Russell Berrie Nanotechnology Institute, Technion, Haifa, Israel.
Drug Resist Updat. 2011 Jun;14(3):150-63. doi: 10.1016/j.drup.2011.01.003. Epub 2011 Feb 16.
Anticancer drug resistance almost invariably emerges and poses major obstacles towards curative therapy of various human malignancies. In the current review we will distinguish between mechanisms of chemoresistance that are predominantly mediated by ATP-driven multidrug resistance (MDR) efflux transporters, typically of the ATP-binding cassette (ABC) superfamily, and those that are independent of such drug efflux pumps. In recent years, multiple nanoparticle (NP)-based therapeutic systems have been developed that were rationally designed to overcome drug resistance by neutralizing, evading or exploiting various drug efflux pumps and other resistance mechanisms. NPs are being exploited for selective drug delivery to tumor cells, to cancer stem/tumor initiating cells and/or to the supportive cancer cell microenvironment, i.e. stroma or tumor vasculature. Some of these NPs are currently undergoing preclinical in vivo studies as well as advanced stages of clinical evaluation with promising results. Nanovehicles harboring a payload of therapeutic drug combinations for the selective targeting and elimination of tumor cells as well as the simultaneous overcoming of mechanisms of drug resistance are a subject of intense research efforts, some of which are expected to enter clinical trials in the near future. In the present review we highlight novel approaches to selectively target cancer cells and overcome drug resistance phenomena, through the use of various nanometric drug delivery systems. In the near future, it is anticipated that innovative theragnostic nanovehicles will be developed which will harbor four major components: (1) a selective targeting moiety, (2) a diagnostic imaging aid for the localization of the malignant tumor and its micro- or macrometastases, (3) a cytotoxic, small molecule drug(s) or novel therapeutic biological(s), and (4) a chemosensitizing agent aimed at neutralizing a resistance mechanism, or exploiting a molecular "Achilles hill" of drug resistant cells. We propose to name these envisioned four element-containing nanovehicle platform, "quadrugnostic" nanomedicine. This targeted strategy holds promise in paving the way for the introduction of highly effective nanoscopic vehicles for cancer therapeutics while overcoming drug resistance.
抗癌药物耐药性几乎总是会出现，并对各种人类恶性肿瘤的治愈治疗构成重大障碍。在本次综述中，我们将区分主要由 ATP 驱动的多药耐药（MDR）外排转运蛋白介导的化学耐药机制与不依赖于此类药物外排泵的机制。近年来，已经开发出多种基于纳米颗粒（NP）的治疗系统，这些系统被合理设计为通过中和、逃避或利用各种药物外排泵和其他耐药机制来克服耐药性。NP 被用于选择性地将药物递送到肿瘤细胞、癌症干细胞/肿瘤起始细胞和/或支持性肿瘤细胞微环境（即基质或肿瘤脉管系统）。其中一些 NP 目前正在进行临床前体内研究以及临床评估的高级阶段，结果令人鼓舞。携载治疗性药物组合的纳米载体用于选择性靶向和消除肿瘤细胞以及同时克服耐药机制是目前研究的热点，其中一些预计将在不久的将来进入临床试验。在本综述中，我们强调了通过使用各种纳米药物递送系统，选择性靶向癌细胞并克服耐药性现象的新方法。在不久的将来，预计将开发出创新性的治疗诊断纳米载体，其将包含四个主要组成部分：（1）选择性靶向部分，（2）用于定位恶性肿瘤及其微转移或宏观转移的诊断成像辅助工具，（3）细胞毒性小分子药物或新型治疗性生物制剂，以及（4）旨在中和耐药机制或利用耐药细胞的分子“阿喀琉斯之踵”的化学增敏剂。我们提议将这些包含四个元素的设想纳米载体平台命名为“四重诊断”纳米医学。这种靶向策略有望为引入高效的纳米级癌症治疗药物铺平道路，同时克服耐药性。
