主动靶向脂质体药物的研究进展

［摘要］近年来,国内外主动靶向脂质体药物的研究开发取得很大进展。分别简述主动靶向脂质体药物的优点、分类、制备方法及其主动靶向性的评价。主动靶向脂质体药物已应用于抗肿瘤、介导基因转染、抗菌、抗病毒等治疗,具有广阔的应用前景。     

双重修饰的主动靶向脂质体研究进展

主动靶向脂质体是靶向递药体系的一个重要角色。由于传统的单一基团修饰的主动靶向脂质体存在靶向效率不高、细胞摄取率不高等缺点,人们不断探索采用两种或多种不同识别分子或其他协同分子共同修饰脂质体。本文拟针对双重修饰脂质体技术的研究进展进行综述。通过对两种特异性配体或抗体共同修饰、特异性配体与细胞穿透肽共同修饰、两种细胞穿透肽共同修饰等不同类型的双重修饰脂质体的综述分析,我们发现双重修饰技术具有提高靶向准确性和靶向效率,提高药物摄取,提高对靶点的黏附能力和血流稳定性等优势,尤其在跨膜穿越屏障系统的应用中凸显作用。     

脂质体靶向性的研究进展

近年来,为了提高脂质体的靶向性,国内外进行了广泛研究,开发出多种多样的靶向脂质体,为药物及基因的定向转移提供了有效手段,并为最终实现药物的体内控释开辟了前景。该文简要综述这方面的研究进展。     

包合物脂质体靶向系统在给药中的应用

近年来,包合物和脂质体作为药物的载体被广泛用于药物制剂领域,各自发挥着自身的优势。将环糊精包合物应用于脂质体给药系统——这一新型的药物载体,能够更好地提高靶向给药效果。本文通过概述包合物及脂质体的优势,阐明包合物脂质体这一新型给药系统能提高药物的载药量,增加脂质体的稳定性,对提高药物的吸收和临床疗效等方面具有重要意义,对于靶向给药系统的进一步发展具有新的参考价值。     

抗肿瘤热敏靶向脂质体的研究进展

脂质体具有靶向传递药物进入肿瘤部位的优势,被广泛用于肿瘤的临床治疗,但是靶向传递并不能保证药物在肿瘤部位被生物利用。为了解决此问题,热敏靶向脂质体(TTL)已经成为目前的研究热点。TTL既能提高药物在肿瘤部位的浓度,又能在加热条件下触发释放所载药物,从而显著改善所载药物的抗肿瘤效果。本文主要综述了近年来该领域的研究进展。     

受体介导脂质体的研究进展

配体修饰脂质体通过受体介导的内吞作用主动靶向药物至靶位，增加了药物靶向的特异性，减少了对非靶组织器管损伤，提高了疗效，是一种具有广阔发展前景的剂型。本文综述了近年来受体介导脂质体的研究进展。     

靶向给药系统的研究进展

目的综述及讨论近年来靶向给药系统的研究进展。方法以网络数据库资源为主，查询ScienceDirect，Pubmed等数据库关于靶向给药系统研究进展等方面的资料。结果共收集到多篇文献，选择性的取其中的16篇进行归纳总结与讨论。结论靶向给药系统是一种较为理想的药物制剂类型，利用靶向给药系统作靶向治疗将提高一些疾病的治疗能力。在靶向给药系统的研发中也存在一些问题，主要是靶向给药系统的稳定性，载体材料的安全性。这些问题一旦解决，必将带来这种新型给药系统全面应用于临床的新局面。     

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     

脂质体的研究进展

本文主要介绍了脂质体作为药物靶向制剂载体的研究发展。分析了近年来脂质体在各类药物中的应用及其优点 ,最后提出了目前存在的一些问题及脂质体作为药物载体良好有发展前景     

多肽修饰脂质体靶向药物递送系统研究进展

目的介绍近年来多肽修饰脂质体靶向药物递送系统的研究进展。方法查阅和归纳总结近几年相关文献。结果阐述了精氨酸-甘氨酸-天冬氨酸（RGD）多肽、丙氨酸-脯氨酸-精氨酸-脯氨酸-甘氨酸（APRPG）多肽、细胞穿透肽（CPP）、血管活性肠肽（VIP）等修饰脂质体的研究进展。多肽修饰的包载药物的脂质体可以增加药物在体内的选择性,减少药物毒副作用,提高药物治疗指数。结论多肽分子是机体内一类重要的生物活性物质,将其作为导向物以配体-受体特异性结合的方式应用于靶向药物递送系统,具有良好的研究价值和应用前景。     

