene therapeutics. Present applications of the liposomes are in the immunology, dermatology, vaccine adjuvant, eye disorders, brain targeting, infective disease and in tumour therapy. The new developments in this field are the specific binding properties of a drug-carrying liposome to a target cell such as a tumor cell and specific molecules in the body (antibodies, proteins, peptides etc.); stealth liposomes which are especially being used as carriers for hydrophilic (water soluble) anticancer drugs like doxorubicin, mitoxantrone; and bisphosphonate-liposome mediated depletion of macrophages. This review would be a help to the researchers working in the area of liposomal drug delivery.     

Nanoparticle drug delivery systems: an excellent carrier for tumor peptide vaccines

In the past 40 years, the nanoparticle drug delivery system for tumor peptide vaccines has been widely studied which also reached a splendid result. Nanomaterial can enhance the targeting of vaccines, help vaccines enter the cells and trigger immune response by themselves. They also help in increasing cellular uptake, improving permeability and efficacy. Currently, several categories of nanopreparation, such as liposome, polymeric micelle, polymeric nanoparticle, gold nanoparticle and so on, are proved that they are appropriate for peptide vaccines. This review we discussed the possible mechanisms of nanomaterial’s action on the regulation of immunological functions and several major applications of this advanced drug delivery system for tumor peptide vaccine.     

Recent approaches of lipid-based delivery system for lymphatic targeting via oral route

Abstract

Lymphatic system is a key target in research field due to its distinctive makeup and huge contributing functions within the body. Intestinal lymphatic drug transport (chylomicron pathway) is intensely described in research field till date because it is considered to be the best for improving oral drug delivery by avoiding first pass metabolism. The lymphatic imaging techniques and potential therapeutic candidates are engaged for evaluating disease states and overcoming these conditions. The novel drug delivery systems such as self-microemulsifying drug delivery system, nanoparticles, liposomes, nano-lipid carriers, solid lipid carriers are employed for delivering drugs through lymphatic system via various routes such as subcutaneous route, intraperitoneal route, pulmonary route, gastric sub-mucosal injection, intrapleural and intradermal. Among these colloidal particles, lipid-based delivery system is considered to be the best for lymphatic delivery. From the last few decades, mesenteric lymph duct cannulation and thoracic lymph duct cannulation are followed to assess lymphatic uptake of drugs. Due to their limitations, chylomicrons inhibitors and in-vitro models are employed, i.e. lipolysis model and permeability model. Currently, research on this topic still continues and drainage system used to deliver the drugs against lymphatic disease as well as targeting other organs by modulating the chylomicron pathway.     

Liposomes in the treatment of infectious diseases

Phospholipids and other polar lipids can form liposomes and similar colloidal particles that can be used as drug carrier systems. The potential of liposomal delivery systems to increase the therapeutic index (efficacy to safety ratio) of clinically important drugs has been realised with the recent approval of liposomal oncologic and antifungal drugs. The application of liposomes to the treatment of infectious diseases initially focused on intracellular pathogens, based on the natural targeting of liposomes to phagocytic cells and on the antifungal drug amphotericin B, based on its unique affinity for lipids. Recent studies with small, low-clearance liposomes have shown that more specialised formulations may provide benefits over simpler ‘first generation’ liposomes for the treatment of infectious diseases, including prolonged residence in plasma, increased tissue exposure and targeting to sites of infection. These improved biopharmaceutical properties have been associated with both curative and prophylactic activity against a range of non-intracellular pathogens, including Staphylococcus and Klebsiella. These and other highly engineered liposome formulations may provide effective delivery systems for specific antibacterial, antifungal and antiviral indications in the future. Adequate patent protection will be crucial in fully exploiting these advanced liposome technologies and in maintaining market share for liposomal products. This review discusses some of the patent issues related to liposomes and their use in the treatment of infectious diseases.     

Pharmacokinetics and pharmacodynamics of lipidic nano-particles in cancer

Nanoscale drug delivery systems (DDS) are used to circumvent some of the non-ideal properties of conventional anticancer chemotherapy drugs. Manipulation of the physical properties of DDS provides improved control over the pharmacokinetics (PK) and pharmacodynamics (PD) of the encapsulated drugs relative to free drugs. Liposomes are the archetypical nanoscale DDS and the first of these received clinical approval in 1990. DOXIL, liposomal doxorubicin, was the first commercially available liposomal anticancer drug (1995). It has an enhanced circulation half-life compared to the free drug because of its surface-grafted polyethylene glycol coating. DOXIL passively targets solid tumors, and once the liposomes localize in the tumor interstitial space, the cytotoxic drug is slowly released within the tumor. Liposomes can act as sustained release delivery system and manipulation of properties such as, liposome diameter, drug release rate, bioavailability and dosing schedule can significantly impact the therapeutic outcome of the liposomal drugs. This review will focus on how alteration of these properties can impact the therapeutic efficacy and side effect profiles of DDS.     

