主动靶向脂质体研究进展

目的 介绍主动靶向脂质体最新研究进展。方法 查阅近年来国内外相关文献,对主动靶向脂质体的表面修饰、配体选择及应用进行进行总结和归纳。结果 主动靶向脂质体的表面修饰有三种方法：作为组份直接制备;键合到脂质体表面;后插入法。主动靶向脂质体可以将药物传递到靶组织、靶向细胞或靶细胞器,提高药物的生物利用度,而不增加对正常组织或细胞的毒性,是近年研究最为广泛的主动靶向给药系统。结论 主动靶向脂质体是一种非常有前途的给药系统。     

Liposomes and their applications in molecular imaging

Molecular imaging is a relatively new discipline with a crucial role in diagnosis and treatment tracing of diseases through characterization and quantification of biological processes at cellular and sub-cellular levels of living organisms. These molecular targeted systems can be conjugated with contrast agents or radioligands to obtain specific molecular probes for the purpose of diagnosis of diseases more accurately by different imaging modalities. Nowadays, an interesting new approach to molecular imaging is the use of stealth nanosized drug delivery systems such as liposomes having convenient properties such as biodegradability, biocompatibility and non-toxicity and they can specifically be targeted to desired disease tissues by combining with specific targeting ligands and probes. The targeted liposomes as molecular probes in molecular imaging have been evaluated in this review. Therefore, the essential point is detection of molecular target of the disease which is different from normal conditions such as increase or decrease of a receptor, transporter, hormone, enzyme etc, or formation of a novel target. Transport of the diagnostic probe specifically to targeted cellular, sub-cellular or even to molecular entities can be performed by molecular imaging probes. This may lead to produce personalized medicine for imaging and/or therapy of diseases at earlier stages.     

Effective Targeting of Liposomes to Liver and Hepatocytes In Vivo by Incorporation of a Plasmodium Amino Acid Sequence

Purpose Several species of the protozoan Plasmodium effectively target mammalian liver during the initial phase of host invasion. The purpose of this study was to demonstrate that a Plasmodium targeting amino acid sequence can be engineered into therapeutic nanoparticle delivery systems. Methods A 19-amino peptide from the circumsporozoite protein of Plasmodium berghei was prepared containing the conserved region I as well as a consensus heparan sulfate proteoglycan binding sequence. This peptide was attached to the distal end of a lipid–polyethylene glycol bioconjugate. The bioconjugate was incorporated into phosphatidylcholine liposomes containing fluorescently labeled lipids to follow blood clearance and organ distribution in vivo. Results When administered intravenously into mice, the peptide-containing liposomes were rapidly cleared from the circulation and were recovered almost entirely in the liver. Fluorescence and electron microscopy demonstrated that the liposomes were accumulated both by nonparenchymal cells and hepatocytes, with the majority of the liposomal material associated with hepatocytes. Accumulation of liposomes in the liver was several hundredfold higher compared to heart, lung, and kidney, and more than 10-fold higher compared to spleen. In liver slice experiments, liposome binding was specific to sites sensitive to heparinase. Conclusions Incorporation of amino acid sequences that recognize glycosaminoglycans is an effective strategy for the development of targeted drug delivery systems. K. J. Longmuir and R. T. Robertson were the primary investigators for this study.     

Liposomes for targeted delivery of antithrombotic drugs

Background: Targeted delivery of antithrombotic (thrombolytic) drugs is expected to increase their efficacy and decrease side effects, especially in the case of thrombolytic enzymes. Liposomes, phospholipid nanosized bubbles with a bilayered membrane structure, have drawn a lot of interest as pharmaceutical carriers for drugs and genes. In particular, several attempts have been made to use liposomes as vehicles for antithrombotic agents. Objective: This review analyzes the available data on the application of liposomes, including liposomes targeted by specific ligands, for the delivery of antithrombotic/thrombolytic agents in order to increase their efficacy and decrease side effects. Methods: The papers published on the subject of liposomes loaded with antithrombotic agents, mainly over the last 10 – 15 years, will be discussed. Conclusion: Liposomes loaded with various antithrombotic drugs, though they have been the subject of a significant number of experimental papers, can hardly be considered as real candidates for clinical application in the near future.     

