短肽在靶向药物递送系统中的研究进展

近年来研究发现许多肿瘤细胞表面高表达一些肽类受体，这些肽类受体与相应的配体亲和性高，能以配体-受体方式特异性结合。以小片段活性肽作为导向物形成复合物而发展的靶向药物递送系统，能够将药物定向转运到靶细胞内，显示了良好的研究价值和应用前景。如蛙皮素/胃泌素释放肽受体介导的靶向药物递送系统、生长抑素受体介导的靶向药物递送系统、十肽SynB₃受体介导的靶向药物递送系统、黄体酮释放激素受体介导的靶向药物递送系统及其他肽类受体介导的靶向药物递送系统，其中短肽作为靶向基团与阿霉素、吡咯阿霉素、甲氨蝶呤、顺铂和喜树碱等结合形成高效的复合物，用于表达有相应受体的肿瘤，获得靶向治疗的研究非常有意义。     

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。     

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。     

受体介导肿瘤主动靶向的研究进展

肿瘤细胞表面过度表达一系列受体,能与特异性的配体或抗体结合并诱导细胞内化。以这些受体作为靶点,使药物与特异性配体或抗体结合即可将药物主动靶向肿瘤细胞。本文综述目前在临床和实验研究中用于肿瘤主动靶向的几种受体,包括酪氨酸激酶受体、叶酸受体、激素受体、脂蛋白受体、转铁蛋白受体等。通过了解这些受体及其在肿瘤主动靶向方面的作用,有助于我们对抗肿瘤药物和新型抗肿瘤药物载体的研究。     

配体修饰脂质体的研究进展

目的:寻找较为稳定、有效且制备方法可靠的新的配体修饰脂质体(Ligand-modified liposomes,LML)。方法:查阅配体修饰脂质体的相关文献,综述了叶酸、甘露糖基、抗体、肽等不同配体修饰的脂质体的研究进展。结果与结论:配体修饰后的脂质体在靶向性与药效学方面有明显的提升,但也面临着巨大的挑战,如抗体和蛋白质等大分子配体会增加脂质体的免疫性,加快脂质体的循环清除等。配体修饰脂质体作为药物载体将会逐渐在疫苗接种、基因转染、靶向制剂方面发挥更加重要的作用。     

叶酸靶向的肿瘤治疗研究进展

叶酸靶向的递药系统是一种新兴的治疗多种恶性肿瘤的方法。利用叶酸分子与肿瘤细胞表面叶酸受体的高亲和力,叶酸偶联的化合物能够将分子大小不同的复合物递送给病理细胞而不对正常组织造成伤害。目前,通过这种方法成功递送到叶酸受体高表达肿瘤细胞的复合物包括:蛋白毒素、化疗药物、免疫治疗剂、基因载体、反义寡核苷酸、小分子干扰RNA和纳米载体。该文综述了多种叶酸作为靶向配体治疗恶性肿瘤的方法。     

RGD肽在肿瘤靶向纳米给药系统中的应用

RGD肽是一类含有精氨酸一甘氨酸一天冬氨酸(Arg-Gly-Asp)的短肽,作为肿瘤细胞或者新生血管特异表达的整合素和其配体相互作用的识别位点,可介导肿瘤的靶向治疗.抗肿瘤药物及其递送系统经过RGD肽修饰.可增加药物的肿瘤主动靶向特性,达到更有效、精确和安全的治疗.本文主要综述了RGD肽在脂质体、聚合物胶束、基因载体等...     

配体-受体系统介导的药物靶向性研究进展

配体-受体系统介导的药物靶向性研究在过去10年中得到了很大的发展。配体介导的主动靶向能够将药物定向运送到血管腔隙、细胞表面和细胞内。使用的配体包括抗体、蛋白质、肽、脂蛋白、糖类以及其他内源性分子。文章介绍了药物靶向研究中使用的多种配体-受体系统，包括运铁蛋白受体、脂蛋白受体、细胞因子受体、凝集素受体、清道夫受体和叶酸受体。     