Translocation of liposomes into cancer cells by cell-penetrating peptides penetratin and tat: a kinetic and efficacy study

Unlike conventional liposomes, sterically stabilized liposomes, with their smaller volume of distribution and reduced clearance, preferentially convey encapsulated drugs into tumor sites. Despite these improvements, intracellular delivery is hampered by the stable drug retention of the liposomes, which diminishes the efficacy of the liposomal drug. To facilitate uptake of liposomal drugs into cells, two cell-penetrating peptides, penetratin (PEN) and TAT, derived from the HIV-1 TAT protein, were studied. In contrast to control peptides, both TAT and PEN enhanced the translocation efficiency of liposomes in proportion to the number of peptides attached to the liposomal surface. A peptide number of as few as five could enhance the intracellular delivery of liposomes. The kinetics of uptake was peptide- and cell-type dependent. Intracellular accumulation of TAT-liposomes increased with incubation time, but PEN-liposomes peaked at 1 h and then declined gradually. After treatment with 1 microg/ml doxorubicin equivalents of liposome for 2 h, TAT increased the doxorubicin uptake of A431 cells by 12-fold. However, the improvement of uptake of liposomal doxorubicin was not reflected by cytotoxicity in vitro or tumor control in vivo. Our results demonstrated that merely adding CPP to a liposome encapsulating anticancer drug was inadequate in improving its antitumor activity. An additional approach to enhance the intracellular release of the encapsulated drug is obviously necessary.     

Liposomes and liposome-like nanoparticles: From anti-fungal infection to the COVID-19 pandemic treatment

The liposome is the first nanomedicine transformed into the market and applied to human patients. Since then, such phospholipid bilayer vesicles have undergone technological advancements in delivering small molecular-weight compounds and biological drugs.Numerous investigations about liposome uses were conducted in different treatment fields,including anti-tumor, anti-fungal, anti-bacterial, and clinical analgesia, owing to liposome’s ability to reduce drug cytotoxicity and improve the therapeut...     

Liposomal drug formulations in the treatment of rheumatoid arthritis

Liposomes have been extensively investigated as drug delivery systems in the treatment of rheumatoid arthritis (RA). Low bioavailability, high clearance rates and limited selectivity of several important drugs used for RA treatment require high and frequent dosing to achieve sufficient therapeutic efficacy. However, high doses also increase the risk for systemic side effects. The use of liposomes as drug carriers may increase the therapeutic index of these antirheumatic drugs. Liposomal physicochemical properties can be changed to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to nontarget tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells in RA. This review gives an overview of liposomal drug formulations studied in a preclinical setting as well as in clinical practice. It covers the use of liposomes for existing antirheumatic drugs as well as for new possible treatment strategies for RA. Both local administration of liposomal depot formulations and intravenous administration of passively and actively targeted liposomes are reviewed.     

Roles of dextrans on improving lymphatic drainage for liposomal drug delivery system

Our aim was to develop a novel liposomal drug delivery system containing dextrans to reduce undesirable retention of antineoplastic agents and thus alleviate local tissue damage. At the cell level, diethylaminoethyl-dextran (DEAE-Dx) showed the strongest inhibiting effect on liposome uptake by macrophages among tested dextrans. The distribution of radiolabeled liposomes mixed with dextrans in injection site and draining lymph node was investigated in rats after subcutaneous injection. DEAE-Dx substantially reduced the undesired local retention and promoted the draining of liposome into lymphatics, which was further confirmed by confocal microscopy images revealing the substantial prevention of rhodamine B-labelled liposome sequestration by macrophages in normal lymph node in rats. Pharmacokinetic data indicated the accelerated drainage of liposome through lymphatics back to systemic circulation by mixing with DEAE-Dx. In the toxicological study in rabbits, DEAE-Dx alleviated the local tissue damage caused by liposomal doxorubicin. In conclusion, dextrans, particularly DEAE-Dx, could efficiently enhanced liposomes drainage into lymphatics, which proves themselves as promising adjuvants for lymphatic-targeted liposomal drug delivery system.     