Accumulation of Protein-Loaded Long-Circulating Micelles and Liposomes in Subcutaneous Lewis Lung Carcinoma in Mice

Purpose. The purpose of our work was to compare the biodistribution and tumor accumulation of a liposome- or micelle-incorporated protein in mice bearing subcutaneously-established Lewis lung carcinoma. Methods. A model protein, soybean trypsin inhibitor (STI) was modified with a hydrophobic residue of N-glutaryl-phosphatidyl-ethanolamine (NGPE) and incorporated into both polyethyleneglycol(MW 5000)-distearoyl phosphatidyl ethanolamine (PEG-DSPE) micelles (< 20 nm) and PEG-DSPE-modified long-circulating liposomes (ca. 100 nm). The protein was labeled with ¹¹¹In via protein-attached diethylene triamine pentaacetic acid (DTPA), and samples of STI-containing liposomes or micelles were injected via the tail vein into mice bearing subcutaneously-established Lewis lung carcinoma. At appropriate time points, mice were sacrified and the radioactivity accumulated in the tumor and main organs was determined. Results. STI incorporated into PEG-lipid micelles accumulates in sub-cutaneously established Lewis lung carcinoma in mice better than the same protein anchored in long-circulating PEG-liposomes. Conclusions. Small-sized long-circulating delivery systems, such as PEG-lipid micelles, are more efficient in the delivery of protein to Lewis lung carcinoma than larger long-circulating liposomes.     

Liposomes in cosmeceutics

Introduction: Cosmeceuticals are cosmetic products with biologically active ingredients purporting to have medical or drug-like benefits. Some cosmeceuticals can act effectively when reaching their target sites in the deeper layers of the skin. However, the barrier nature of skin causes significant difficulties for compounds to be delivered through. Therefore, scientists are investigating various strategies to overcome these barrier properties. Liposomes have been claimed to improve the topical delivery of compounds.

Areas covered: This paper offers a brief overview of current approaches in the research and development of liposomal formulations to improve the performance of cosmeceuticals, from recent literature. This review deals with the potential of liposomes as a skin delivery system for cosmeceuticals, with a focus on the clinical application of liposomes.

Expert opinion: Liposomes are well-known vesicular cosmetic delivery systems. The topical application of liposomes offers a wide range of advantages including increased moisturization, restoring action, biodegradability, biocompatibility and extended and slow dermal release. Their similar structure to biological membranes allows penetration into the epidermal barrier, compared with other delivery systems. The incorporation of cosmeceuticals using suitable delivery systems is important in the management of cosmetic disorders.     

Adenosine Triphosphate Liposomes: Encapsulation and Distribution Studies

Four methods for encapsulating adenosine triphosphate (ATP) in liposomes were evaluated. Optimum entrapment required emulsifying ATP with the lipids used to form the liposome membrane in a high-speed homogenizer followed by evaporating the organic solvent with vigorous stirring. Under these optimum conditions ATP entrapment was 38.9%; i.e., the dosage form contained 38.9 g of ATP per 100 g of lipid. The distribution of positively charged liposomes loaded with ATP was studied in dogs with experimentally induced myocardial infarction. Intravenous injection of positively charged ATP liposomes caused accumulation of ATP in myocardial infarct tissue. Myocardial infarct tissue has reduced blood flow; since positively charged liposomes accumulated in infarct tissue, liposomes may be a drug delivery system for this disease state.     

Targeted drug delivery for treatment and imaging of glioblastoma multiforme

Glioblastoma multiforme is a grade IV astrocytic tumor with a very high mortality rate. Although current treatment often includes surgical resection, this rarely removes all primary tumor cells, so is usually followed by radiation and/or chemotherapy. Remaining migratory tumor cells invade surrounding healthy tissue and contribute to secondary and tertiary tumor recurrence; therefore, despite significant research into glioma removal and treatment, prognosis remains poor. A variety of treatment modalities have been investigated to deliver drug to these cells, including systemic, diffusive and convection-enhanced delivery (CED). As systemic delivery is limited by molecules larger than ～ 500 Da being unable to cross the blood–brain barrier (BBB), therapeutic concentrations are difficult to attain; thus, localized delivery options relying on diffusion and CED have been used to circumvent the BBB. Although CED enables delivery to a greater volume of tissue than diffusive delivery alone, limitations still exist, requiring that these delivery strategies be improved. This review enumerates the strengths and weaknesses of these currently used strategies and details how predictive mathematical modeling can be used to aid investigators in optimizing these delivery modalities for clinical application.     