受体介导肿瘤主动靶向的研究进展

肿瘤细胞表面过度表达一系列受体，能与特异性的配体或抗体结合并诱导细胞内化。以这些受体作为靶点，使药物与特异性配体或抗体结合即可将药物主动靶向肿瘤细胞。本文综述目前在临床和实验研究中用于肿瘤主动靶向的几种受体，包括酪氨酸激酶受体、叶酸受体、激素受体、脂蛋白受体、转铁蛋白受体等。通过了解这些受体及其在肿瘤主动靶向方面的作用，有助于我们对抗肿瘤药物和新型抗肿瘤药物载体的研究。     

叶酸受体介导的靶向给药系统研究进展

叶酸受体在多种肿瘤细胞表面过度表达,能与特异性的配体结合并将药物靶向运输到特定的肿瘤细胞。本文介绍了叶酸受体介导的靶向给药系统的作用机制和几种常见的药物载体系统。     

Ligand based dendritic systems for tumor targeting

Medications that can selectively target tumors at the same time avoid access of the drug to nontarget areas, employ utilization of homing devices termed as ligands, that can bind to specific epitopes expressed on the surface of the necrotic mass of cells. Molecular signatures for transferrin, Epidermal Growth Factor, Sialic Lewis and folic acid are expressed on the surface of these cells. Dendrimers are nanosized, non-immunogenic, and hyper-branched vehicles that can be efficiently tailored for spatial distribution of bioactives, thereby reducing untoward cytotoxicity on normal cells. These nanoparticulate drug delivery vehicles provide a unique platform that has precisely placed functional groups so that multiple copies of ligands can be attached to it and facilitate targeting to the tumor surface or neo-vascularizing vessels proliferating around these cells. The article reviews the scope of ligand based dendritic system as a prospective for delivery of anti-cancer drugs, via active targeting with interception of minimal side effects.     

Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progress

Drug therapy for the treatment of tumors is often limited by a narrow therapeutic index. One approach that overcomes this limitation is the active targeting of tumors with particulate drug carriers. The derivatization of particulate drug carriers with a ligand leads to the selective targeting of the particulate to selected cells, thereby focusing drug delivery. In addition, particulate drug carriers have a high loading capacity, do not need covalent conjugation of the drug and the formulation protects the entrapped drug from enzymatic inactivation. Despite these favorable properties, their therapeutic efficacy in animal models has been reported only in recent years. The use of internalizing ligands and the targeting of intravascular tumor cells and endothelial cells of tumor blood vessels have been instrumental in demonstrating the clinical effectiveness of particulate drug carriers in animal models. As a result, several actively targeted particulate carriers have now entered, or are about to enter, clinical investigation. Recent findings, for example, the identification of cell-penetrating peptides with restricted cell selectivity, suggest that further improvements in this approach are likely in the near future.     

Targeted Delivery with Peptidomimetic Conjugated Self-Assembled Nanoparticles

Peptides produce specific nanostructures, making them useful for targeting in biological systems but they have low bioavailability, potential immunogenicity and poor metabolic stability. Peptidomimetic self-assembled NPs can possess biological recognition motifs as well as providing desired engineering properties. Inorganic NPs, coated with self-assembled macromers for stability and anti-fouling, and conjugated with target-specific ligands, are advancing imaging from the anatomy-based level to the molecular level. Ligand conjugated NPs are attractive for cell-selective tumor drug delivery, since this process has high transport capacity as well as ligand dependent cell specificity. Peptidomimetic NPs can provide stronger interaction with surface receptors on tumor cells, resulting in higher uptake and reduced drug resistance. Self-assembled NPs conjugated with peptidomimetic antigens are ideal for sustained presentation of vaccine antigens to dendritic cells and subsequent activation of T cell mediated adaptive immune response. Self-assembled NPs are a viable alternative to encapsulation for sustained delivery of proteins in tissue engineering. Cell penetrating peptides conjugated to NPs are used as intracellular delivery vectors for gene expression and as transfection agents for plasmid delivery. In this work, synthesis, characterization, properties, immunogenicity, and medical applications of peptidomimetic NPs in imaging, tumor delivery, vaccination, tissue engineering, and intracellular delivery are reviewed.     

Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer

Nano-targeted delivery systems have been widely used for breast tumor drug delivery. Estrogen receptors are considered to be significant drug delivery target receptors due to their overexpression in a variety of tumor cells. However, targeted ligands have a significant impact on the safety and effectiveness of active delivery systems, limiting the clinical transformation of nanoparticles. Phytoestrogens have shown good biosafety characteristics and some affinity with the estrogen receptor. In the present study, molecular docking was used to select tanshinone IIA (Tan IIA) among phytoestrogens as a target ligand to be used in nanodelivery systems with some modifications. Modified Tan IIA (Tan-NH₂) showed a good biosafety profile and demonstrated tumor-targeting, anti-tumor and anti-tumor metastasis effects. Moreover, the ligand was utilized with the anti-tumor drug Dox-loaded mesoporous silica nanoparticles via chemical modification to generate a nanocomposite Tan-Dox-MSN. Tan-Dox-MSN had a uniform particle size, good dispersibility and high drug loading capacity. Validation experiments in vivo and in vitro showed that it also had a better targeting ability, anti-tumor effect and lower toxicity in normal organs. These results supported the idea that phytoestrogens with high affinity for the estrogen receptor could improve the therapeutic efficacy of nano-targeted delivery systems in breast tumors.     

Transferrin As A targeting ligand for liposomes and anticancer drugs.

In cancer treatment, one of the approaches is targeting of the drug to tumor cells via receptor specific ligands. Transferrin (molecular weight 80,000) has been used as a ligand for delivering anticancer drugs or drug containing liposomes mostly due to the increased number of transferrin (trf) receptors found on tumor cells as compared to normal cells. Transferrin was linked to methotrexate (MTX) containing small unilamellar liposomes and its activity was compared to antitransferrin receptor antibody (7D-3) linked to MTX liposomes. In each of these conjugates, the method of coupling was the same and a disulphide linkage was formed between the ligand and MTX liposomes. No significant differences in the potency of 7D-3 conjugate or trf conjugate with MTX liposomes were observed in studies performed in vitro against various human tumor cell lines (Hela, KB and Colon). Trf was also linked to adriamycin via a schiff base which was formed by using glutaraldehyde. This conjugate was found to be effective in vitro against various human tumors (Lovo, HL-60, SW 403 and Hep2) and also in vivo against H-mesothelioma tumors. Transferrin receptor has also been used for gene delivery. Gene delivery to K562 haematopoietic leukaemic cells was achieved by using a transferrin-polycation (poly-L-lysine or protamine) conjugate. This review will cover the various important applications of transferrin based drug delivery formulations in the chemotherapy of cancer and the related work performed in our and other laboratories.     

Small molecule toxins targeting tumor receptors

Targeting toxic therapeutics to tumors through receptors over expressed on the surface of cancer cells can reduce systemic toxicity and increase the effectiveness of the targeted compounds. Small molecule targeted therapeutics have a number of advantages over toxic immunoconjugates including better tumor penetration, lack of neutralizing host immune response and superior flexibility in selection of drug components with optimal specificity, potency and stability in circulation. Three major components of the targeted drug, the toxic warhead, tumor-specific ligand and the linker can influence the properties of each other and thus have to be optimized for each system. All receptor-targeted drugs are delivered inside the cells through endocytosis and undergo processing liberating the toxins in endosomes and lysosomes. Common delivery route defines a number of general requirements for each drug component. The review addresses currently known possible receptor targets and their ligands along with toxins that have been used and that have a potential to be successfully applied in tumor targeting. Linkers that are stable in circulation, but efficiently cleaved in lysosomes constitute an essential component of receptor-targeted drugs and are evaluated in greater detail.     

