胶束传递系统逆转肿瘤多药耐药的研究进展

肿瘤多药耐药是目前肿瘤治疗的一大障碍。研究采用药物传递系统如胶束、脂质体、纳米粒等, 以逆转多药耐药, 显示其安全可靠, 并具有良好的应用前景。本文重点综述了药物传递系统中的聚合物胶束逆转多药耐药的研究结果及其可能的作用机制。随着研究的深入, 药物传递系统在逆转肿瘤多药耐药的研究领域将发挥更加重要的作用。     

纳米载药系统逆转肿瘤多药耐药的研究进展

目的:介绍纳米载药系统在逆转肿瘤多药耐药(MDR)方面的研究进展。方法:查阅近年来的相关文献,对纳米载体的特点,逆转MDR的机制及其在此领域的应用进行综述。结果:纳米技术可以使药物通过主动或被动靶向作用,更多地被肿瘤细胞摄取而逆转MDR。纳米载药系统还可以作为RNA的载体,通过基因干扰技术逆转肿瘤的MDR。结论:与单一功能和组成的载药系统相比,多功能或药物联用的纳米载药系统在逆转MDR方面更具优势。     

纳米载药系统逆转肿瘤及骨肉瘤多药耐药的研究进展

多药耐药是肿瘤化疗中的重要难题,多药耐药的机制复杂,目前尚无有效的治疗策略。纳米载药系统具有靶向性、载药种类多样等优点,近年来成为对抗肿瘤多药耐药的递药载体的重要研究方向。对肿瘤抑制的不同机制进行讨论,并对纳米载药系统逆转骨肉瘤多药耐药的研究进展进行综述。     

纳米粒给药系统逆转肿瘤多药耐药性的研究进展

多药耐药是导致肿瘤化疗失败的主要原因。对于大多数抗肿瘤药物,肿瘤细胞均会产生多药耐药现象, 但其耐药机制,目前没有统一的看法。本文对纳米粒给药系统逆转肿瘤多药耐药性进行了综述, 包括3种载药系统: 非修饰的、配体修饰的和多功能纳米粒给药系统,并对纳米粒给药系统逆转肿瘤多药耐药性的机制进行探讨。纳米粒通过拮抗和抵消肿瘤细胞主动外排药物的作用,提高肿瘤细胞内的药物浓度,同时减小对正常细胞的毒副作用, 逆转肿瘤的多药耐药性。这种新型的给药系统,结合了纳米技术及主动和被动靶向给药策略,在癌症治疗方面已显示出巨大的应用前景。       

多柔比星纳米递药系统在三阴性乳腺癌靶向治疗中的应用

三阴性乳腺癌为高度恶性肿瘤。多柔比星是三阴性乳腺癌的常规化疗药物,该药药理作用是通过嵌入DNA碱基对之间,干扰基因转录,抑制mRNA和DNA合成。常规给药方式对正常组织损伤严重。多柔比星纳米递药系统借助肿瘤酸性微环境实现缓控释效应,多柔比星与肿瘤细胞的组织相容性增加,对正常组织影响较小。该系统有效抑制和杀灭肿瘤细胞,明显减轻正常细胞的细胞毒性。本文综述了近年来多柔比星靶向纳米递药系统的应用,以期开拓三阴性乳腺癌的的靶向治疗新视野。     

纳米载体药物逆转P-gp介导的肿瘤多药耐药研究进展

纳米载药系统不但可提高抗肿瘤治疗的指数,而且有降低肿瘤耐药性的产生及逆转MDR的作用。因此,研究纳米载体药物用于逆转P-gp介导的肿瘤多药耐药具有广泛和重要的实际意义。     

纳米药物载体介导的联合给药逆转肿瘤多药耐药的研究进展

目的:为设计用于联合给药逆转肿瘤多药耐药的新型纳米药物载体提供参考。方法:以"纳米药物载体""联合给药""多药耐药""Multidrug resistance""Co-delivery""Nanoparticle"等为关键词,组合查询2012-2017年在中国知网、万方、维普、Pub Med、Elsevier等数据库中的相关文献,对纳米药物载体介导的联合给药在逆转肿瘤多药耐药中的优势及联合给药的类型进行综述。结果与结论:共检索到相关文献282篇,其中有效文献47篇。药物经纳米载体包载后具有增加药物在肿瘤部位的蓄积、延长药物在体内的循环时间、促进药物在肿瘤部位的靶向递送、控制联合给药药物比例、增强逆转多药耐药的协同作用等优势。纳米载体可以介导不同类型药物的联合给药用于逆转肿瘤多药耐药。联合递送的药物组合类型包括化疗药与化疗药、化疗药与多药耐药逆转剂、化疗药与小干扰RNA、化疗药与单克隆抗体、天然产物与天然产物等。其中,采用化疗药与其他药联合给药是最常见的联合给药类型。纳米药物载体介导的联合给药是逆转肿瘤多药耐药的非常具有潜力的给药形式,但目前均未进入临床阶段。为使纳米药物载体介导的联合给药更好地应用于临床,在处方工艺和临床效果评价等方面尚需大量的研究工作。     