Surface structured liposomes for site specific delivery of an antiviral agent-indinavir

The present investigation was aimed at targeting indinavir, a protease inhibitor to cells of mononuclear phagocyte system (MPS) via mannosylated liposomes. β-d-1-thiomannopyranoside residues were covalently coupled with dimyristoyl phosphatidylethanolamine (DMPE) to generate mannosylated-DMPE (Man-DMPE) conjugate which was further incorporated with disteroyl phosphatidyl choline and cholesterol to prepare mannosylated liposomes. The optimized mannosylated liposomes were nanometric in size (142?±?2.8?nm) with optimum entrapment efficiency (88.7?±?2.3%). Less than 20% cumulative drug release was observed from the prepared formulations in 24?h in phosphate buffer saline (pH 7.4). Cellular uptake studies performed on J774.A1 macrophage cell line via flow cytometric analysis depicted enhanced uptake of mannosylated liposomes as compared to plain liposomes. Annexin-V-fluorescein isothiocyanate/propidium iodide apoptosis assay delineated marginal cytotoxicity in macrophages from the developed formulation. Plasma and tissue distribution studies performed to assess the drug reach to macrophage rich regions depicted a significant level (P?<?0.05) of indinavir in macrophage rich tissues like liver, spleen, and lungs from mannosylated liposomes as compared to plain liposomes and free drug. The conducted studies suggest the potential of indinavir loaded mannosylated liposomes for anti-human immunodeficiency virus therapy.     

Elastin-like polypeptides and their applications in anticancer drug delivery systems: a review

Abstract

Elastin-like polypeptides (ELPs) are large molecular weight biopolymers. They have been widely studied as macromolecular carriers for targeted delivery of drugs. The aim of the present article is to review the available information on ELPs (including our recent investigations), their properties, drug delivery applications to tumor sites and future perspectives. This review also provides information on the use of short synthetic ELPs for making ELP-drug conjugates, for targeted delivery of anticancer drugs. In the present review we also focus on the point that short ELPs can also be used for targeting anticancer drugs to tumor sites as they behave similar to long ELPs regarding their capacity to undergo inverse temperature transition (ITT) behavior.     

Magnetically-Responsive Polymerized Liposomes as Potential Oral Delivery Vehicles

Pharmaceutical Research -     

Herbal and polymeric approaches for liver-targeting drug delivery: novel strategies and their significance

Abstract

The liver is a vital organ present in vertebrates, which performs many functions including detoxification, protein synthesis and production of various bio-chemicals which are very important for digestion. A large number of serious liver disorders affect millions of people worldwide which are very difficult to treat properly despite many efforts. There are several factors which are responsible for liver injuries, include plants (Crotalaria Senecio Heliotropium Symphytum officinale), drugs (analgesic and antibiotics), industrial toxins (mercury and lead), water, alcohol and so on. Herbal medicinal preparations can be used for the treatment of a large number of human liver disorders like cirrhosis, hepatitis, carcinomas, etc. Indian Medicinal Practitioner’s Co-operative pharmacy and Stores (IMPCPS) approved herbal-based systems (Unani, Siddha and Ayurveda) for the treatment of various chronic liver disorders. Different types of the receptors are found on the surface of hepatocytes, Kupffer cell, hepatic stellate cell and sinusoidal endothelial cells, etc., which can be used for achieving liver targeting. These receptors bind to different types of ligands (galactosylated, lactobionic acid, asialofetuin, etc.) which can be used in the formulation to achieve targeted delivery of the drug. Various novel particulate approaches (liposomes, niosomes, nanoparticles, micelles, nanosuspensions, etc.) can be used to enhance the targeting efficiency of systems to receptors found on the surface of different cells present in the liver. In this review, we focused on the status of liver targeting via herbal and nanotechnology inspired formulation approaches.     

Lectin-bearing Polymerized Liposomes as Potential Oral Vaccine Carriers

Purpose. The potential of using lectin-modified polymerized liposomes as Peyer's patch targeted oral delivery vehicles was examined. Methods. Two types of lectins, Ulex Europaeus Agglutinin I (UEA I) and Wheat Germ Agglutinin (WGA), were modified with a hydrophobic anchor N-glutaryl-phosphotidylethanolamine (NGPE). The modified lectins were incorporated into liposome bilayers and the liposomes were subsequently stabilized through polymerization. The presence of the lectins on the liposome surfaces was first confirmed with X-ray photoelectron spectroscopy. Surface-immobilized lectins were then shown to retain their carbohydrate binding activities as well as specificities based on an in vitro aggregation assay. Finally, delivery efficiencies of lectin-bearing liposomes were determined in mice. Results. About 10.5% UEA I liposomes and 5.8% WGA liposomes were taken up from the gastrointestinal tract. These numbers are significantly higher than the 3.2% observed in the case of lectin-free liposomes. At the same time, UEA I liposomes exhibited the most effective Peyer's patch targeting among the three, which directly correlated with the highest delivery efficiency observed. Conclusions. This establishes that lectin modification of liposomes can promote binding to Peyer's patches, which will give improved efficiency for Peyer's patch targeted delivery. All these point to the potential for these lectin-modified liposomes as novel vehicles for oral vaccination.     