New generation of liposomal drugs for cancer

This review is focused on liposomes as a delivery system for anticancer agents and more specifically on the advantages of using liposomes as drug nanocarrier in cancer chemotherapy. The main advantages of liposomal drugs over the non-encapsulated drugs include: (1) improved pharmacokinetics and drug release, (2) enhanced intracellular penetration, (3) tumor targeting and preventing adverse side effects and (4) ability to include several active ingredients in one complex liposomal drug delivery system (DDS). The review also includes our recent data on advanced liposomal anticancer drug delivery systems. As a conclusion we propose a novel liposomal DDS which includes inhibitors of pump resistance combined in one liposomal drug delivery system with an inhibitor of antiapoptotic cellular defense, an apoptosis inducer (a traditional anticancer drug) and a targeting moiety. The proposed drug delivery system utilizes a novel three tier approach, simultaneously targeting three molecular targets: (1) extracellular receptors or antigen expressed on the surface of plasma membrane of cancer cells in order to direct the whole system specifically to the tumor, preventing adverse side effects on healthy tissues; (2) drug efflux pumps in order to inhibit them and enhance drug retention by cancer cells, increasing intracellular drug accumulation and thereby limiting the need for prescribed high drug doses that cause adverse drug side effects; and (3) intracellular controlling mechanisms of apoptosis in order to suppress cellular antiapoptotic defense.     

Targeting Anticancer Drugs to Tumor Vasculature Using Cationic Liposomes

Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.     

Fate and behavior of liposomes in vivo: a review of controlling factors

Of fundamental importance in the design of a therapeutic drug carrier system is a thorough understanding of the factors which control its fate in the living animal. The use of liposomes as a carrier system able to improve the therapeutic efficacy of a wide range of drugs, requires manipulation of its physical characteristics, thereby influencing in vivo behavior. This review brings together findings of recent studies which describe how liposomal stability and clearance in vivo are controlled by the architecture of the vesicles themselves which in turn, via interaction with humoral factors, controls the fate in terms of tissue distribution of the carrier and its contents. Based on these studies, a rationale for liposome design aimed at in vivo drug delivery is discussed.     

Bone marrow-targeted liposomal carriers

INTRODUCTION: Bone marrow-targeted drug delivery systems appear to offer a promising strategy for advancing diagnostic, protective and/or therapeutic medicine for the hematopoietic system. Liposome technology can provide a drug delivery system with high bone marrow targeting that is mediated by specific phagocytosis in bone marrow. AREA COVERED: This review focuses on a bone marrow-specific liposome formulation labeled with technetium-99 m. Interspecies differences in bone marrow distribution of the bone marrow-targeted formulation are emphasized. This review provides a liposome technology to target bone marrow. In addition, the selection of proper species for the investigation of bone marrow targeting is suggested. EXPERT OPINION: It can be speculated that the bone marrow macrophages have a role in the delivery of lipids to the bone marrow as a source of energy and for membrane biosynthesis or in the delivery of fat-soluble vitamins for hematopoiesis. This homeostatic system offers a potent pathway to deliver drugs selectively into bone marrow tissues from blood. High selectivity of the present bone marrow-targeted liposome formulation for bone marrow suggests the presence of an active and specific mechanism, but specific factors affecting the uptake of the bone marrow mononuclear phagocyte system are still unknown. Further investigation of this mechanism will increase our understanding of factors required for effective transport of agents to the bone marrow, and may provide an efficient system for bone marrow delivery for therapeutic purposes.     

纳米粒淋巴靶向的研究进展

目的从淋巴靶向方面综述脂质体、纳米活性炭以及纳米碳管纳米粒的研究进展。方法参考近年来32篇相关的中外文献,在淋巴系统的生理基础上,探讨上述纳米粒的淋巴靶向性及其在淋巴靶向方面的应用。结果脂质体具有天然的淋巴靶向性。纳米活性炭有较好的淋巴趋向性,并能在淋巴结处缓缓释放出药物。纳米碳管可通过表面修饰来提高其淋巴靶向性。上述纳米粒均可以作为显影剂与药物载体以提高其淋巴靶向性。结论纳米粒有较好的淋巴靶向性,可以作为显影剂和药物靶向淋巴的理想载体。     

Drug delivery systems. 1. site-specific drug delivery using liposomes as carriers

