On the formulation of pH-sensitive liposomes with long circulation times

Strategies used to enhance liposome-mediated drug delivery in vivo include the enhancement of stability and circulation time in the bloodstream, targeting to specific tissues or cells, and facilitation of intracytoplasmic delivery. pH-sensitive liposomes have been developed to mediate the introduction of highly hydrophilic molecules or macromolecules into the cytoplasm. These liposomes destabilize under acidic conditions found in the endocytotic pathway, and usually contain phosphatidylethanolamine (PE) and titratable stabilizing amphiphiles. Formulations without PE have also been developed. Encapsulated compounds are thought to be transported into the cytoplasm through destabilization of or fusion with the endosome membrane. Incorporation of a low mole percentage of poly(ethylene glycol) (PEG)-conjugated lipids into pH-sensitive liposomes confers prolonged circulation times to these liposomes, which are otherwise cleared rapidly. While the incorporation of PEG-lipids reduces the pH-dependent release of encapsulated fluorescent markers in vitro, it does not hinder the cytoplasmic delivery of the markers per cell-associated liposome. This suggests that intracellular delivery is not dictated simply by the destabilization of the liposomes. Antibodies or ligands to cell surface receptors can be coupled to pH-sensitive or sterically stabilized pH-sensitive liposomes for targeting. pH-sensitive liposomes have been used to deliver anticancer drugs, antibiotics, antisense oligonucleotides, ribozymes, plasmids, proteins and peptides to cells in culture or in vivo.     

Solid lipid nanoparticles as drug delivery systems

For a decade, trials have been made to utilize solid lipid nanoparticles (SLNs) as alternative drug delivery systems to colloidal drug delivery systems such as lipid emulsions, liposomes, and polymeric nanoparticles. Various lipid matrices, surfactants, and other excipients used in formulation, preparation methods, sterilization and lyophilization of SLNs are discussed in this article. Entrapment efficiency of drug carrier and its effect on physical parameters, drug release, and release mechanisms of various compositions are reviewed and discussed. Important points in characterization and stability of SLNs are outlined. Various in vitro studies carried out by different research groups are mentioned in addition to in vivo evaluation. Exploitation potential of SLNs to administer by various routes of administration are covered. Passive and active drug targeting using SLNs are presented.     

Current methods for attaching targeting ligands to liposomes and nanoparticles

Liposomes and nanoparticles have emerged as versatile carrier systems for delivering active molecules in the organism. These colloidal particles have demonstrated enhanced efficacy compared to conventional drugs. However, the design of liposomes and nanoparticles with a prolonged circulation time and ability to deliver active compounds specifically to target sites remains an ongoing research goal. One interesting way to achieve active targeting is to attach ligands, such as monoclonal antibodies or peptides, to the carrier. These surface-bound ligands recognize and bind specifically to target cells. To this end, various techniques have been described, including covalent and noncovalent approaches. Both in vitro and in vivo studies have proved the efficacy of the concept of active targeting. The present review summarizes the most common coupling techniques developed for binding homing moieties to the surface of liposomes and nanoparticles. Various coupling methods, covalent and noncovalent, will be reviewed, with emphasis on the major differences between the coupling reactions, on their advantages and drawbacks, on the coupling efficiency obtained, and on the importance of combining active targeting with long-circulating particles.     

脂质体肺部给药研究进展

就脂质体雾化肺部给药剂型的稳定性、靶向性、安全性作一综述     

GABA-containing liposomes: neuroscience applications and translational perspectives for targeting neurological diseases

There are multiple challenges for neuropharmacology in the future. Undoubtedly, one of the greatest challenges is the development of strategies for pharmacological targeting of specific brain regions for treatment of diseases. GABA is the main inhibitory neurotransmitter in the central nervous system, and dysfunction of GABAergic mechanisms is associated with different neurological conditions. Liposomes are lipid vesicles that are able to encapsulate chemical compounds and are used for chronic drug delivery. This short review reports our experience with the development of liposomes for encapsulation and chronic delivery of GABA to sites within the brain. Directions for future research regarding the efficacy and practical use of GABA-containing liposomes for extended periods of time as well as understanding and targeting neurological conditions are discussed.     