Advances in Targeting Drug Delivery to Glomerular Mesangial Cells by Long Circulating Cationic Liposomes for the Treatment of Glomerulonephritis

Purpose Newly designed polyethylene glycol (PEG)-modified cationic liposomes, containing a novel cationic lipid TRX-20 (3,5-dipentadecyloxybenzamidine hydrochloride), bind specifically to cultured human mesangial cells, and not to endothelial cells. In this study, we investigated targeting the delivery of PEG-modified liposomes containing TRX-20 (TRX-liposomes) to mesangial cells and evaluated their pharmacokinetic behavior in a rat experimental glomerulonephritis model, using prednisolone phosphate (PSLP) as a model drug. Material and Methods TRX-liposomes were injected intravenously into experimental glomerulonephritic rats and normal rats to compare its pharmacokinetic behavior with that of non-cationic liposomes (PEG-liposomes). Rhodamine-labeled liposomes were used to evaluate the accumulation in inflamed kidneys. Pharmacological effects of three formulations of PSLP (i.e., a single injection of two liposomal formulations and daily injections of PSLP in saline solution) were estimated in terms of suppressing glomerular cell proliferation in the rat nephritis model. Results TRX-liposomes markedly accumulated in the glomeruli of inflamed kidneys, but did not accumulate in the glomeruli of normal kidneys. Although the PEG-liposomes also accumulated in the glomeruli of the inflamed kidneys, their pharmacological behavior was quite different from that of the TRX-liposomes, which were internalized by the target cells. In a comparison among the three formulations of PSLP, the dose of TRX-liposomes required for significant suppression of glomerular cell proliferation was much less (dose of 0.032 mg/kg and above) than that required for the same effect by the PSLP saline solution (3.2 mg/kg daily; 12.8 mg/kg total) and PEG-liposomes (0.32 mg/kg). Interestingly, significant suppression of mesangial cell activation, as assessed by the expression of α-smooth muscle actin, was observed in nephritic rats treated with TRX-liposomes, but not in the other two treatment groups. Conclusions The pharmaceutical properties of TRX-liposomes due to their preferential binding to mesangial cells and long circulation time make this a likely candidate system for targeted drug delivery to the inflamed glomeruli of glomerulonephritis.     

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.     

Liposomes Modified with Cyclic RGD Peptide for Tumor Targeting

Cyclic RGD peptide anchored sterically stabilized liposomes (RGD-SL) were investigated for selective and preferential presentation of carrier contents at angiogenic endothelial cells overexpressing α_vβ₃ integrins on and around tumor tissue and thus for assessing their targetabilty. Liposomes were prepared using distearoylphosphatidylcholine (DSPC), cholesterol and distearoylphosphatidylethanolamine–polyethyleneglycol–RGD peptide conjugate (DSPE–PEG–RGD) in a molar ratio 56:39:5. The control RAD peptide anchored sterically stabilized liposomes (RAD-SL) and liposome with 5 mol% PEG (SL) without peptide conjugate which had similar lipid composition were used for comparison. The average size of all liposome preparations prepared was approximately 105 nm and maximum drug entrapment was 10.2±1.1%. In vitro endothelial cell binding of liposomes exhibited 7-fold higher binding of RGD-SL to HUVEC in comparison to the SL and RAD-SL. Spontaneous lung metastasis and angiogenesis assays show that RGD peptide anchored liposomes are significantly (p<0.01) effective in the prevention of lung metastasis and angiogenesis compared to free 5-FU, SL and RAD-SL. In therapeutic experiments, 5-FU, SL, RGD-SL and RAD-SL were administered intravenously on day 4 at the dose of 10 mg 5-FU/kg body weight to B16F10 tumor bearing BALB/c mice resulting in effective regression of tumors compared with free 5-FU, SL and RAD-SL. Results indicate that cyclic RGD peptide anchored sterically stabilized liposomes bearing 5-FU are significantly (p<0.01) active against primary tumor and metastasis than the non-targeted sterically stabilized liposomes and free drug. Thus cyclic RGD peptide anchored sterically stabilized liposomes hold potential of targeted cancer chemotherapeutics.     

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。     

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.     