Drug delivery systems, offering controlled delivery of biologically active agents, are rapidly gaining importance in pharmaceutical research and development. To achieve controlled drug delivery, i.e., the administration of drugs so that optimal amount reaches the target site to cure or control the disease state, increasingly sophisticated systems containing different carriers have been developed. Macromolecules represent one of the carriers involved, and they have taken on a significantly prominent role in various modes of administration of therapeutic agents. Among macromolecules, for example, synthetic copolymers, polysaccharides, liposomes, polyanions and antibodies, as drug carriers, liposomes have proved most effective for diseases affecting the reticuloendothelial system and blood cells in particular. Liposomes, which are vesicles consisting of one or more concentrically ordered assemblies of phospholipids bilayers, range in size from a nanometer to several micrometers. Phospholipids such as egg phosphatidylcholine, phosphatidylserine, synthetic dipalmitoyl-DL-alpha-phosphatidylcholine or phosphatidylinositol, have been used in conjunction with cholesterol and positively or negatively charged amphiphiles such as stearylamine or phosphatidic acid. Alteration of surface charge has been shown to enhance drug incorporation and also influence drug release. Because of the multifold characteristics as drug carriers, liposomes have been investigated extensively as carriers of anticancer agents for the past several years. Liposomal entrapments include a variety of pharmacologically active compounds such as antimalarial, antiviral, anti-inflammatory and anti-fungal agents as well as antibiotics, prostaglandins, steroids and bronchodilators to name a few. The liposomal entrapment has been shown to have considerable effect on the pharmacokinetics and tissue distribution of administered drugs. Despite the potential value of liposomes as unique carriers, the major obstacles are the first order targeting of a systemically given liposomes, physical stability and manufacture of the liposomal products and these problems still remain to be overcome. Drug delivery systems evolving in the 1980s have become increasingly dependent on fundamental cell-biology and receptor-mediated endocytotic mechanisms. Drug delivery systems during the 1990s may take advantage of the specificity of receptor-mediated uptake mechanisms as well as polymer chemistry and cell-biology in order to introduce more precise and efficient target-specific delivery systems that are based especially on the liposome technology.     

Lymphatic targeting with nanoparticulate system

Much effort has been made to achieve lymphatic targeting of drugs using colloidal carriers. This paper reviews the recent progress in the development of biodegradable nanoparticulate systems, including nanospheres, emulsions, and liposomes. The major purpose of lymphatic targeting is to provide an effective anticancer chemotherapy to prevent the metastasis of tumor cells by accumulating the drug in the regional lymph node via subcutaneous administration. The objectives of lymph targeting also involve the localization of diagnostic agents to the regional lymph node to visualize the lymphatic vessels before surgery, and the improvement of peroral bioavailability of macromolecular drugs, like polypeptides or proteins, which are known to be selectively taken up from the Peyer's patch in the intestine. Nanocapsules, which are ultrafine oily droplet-coated polymeric substances, are probably one of the most promising candidates of colloidal carriers. Surface engineering by the interfacial deposition method can provide a suitable size distribution and necessary surface characteristics to the nanocapsules. Our recent in vivo study proved that polyisobutylcyanoacrylate nanocapsules showed enhanced accumulation of drug in the lymph node, compared with other carriers such as emulsions and liposomes.     

Protein-coated and polysaccharide-coated liposomes as drug carriers

Saccharides on the surface of cell membranes play an important role in cell-cell recognition, which is the most important process utilizable for targeting of drugs encapsulated in an artificial cell, liposome. To design a targetable drug carrier, hence, employing synthesized or natural glycolipids as the recognition site of the liposomal drug carrier is certainly one of useful approach. On the other hand, coating the outermost surface of liposomes with polysaccharide derivatives is also another way for liposomes to be utilized as a targetable drug carrier. In this review, from such a viewpoint, the importance and usefulness of saccharide moiety on the surface of liposomes will be discussed in conjunction with the targeting of drugs.     

Liposome formulated with TAT-modified cholesterol for improving brain delivery and therapeutic efficacy on brain glioma in animals

The treatment of central nervous system diseases such as brain glioma is a major challenge due to the presence of the blood-brain barrier (BBB). A cell-penetrating peptide TAT (AYGRKKRRQRRR), which appears to enter cells with alacrity, was employed to enhance the delivery efficiency of normal drug formulation to the brain. Targeting liposomal formulations often apply modified phospholipids as anchors. However, cholesterol, another liposomal component more stable and cheaper, has not been fully investigated as an alternative anchor. In our study, TAT was covalently conjugated with cholesterol for preparing doxorubicin-loaded liposome for brain glioma therapy. Cellular uptake by brain capillary endothelial cells (BCECs) and C6 glioma cells was explored. The anti-proliferative activity against C6s confirmed strong inhibitory effect of the liposomes modified with doxorubicin-loaded TAT. The bio-distribution findings in brains and hearts were evident of higher efficiency of brain delivery and lower cardiotoxic risk. The results on survival of the brain glioma-bearing animals indicate that survival time of the glioma-bearing rats treated with TAT-modified liposome was much longer than in the other groups. In conclusion, the potency of the TAT-modified liposome to enter the BBB appears to be related with the TAT on the liposome's surface. The TAT-modified liposome may improve the therapeutic efficacy on brain glioma in vitro and in vivo.