细胞膜仿生纳米载体的制备及应用研究进展

由有机或无机纳米材料制备的药物载体系统广泛用于药物靶向递送和疾病的诊断治疗研究。但其存在靶向性差、体内循环时间短、生物相容性欠佳亟需提高等问题。仿生纳米药物系统是以不同种类的细胞膜修饰纳米载体,利用内源性的细胞膜提高载体的体内生物相容性、实现更精准的靶向、甚至由细胞自身的免疫原性产生免疫治疗作用。对细胞膜仿生纳米载体技术的原理、方法及其靶向机制和治疗作用作一综述,为新型给药系统研究提供思路。     

Mechanisms and kinetics of liposome-cell interactions

Although the possibility of targeting drugs to specific tissues and cells, as well as facilitating their uptake and cytoplasmic delivery has rendered liposomes a versatile drug carrier system with numerous potential applications in medicine, the molecular mechanisms of liposome-cell interactions are not understood well. Here we have reviewed the early and current concepts of liposome-cell interactions, including possible liposome receptors. Uptake of liposomes by cells can be modified by the lipid composition, particularly by the inclusion of steric stabilizers such as PEG-conjugated lipids. Such modifications also alter the circulation time and biodistribution of liposomes, which can thus be tailored for particular applications. The intracellular fate of encapsulated molecules can be modified by the use of pH-sensitive liposomes which can also be sterically stabilized. Cationic liposomes that can undergo lipid mixing with cellular membranes can deliver complexed DNA to cells, but most likely via an endocytotic process. Kinetic analysis of liposome-cell interactions can elucidate the numbers of liposome receptors of several types and the corresponding binding constants. It is likely that liposomes bind to different cell surface receptors on different cells, and that they utilize more than one type of receptor on a particular cell. The kinetic analysis also provides the rate constants of endocytosis and the percentages of liposomes that are bound or endocytosed.     

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.     

Steroid-coupled liposomes for targeted delivery to tumor

The steroidal receptors play a key role in protein synthesis and maintain the homeostasis in normal and diseased state, including tumorigenesis at the target tissues when overactivated. Thus steroidal receptors may act as potential targets for selective delivery of different therapeutic agents as they are overexpressed by a number of endocrinal tumors. The selective delivery of these agents may be a better treatment strategy for endocrinal cancer as it may also result in cytosolic and nuclear delivery of cytotoxic agents. In this review, the targeting potential of steroidal receptors for the drug or bioactive(s) delivery is discussed. The ligands that have been proven to be effective for specific steroidal receptors can be used as vectors for carrying the drug or drug-delivery system to the desired site of drug action in an optimum concentration. This strategy will not only minimize the undesired side effects associated with nonspecific delivery of drug, but will also maximize the drug utilization. Ligand-conjugated liposomes as a carrier of bioactives prevent passive diffusion of the encapsulated drug to normal cells, increase the time of circulation and reduce the undesirable side effects of a drug.     

脂质体修饰性材料应用研究进展

脂质体作为低毒性与免疫原性的药物载体已被应用于难溶性、不稳定、毒性等药物的递送,但传统脂质体仍存在稳定性差、体内循环时间不足、主动靶向性不明显等缺陷,因此选择适宜的修饰性材料制备脂质体已成为必要手段。修饰脂质体的方法主要有：在膜材中加入表面活性剂或改性物质,在膜表面嵌插靶向配体物质,将配体与膜材偶联共同组成脂质体结构。通过总结近年来脂质体常用的修饰性材料,阐释修饰原理并分析其优势及弊端,为脂质体的研究与开发提供借鉴。     