前列腺癌主动靶向药物传递系统的研究进展

目的 介绍前列腺癌主动靶向药物传递系统的研究进展。方法 查阅近年来国内外相关文献,对前列腺癌作用靶点为基础的主动靶向药物传递系统进行总结和归纳。结果 以前列腺特异性抗原和前列腺特异性膜抗原等作为靶点,应用抗体、适体或者多肽靶向修饰的脂质体、胶束、纳米粒、前体药物传递系统,可以将药物有效传递到前列腺癌靶组织、靶细胞,提高抗肿瘤药物作用效果。结论 主动靶向前列腺癌的药物传递系统具有广阔的研究和应用前景。     

Small Molecule Ligands for Active Targeting of TrkC-Expressing Tumor Cells

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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.     

Liposomes,a promising strategy for clinical application of platinum derivatives

Introduction: Liposomes represent a versatile system for drug delivery in various pathologies. Platinum derivatives have been demonstrated to have therapeutic efficacy against several solid tumors. But their use is limited due to their side effects. Since liposomal formulations are known to reduce the toxicity of some conventional chemotherapeutic drugs, the encapsulation of platinum derivatives in these systems may be useful in reducing toxicity and maintaining an adequate therapeutic response.

Areas covered: This review describes the strategies applied to platinum derivatives in order to improve their therapeutic activity, while reducing the incidence of side effects. It also reviews the results found in the literature for the different platinum-drugs liposomal formulations and their current status.

Expert opinion: The design of liposomes to achieve effectiveness in antitumor treatment is a goal for platinum derivatives. Liposomes can change the pharmacokinetic parameters of these encapsulated drugs, reducing their side effects. However, few liposomal formulations have demonstrated a significant advantage in therapeutic terms. Lipoplatin, a cisplatin formulation in Phase III, combines a reduction in the toxicity associated with an antitumor activity similar to the free drug. Thermosensitive or targeted liposomes for tumor therapy are also included in this review. Few articles about this strategy applied to platinum drugs can be found in the literature.     

Targeting and Blocking B7 Costimulatory Molecules on Antigen-Presenting Cells Using CTLA4Ig-Conjugated Liposomes: In Vitro Characterization and in Vivo Factors Affecting Biodistribution

Purpose. CTLA4Ig, a fusion protein of CTLA-4 and Fc of immunoglobulin (Ig) heavy chain, inhibits the essential costimulatory signal for full T cell activation via blocking the interaction between CD28 and B7 molecules and renders T cell nonresponsiveness. CTLA4Ig has been used to control deleterious T cell activation in many experimental systems. We hypothesized that by conjugating CTLA4Ig to liposomes the efficacy of CTLA4Ig could be enhanced through multivalent ligand effect, superior targetability, and modification of the fate of ligated costimulatory molecules. Methods and Results. Consistent with this hypothesis, liposome-conjugated CTLA4Ig bound to B7 and blocked their binding sites more efficiently than free CTLA4Ig, lowering the half maximal dose for B7 blocking by an order of the magnitude. These results were similar both in B7-1 expressing p815 cells and in activated macrophages. Moreover, CTLA4Ig-liposomes underwent rapid internalization upon cell surface binding through B7 molecules. In allogenic mixed lymphocyte reaction assays, the CTLA4Ig-liposomes were tested to show effective inhibition of T cell proliferation. In vivo, however, when CTLA4Ig-liposomes were injected into mice, a significant fraction was localized to the reticuloendothelial system (RES), presumably because of its binding to Fc receptors expressed on tissue macrophages. The Fc receptor-mediated uptake could be alleviated by coinjection of anti-FcR monoclonal antibody. In the mouse engrafted with pancreatic islets of Langerhans underneath the capsule of one kidney, despite the increased localization in RES, enhanced accumulation of CTLA4Ig-conjugated liposome was observed in the engrafted kidney compared to the contralateral kidney. Conclusion. We show that the conjugation of CTLA4Ig to liposome could increase the efficiency of the targeting by increasing the binding avidity at cellular level and by increasing the concentration at the target site in in vivo system. The biodistribution and circulation time data suggested that the CTLA4Ig-liposomes could be improved upon minimizing the FcR-mediated uptake by Fc receptor-bearing cells. Thus, the strategy of conjugating CTLA4Ig to liposomes could be exploited for immune intervention in transplantation and autoimmune diseases for the efficient blocking of costimulation.