Monitoring safety of liposomes containing rifampicin on respiratory cell lines and in vitro efficacy against Mycobacterium bovis in alveolar macrophages

Rifampicin-encapsulated liposome suspensions were prepared by a chloroform-film method and converted to dry powders by freeze-drying with mannitol as a cryoprotectant. The liposome suspension had multilamellar nanovesicles with 50% rifampicin encapsulation. The liposome dry powder comprised particles with a mass median aerodynamic diameter of 3.4?μm, with 60% present as a fine particle fraction. Rifampicin-encapsulated liposomes were evidently nontoxic to respiratory associated cells, including bronchial epithelial cells, small airway epithelial and alveolar macrophages (AMs). Furthermore, the liposomes did not activate AMs to produce interleukin-1β, tumor necrosis factor-α, and nitric oxide at a level that would cascade to other inflammatory effects. The minimum inhibitory concentrations against Mycobacterium bovis was 0.2 and 0.8?μM for liposomes containing rifampicin and free rifampicin, respectively. The less negatively charged reconstituted liposome displayed the greatest activity against intracellular growth of M. bovis.     

分子影像技术在药物研发中的应用

分子影像可在活体状态下对生物和生化过程进行无创研究。该技术包括分子探针和分子成像技术,可通过特异性探针或报告基因成像。运用分子影像技术可筛选侯选化合物,评价药物对肿瘤代谢、增殖、血管发生和凋亡的影响,评价药物对组织缺氧的影响。分子影像技术是药物作用机制研究的重要手段,将大大加快药物研发进程。     

壳聚糖包覆脂质体递药系统的研究进展

脂质体在药物传递方面被广泛研究,但因结构稳定性差等因素使其应用受到了限制.壳聚糖是一种阳离子多糖,具有良好的生物相容性、生物降解性以及生物黏附性,并且可经化学改性成为性能更佳的壳聚糖衍生物.近年来,壳聚糖及其衍生物包覆脂质体在载药方面的研究得到了越来越多学者的关注.壳聚糖或其衍生物修饰脂质体,可提高其稳定性、黏附渗透性...     

Entrapment of Cyclodextrin-Drug Complexes into Liposomes: Potential Advantages in Drug Delivery

Abstract

A novel concept in drug delivery discussed here, takes advantage of certain properties of the drug “containers” cyclodextrins and liposomes to combine them into a single system thus circumventing problems associated with both systems. The concept, entailing entrapment of water-soluble cyclodextrin-drug inclusion complexes in liposomes, would allow accommodation of insoluble drugs in the aqueous phase of vesicles. This would potentially increase the drug to lipid mass ratio to levels above those attained by conventional drug incorporation into the lipid phase, enlarge the range of insoluble drugs amenable to encapsulation to include, for instance, membrane destabilizing agents, allow targeting of complexes to specific sites and reduce toxicity. In the present work, soluble inclusion complexes of hydroxypropyl-β-cyclodextrin with dehydroepiandrosterone, retinol and retinoic acid were prepared and entrapped into mutlilamellar liposomes by the dehydration-rehydration procedure. Complex-containing liposomes were then exposed to blood plasma. Results show that complex entrapment into liposomes depends on the lipid composition used. Nearly all of the cyclodextrin and considerable portions of the drugs were found to remain associated with the carrier in the presence of plasma.     

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。     

Nanodiamond-mediated drug delivery and imaging: challenges and opportunities

Introduction: The field of nanoparticle-based therapeutic systems is rapidly expanding encompassing a wide variety of practices ranging from detection to diagnosis to treatment. Recently a great potential of nanodiamond (ND) particles as a multimodal imaging/therapy platform has been demonstrated.

Areas covered: This review describes a unique set of properties of ND particles attractive for drug delivery and imaging applications and highlights the most recent ND-based multimodal imaging/therapy approaches and related biocompatibility studies. The spectrum of major advancements includes marked improvements in tumor treatment efficacy and safety based on integration of ND with doxorubicin (DOX). Recent progress of ND-mediated drug delivery in orthopedic, dental and ophthalmic applications is also discussed.

Expert opinion: ND particles possess a unique set of properties attractive for drug delivery applications, including exceptional biocompatibility, large carrier capacity and versatile surface chemistry properties, which enhance drug binding and provide sustainable drug release. Other unique attributes of NDs embrace bright stable fluorescence based on crystallographic defects. A roadmap toward a clinical translation comprises identification of ND-therapeutic compounds that display marked improvements over clinical standards with respects to efficacy, safety and cost.