多柔比星海藻酸钙微球的制备及其载药、释药性质的研究

目的：考察多柔比星海藻酸钙微球的制备工艺及载药、释药性质。方法：考察不同处方微球的粒径、机械强度、降解等性质，筛选出最佳处方；以多柔比星为模型药物研究其对药物的承载能力及体外释药特性。结果：制备的微球圆整且分散性好，粒径均匀。多柔比星海藻酸钙微球的载药量达30％以上，包封率在90％以上；在体外37℃生理氯化钠溶液中释放显示具有缓释作用。结论：该微球对多柔比星具有较高的承载能力，并有较好的缓释作用，可满足临床治疗动脉栓塞需要。     

多柔比星-五味子乙素共载脂质体克服多药耐药的机制研究

目的 探讨多柔比星-五味子乙素共载脂质体克服肿瘤多药耐药机制。方法 制备多柔比星-五味子乙素共载脂质体,以人慢性髓系白血病耐药细胞株K562/DOX为模型细胞,分别探讨不同温度、内吞抑制剂存在下的细胞摄取药物的情况,并检测耐药细胞P-gp表达和细胞凋亡情况。结果 共载脂质体在4℃及氯喹、叠氮钠和甘露醇内吞抑制剂存在下进入耐药细胞的药物量明显减少;流式细胞仪检测多柔比星-五味子乙素共载脂质体可抑制P-gp表达且诱导凋亡。结论 多柔比星-五味子乙素共载脂质体进入K562/DOX细胞主要通过耗能的内吞途径;而多柔比星-五味子乙素共载脂质体克服肿瘤多药耐药可能是通过抑制P-gp表达和促进凋亡双通道途径。     

共递送抗癌药多柔比星和基因的纳米载药系统研究进展

共递送抗癌药多柔比星和基因治疗肿瘤可以产生协同治疗作用,提高治疗效果,降低毒性以及克服多柔比星引起的多药耐药性。共递送抗癌药和基因的纳米载体近年成为国内外研究的热点,目前,正在研究的共递送纳米载药体系包括脂质体、纳米粒、胶束等。共递送抗癌药和基因能够弥补抗癌药和基因单独治疗肿瘤的不足,有望进一步研究应用于临床。     

Surfactant-polymer Nanoparticles: A Novel Platform for Sustained and Enhanced Cellular Delivery of Water-soluble Molecules

Purpose Nanoparticles, drug carriers in the sub-micron size range, can enhance the therapeutic efficacy of encapsulated drug by increasing and sustaining the delivery of the drug inside the cell. However, the use of nanoparticles for small molecular weight, water-soluble drugs has been limited by poor drug encapsulation efficiency and rapid release of the encapsulated drug. Here we report enhanced cellular delivery of water-soluble molecules using novel Aerosol OT™ (AOT)-alginate nanoparticles recently developed in our laboratory. Materials and Methods AOT-alginate nanoparticles were formulated using emulsion-crosslinking technology. Rhodamine and doxorubicin were used as model water-soluble molecules. Kinetics and mechanism of nanoparticle-mediated cellular drug delivery and therapeutic efficacy of nanoparticle-encapsulated doxorubicin were evaluated in two model breast cancer cell lines. Results AOT-alginate nanoparticles demonstrated sustained release of doxorubicin over a 15-day period in vitro. Cell culture studies indicated that nanoparticles enhanced the cellular delivery of rhodamine by about two–tenfold compared to drug in solution. Nanoparticle uptake into cells was dose-, time- and energy-dependent. Treatment with nanoparticles resulted in significantly higher cellular retention of drug than treatment with drug in solution. Cytotoxicity studies demonstrated that doxorubicin in nanoparticles resulted in significantly higher and more sustained cytotoxicity than drug in solution. Conclusions AOT-alginate nanoparticles significantly enhance the cellular delivery of basic, water-soluble drugs. This translates into enhanced therapeutic efficacy for drugs like doxorubicin that have intracellular site of action. Based on these results, AOT-alginate nanoparticles appear to be suitable carriers for enhanced and sustained cellular delivery of basic, water-soluble drugs.     