Preparation of E-selectin-targeting nanoparticles and preliminary in vitro evaluation

Targeted delivery aims to concentrate therapeutic agents at their site of action and thereby enhance treatment and limit side-effects. E-selectin on endothelial cells is markedly up-regulated by cytokine stimulation of inflamed and some tumoral tissues, promoting the adhesion of leukocytes and metastatic tumor cells, thus making it an interesting molecular target for drug delivery systems. We report here the preparation of targeted nanoparticles from original amphiphilic block copolymers functionalized with an analog of sialyl Lewis X (SLEx), the physiological ligand of E-selectin. Nanoparticles, prepared by nanoprecipitation, caused no significant cytotoxicity. Ligand-functionalized nanoparticles were specifically recognized and internalized better by tumor necrosis factor α (TNF-α)-activated human umbilical vein endothelial cells (HUVECs) than control nanoparticles or HUVECs with low E-selectin expression. These nanoparticles are designed to carry the ligand at the end of a PEG spacer to improve accessibility. This system has potential for the treatment of inflammation, inhibition of tumor metastasis, and for molecular imaging.     

Improved efficacy of alphavbeta3-targeted albumin conjugates by conjugation of a novel auristatin derivative

Cellular handling of drug delivery preparations en route to the lysosomal compartment has been extensively studied, but little is known about cellular handling of drugs subsequent to their release from the delivery system. We studied a series of closely related drug targeting conjugates, consisting of albumins equipped with alpha vbeta 3-selective RGD-peptide homing ligands, PEG stealth domains, and either the antitubulin agent monomethyl auristatin E (MMAE) or a new F-variant (MMAF). Since MMAF has a C-terminal charge, this compound is potentially less prone to passive redistribution after its release from the carrier. We demonstrate that RGD-peptide-equipped albumin conjugates with MMAF were indeed more potent than MMAE conjugates, in killing both alpha vbeta 3-positive tumor cells and proliferating endothelial cells. Efficacy increased more in tumor cells than in endothelial cells, suggesting different drug redistribution behavior for the two cell types. Binding affinity and uptake of the conjugate and the cellular handling of released drug contributed to the final efficacy of drug-carrier conjugates, highlighting the importance of all aspects to be carefully considered in the design of targeted drug delivery preparations.     

Ligand-based targeted therapy for cancer tissue

Background: Limited accessibility of drugs to the tumor tissues, the requirement of high doses, intolerable cytotoxicity, the development of multiple drug resistance and non-specific targeting are obstacles to the clinical use of cancer drugs and cancer therapy. Objective: Drug delivery through carrier systems to cancerous tissue is no longer simply wrapping up cancer drugs in a new formulation for different routes of delivery, rather the focus is on targeted cancer therapy. Methods: This review summarizes the exploitation of drug-loaded nanocarrier conjugates with various targeting moieties for the delivery and targeting of anticancer drugs and describes the current status of and challenges in the field of nanocarrier-aided drug delivery and drug targeting. Conclusion: The discovery of targeting ligand to cancer cells and the development of ligand-targeted therapy will help us to improve therapeutic efficacy and reduce side effects. Unlike other forms of therapy, it will allow us to maintain quality of life for patients, while efficiently attacking the cancer tissue. It indicates that ligands have a pivotal role in cancer cell targeting.     

Advances in Targeted Drug Delivery Approaches for the Central Nervous System Tumors: The Inspiration of Nanobiotechnology

At present, brain tumor is among the most challenging diseases to treat and the therapy is limited by the lack of effective methods to deliver anticancer agents across the blood-brain barrier (BBB). BBB is a selective barrier that separates the circulating blood from the brain extracellular fluid. In its neuroprotective function, BBB prevents the entry of toxins, as well as most of anticancer agents and is the main impediment for brain targeted drug delivery approaches. Nanotechnology-based delivery systems provide an attractive strategy to cross the BBB and reach the central nervous system (CNS). The incorporation of anticancer agents in various nanovehicles facilitates their delivery across the BBB. Moreover, a more powerful tool in brain tumor therapy has relied surface modifications of nanovehicles with specific ligands that can promote their passage through the BBB and favor the accumulation of the drug in CNS tumors. This review describes the physiological and anatomical features of the brain tumor and the BBB, and summarizes the recent advanced approaches to deliver anticancer drugs into brain tumor using nanobiotechnology-based drug carrier systems. The role of specific ligands in the design of functionalized nanovehicles for targeted delivery to brain tumor is reviewed. The current trends and future approaches in the CNS delivery of therapeutic molecules to tumors are also discussed.