Molecular targeting of liposomal nano-particles to lymphatic system

Conventional liposomal drug delivery has been associated with obvious limitations, such as a rapid absorption by the recticulo-endothelial system in the liver and spleen, a short circulation time and a low therapeutic efficacy. Various modifications of liposomal drugs have been developed to prolong the duration of actions of the drugs at target sites, reduce its adverse effects and increase therapeutic index of drugs such as polymeric conjugation and polymeric fixation on the surface of a liposome. The lymphatic system is an important highway to spread the metastasis of most human cancers including breast, colon, and lung, ovarian and prostate. To eradicate those metastatic cancer cells from the lymphatic system, several efforts have been made to develop new and efficient lymphatic targeting drug delivery systems in order to achieve a high initial lymphatic uptake and lymph node localization. Recently, molecule targeting of liposome to lymphatic system may enhance therapeutic efficacy by improving the initial lymphatic uptake and the lymph nodal retention of liposomes such as the ligand-receptor and antibodies binding on the surface of liposome. This article aims to review the emerging liposomal drug, which is targeting the lymphatic system. The significant factors associated with targeting liposomal drugs will also be discussed in more detail in this review.     

The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs

The size of liposomes has been shown to be an important factor in the efficient delivery of an antitumor agent to a tumor. In this paper, the effects of the size of liposomes on the pharmacokinetics of liposomes and liposome-encapsulated drugs are discussed with reference to: (1) the circulation amount and residence time of liposomes in the blood, (2) the accumulation of liposomes in the tumor, and (3) in vivo drug release from liposomes. In addition, the effect of size on therapeutic activity (antitumor efficacy and toxicity) of a liposomal anticancer preparation is discussed. Finally we discuss the importance of liposome size in the design of a more effective liposomal antitumor preparation.     

Glycosylated cationic liposomes for cell-selective gene delivery

Cationic liposomes have been considered as a potential nonviral vector for gene delivery because they possess low immunogenicity, unlike viral vectors. The gene transfer efficiency of cationic liposomes is lower than that ofviral vectors, but recent advances have shown that it is possible to enhance the gene expression levels of cationic liposomes. The main problem with cationic liposomes seems to be the lack of organ or cell selectivity because the lung has the highest level of gene expression after intravenous injection. Applying cell-specific targeting technology to liposomes would improve in vivo gene delivery and reduce any unexpected side effects. Both liver parenchymal and non-parenchymal cells exclusively express large numbers of high-affinity asialoglycoprotein and mannose receptors, respectively. Receptor-mediated gene delivery systems are able to introduce foreign DNA into specific cell types in vivo. However, we have confirmed that not only the nature of the ligands grafted to carriers but also the overall physicochemical properties of the complexes need to be optimized for effective cell-selective targeting of plasmid DNA. In this article, we attempt to evaluate a gene delivery system based on the physicochemical properties of plasmid DNA/glycosylated cationic complexes.     

Recent advances in the design and synthesis of prednisolone and methylprednisolone conjugates

Glucocorticoid drugs are commonly used in the treatment of many acute and chronic inflammatory diseases. However, application of these steroids is limited because of their physico-chemical properties, such as very low water solubility. Glucocorticoids also exhibit serious adverse side effects. Therefore, new drug delivery systems are being developed, with the aim of improving the physicochemical properties of glucocorticoids while avoiding undesirable side effects associated with systemic administration. Here we discuss the design and synthesis of conjugates of prednisolone (PD), methylprednisolone (MPD) and similar glucocorticoids. In this review, possibilities for targeting inflammatory sites, and reducing dosages and administration frequency through increasing drug circulation time are discussed. This review summarises synthetic approaches for the preparation of covalent conjugates, which are divided into two groups: low molecular weight conjugates and polymeric conjugates. These two groups are further divided into subgroups based on the chemical structure of the conjugates. Published results from in vitro and in vivo testing of prepared conjugates are also discussed.     

Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects

The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.     