T lymphocytes as potential therapeutic drug carrier for cancer treatment

The aim of our research is the application of human immune cells (T lymphocytes) as target directed drug carrier. Thereby, the inclusion of therapeutical nanoparticles into immune cells is a new strategy for a localized chemotherapy. The autonomous targeting of diseased sites makes immune cells to perfectly controlled drug delivery systems. The study's aim was to demonstrate the feasibility to mobilise immune cells as therapeutic drug carrier systems which can be combined with existing immunotherapies. Therefore, Jurkat cells as well as T lymphocytes were used to identify the smoothest procedure for loading nanoparticles into immune cells. Different loading processes, incubation times and nanoparticle concentrations were compared. Nanoparticles coated with cytotoxic antibiotic doxorubicin were used in first release experiments. A time dependent liberation of doxorubicin from carrier cells was discussed as first therapeutic approach.     

Multifunctional silica nanoparticles for targeted delivery of hydrophobic imaging and therapeutic agents

This article reports the development of a multifunctional silica nanoparticle system for targeted delivery of hydrophobic imaging and therapeutic agents. Normally, silica nanoparticles have been widely used to deliver hydrophilic drugs such as doxorubicin while difficult to carry hydrophobic drugs. A strategy for loading hydrophobic drugs onto silica nanoparticles via covalent attachment was developed in this study as a universal strategy to solve this problem. Docetaxel, one of the most potent therapeutics for cancer treatment is selected as a model hydrophobic drug and quantum dots (QDs) are used as a model imaging agent. Such a multifunctional delivery system possesses high drug loading capacity, controlled drug release behavior and stable drug reservation. A mixed layer of polyethylene glycol conjugated phospholipids is formed on the nanoparticle surface to further enhance the biocompatibility and cell fusion capability of the delivery system. Folic acid as ligand is then conjugated onto the surface layer for targeting. Such a multifunctional system for targeting, imaging and therapy is characterized and evaluated in vitro. Fluorescent confocal microscopy is used to monitor the cellular uptake by specific cancer cells. Cytotoxicity studies are conducted by using MTT assay.     

Surfactant-polymer nanoparticles overcome P-glycoprotein-mediated drug efflux

Nanoparticles enhance the therapeutic efficacy of an encapsulated drug by increasing and sustaining the delivery of the drug inside the cell. We have previously demonstrated that Aerosol OT (AOT)-alginate nanoparticles, a novel formulation developed recently in our laboratory, significantly enhance the therapeutic efficacy of encapsulated drugs like doxorubicin in drug-sensitive tumor cells. The purpose of this study is to evaluate the drug delivery potential of AOT-alginate nanoparticles in drug-resistant cells overexpressing the drug efflux transporter, P-glycoprotein (P-gp). AOT-alginate nanoparticles were formulated using an emulsion-cross-linking process. Rhodamine 123 and doxorubicin were used as model P-gp substrates. Cytotoxicity of nanoparticle-encapsulated doxorubicin and kinetics of nanoparticle-mediated cellular drug delivery were evaluated in both drug-sensitive and -resistant cell lines. AOT-alginate nanoparticles enhanced the cytotoxicity of doxorubicin significantly in drug-resistant cells. The enhancement in cytotoxicity with nanoparticles was sustained over a period of 10 days. Uptake studies with rhodamine-loaded nanoparticles indicated that nanoparticles significantly increased the level of drug accumulation in resistant cells at nanoparticle doses higher than 200 microg/mL. Blank nanoparticles also improved rhodamine accumulation in drug-resistant cells in a dose-dependent manner. Nanoparticle-mediated enhancement in rhodamine accumulation was not because of membrane permeabilization. Fluorescence microscopy studies demonstrated that nanoparticle-encapsulated doxorubicin was predominantly localized in the perinuclear vesicles and to a lesser extent in the nucleus, whereas free doxorubicin accumulated mainly in peripheral endocytic vesicles. Inhibition of P-gp-mediated rhodamine efflux with AOT-alginate nanoparticles was confirmed in primary brain microvessel endothelial cells. In conclusion, an AOT-alginate nanoparticle system enhanced the cellular delivery and therapeutic efficacy of P-gp substrates in P-gp-overexpressing cells.     

MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide

Targeted delivery of DNA nanoparticles is a promising approach in cancer therapy. Using aptamers, target specific delivery of DNA nanoparticles can be achieved. Further, aptamers can indirectly improve drug encapsulation efficiency of DNA nanoparticles for drugs intercalated within nucleic acid base pairs. Using DNA blocks, a micellar hybrid nanoparticle was prepared for the targeted co-delivery of doxorubicin and a pro-apoptotic peptide, KLA to tumor cells. Results demonstrated that anti-MUC1 aptamer could specifically deliver the synthesized DNA micelle into MCF-7 cells by improving its cellular uptake. Additionally, co-delivery of doxorubicin and KLA could significantly enhance the therapeutic efficacy of the construct resulting in reduction of required dose of doxorubicin that is a pivotal point in reducing chemotherapeutics side effects. Moreover, DOX–KLA–anti-MUC1–micelle remarkably inhibited tumor growth of tumor-bearing mice when compared with free drug. DOX–KLA–anti-MUC1–micelle also reduced toxic effect of free doxorubicin as determined by percent of body weight loss and survival rate in vivo.     

Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma

Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing > 75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~ 92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer.From the Clinical EditorTransferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques.     

载阿霉素介孔二氧化硅纳米粒的细胞毒性及细胞摄取

目的制备载阿霉素的介孔二氧化硅纳米粒(mesoporous silica nanoparticles,MSN),对其理化性质及细胞摄取行为进行初步研究。方法通过聚合法制备MSN,透射电镜表征纳米粒的形态,动态光散射粒径测定仪测定粒子的平均粒径及分布。紫外分光光度计测定阿霉素的负载行为,MTT比色分析法研究粒子的细胞毒性,激光共聚焦显微镜观察其人乳腺癌MCF-7细胞对载药粒子的摄取。结果纳米粒分布均一,平均粒径约70 nm(PDI<0.1),载药量质量分数达到20%。MCF-7细胞对载药粒子的摄取较快,空白纳米粒具有较低的细胞毒性。结论介孔二氧化硅纳米粒具有较高的药物载药量和良好的生物相容性,能较快地被对人乳腺癌MCF-7细胞摄取,有望成为一种新型的药物化疗载体。     

Review: doxorubicin delivery systems based on chitosan for cancer therapy

Objectives This review sheds insight into an increasingly popular polymer that has been widely explored as a potential drug delivery system. The abundant, biodegradable and biocompatible polysaccharide chitosan, with many other favourable properties, has been favoured as a drug delivery system for the purposes of encapsulating and delivery of doxorubicin with reduced side‐effects. Key findings Doxorubicin is frequently used as a frontline chemotherapeutic agent against a variety of cancers. It has largely been able to demonstrate anti‐tumour effects, though there are major shortfalls of doxorubicin, which include serious side‐effects such as cardiomyopathy and myelosuppression, and also an ever‐present danger of extravasation during drug administration. In view of this, drug delivery systems are currently being explored as alternative methods of drug delivery in a bid to more effectively direct doxorubicin to the specific lesion site and reduce its systemic side‐effects. Liposomes and dendrimers have been tested as potential carriers for doxorubicin; however they are not the focus of this review. Summary Recent advancements in doxorubicin and chitosan technology have shown some preliminary though promising results for cancer therapy.     

白蛋白纳米粒药物传递系统的研究进展

目的综述白蛋白纳米粒作为药物传递系统的最新研究进展。方法依据国内外研究文章及专利文献共63篇,将白蛋白的性质及功能、白蛋白纳米粒的制备工艺、靶向肿瘤作用机理、上市药物及其临床前和临床实验结果进行了概括。结果白蛋白是一种良好的药物载体,显示独特的靶向肿瘤机理;白蛋白纳米粒的制备方法中二硫键形成法相对于其他制备方法具有显著优点,避免了很多基于溶剂传递的传统剂型中存在的潜在问题,由其制备的上市药物紫杉醇白蛋白纳米粒(Abraxane)具有较好的临床疗效。结论白蛋白纳米粒给药系统的研究有着重要的临床意义及发展前景。     

泊洛沙姆188-PLGA纳米给药系统对抗耐药肿瘤的研究

目的 利用泊洛沙姆188对PLGA进行化学修饰,制备包载阿霉素的纳米粒,并评价纳米粒在人耐药乳腺癌细胞中的摄取能力及毒性。方法 通过EDC/NHS法合成泊洛沙姆188-PLGA,通过核磁共振对其结构进行表征并测定临界胶束浓度;通过纳米沉淀法制备包载阿霉素的纳米粒,通过粒度仪对纳米粒的粒径及分布进行分析,通过细胞摄取实验及细胞毒性实验对纳米粒的摄取效果及毒性进行评价。结果 成功合成了泊洛沙姆188-PLGA,并制备了粒径在140 nm左右的纳米粒,该纳米粒在人耐药乳腺癌细胞中有较好的摄取效果及较强的毒性。结论 泊洛沙姆188能够逆转耐药,增强耐药细胞对化疗药物的敏感程度。