Synthetic nanocarriers for intracellular protein delivery

Introducing exogenous proteins intracellularly presents tremendous chances in scientific research and clinical applications. The effectiveness of this method, however, has been limited by lack of efficient ways to achieve intracellular protein delivery and poor stability of the delivered proteins. Over the years, a variety of nanomaterials have been explored as intracellular protein delivery vectors, including liposomes, polymers, gold nanoparticles, mesoporous silica particles, and carbon nanotubes. Nanomaterials stand out in various protein delivery systems due to various advantages, such as efficient intracellular delivery, long circulation time, and passive tumor targeting. Additionally, chemistry behind these nanomaterials provides readily engineered materials, enabling versatile designs of delivery agents. Intracellular delivery mediated by such nanocarriers achieved varying degrees of success. Different problems associated with these nanocarriers, however, still hamper their real-world applications. Developing new delivery methods or vectors remains essential but challenging. This review surveys the current developments in protein delivery based on synthetic nanocarriers, including liposomes, polymers and inorganic nanocarriers; Prospects for future development of protein delivery nanocarriers are also provided.     

Liposomes as targetable drug carriers

The general problem of targeted drug transport is critically reviewed and three principle components of targeted systems are discussed: the target, the vector molecule, and the carrier. Different systems of drug targeting are briefly described: local drug application, chemical modification of the drug molecule, physical targeting under the action of pH, temperature, or magnetic field. The idea of a vector molecule is discussed and different methods of vector molecule coupling with the drug are reviewed (direct coupling, coupling via spacer group or polymer molecule, etc.). It is shown that the most promising approach seems to be the use of a drug-containing microcontainer with the vector molecule immobilized on its outer surface. Different types of microcontainers are briefly described: microcapsules, cell hosts, and liposomes. The advantages of liposomes as drug containers are shown and the main problems of their use for drug targeting in vitro and in vivo conditions are discussed. One of the most important problems is the problem of vector molecule immobilization on liposome surfaces. The principle four different immobilization methods: adsorbtion, incorporation, covalent binding, and hydrophobic binding. Targeted liposome transport is described in model systems, cell cultures, and experimental animals. It is shown that targeted liposomes may release a drug via diffusion, lysis, or endocytosis by appropriate cells. The problems of targeted liposome technology and clinical application are analyzed.     

Cell-specific delivery of genes with glycosylated carriers.

Cationic liposomes and polymers have been accepted as effective non-viral vectors for gene delivery with low immunogenicity unlike viral vectors. However, the lack of organ or cell specificity sometimes hampers their application and the development of a cell-specific targeting technology for them attracts great interest in gene therapy. In this review, the potential of cell-specific delivery of genes with glycosylated liposomes or polymers is discussed. Galactosylated liposomes and poly(amino acids) are selectively taken up by the asialoglycoprotein receptor-positive liver parenchymal cells in vitro and in vivo after intravenous injection. DNA-galactosylated cationic liposome complexes show higher DNA uptake and gene expression in the liver parenchymal cells in vitro than DNA complexes with bare cationic liposomes. In the in vitro gene transfer experiment, galactosylated liposome complexes are more efficient than DNA-galactosylated poly(amino acids) complexes but they have some difficulties in their biodistribution control. On the other hand, introduction of mannose residues to carriers resulted in specific delivery of genes to non-parenchymal liver cells. These results suggest advantages of these glycosylated carriers in cell-specific targeted delivery of genes.     

Targeted liposomal drug delivery in cancer

Liposomes, which are biodegradable and essentially non-toxic vehicles, can encapsulate both hydrophilic and hydrophobic materials, and are utilized as drug carriers in drug delivery systems. In addition, liposomes can be used to carry radioactive compounds as radiotracers can be linked to multiple locations in liposomes. One option is the hydrated compartment inside the liposome, another the lipid core into which especially hydrophobic conjugates can be attached, and the third option is the outer lipid leaflet where molecules can be bound by covalent linkage. Delivery of agents to the reticuloendothelial system (RES) is easily achieved, since most conventional liposomes are trapped by the RES. For the purpose of delivery of agents to target organs other than RES, long-circulating liposomes have been developed by modifying the liposomal surface. Understanding of the in vivo dynamics of liposome-carried agents is required for the evaluation of the bioavailability of drugs encapsulated in liposomes. In this review, we focus on the in vivo trafficking of liposomes visualized by positron emission tomography (PET) and discuss the characteristics of liposomes that affect the targeting of drugs in vivo.