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2016年8月，爱思唯尔旗下《生物材料》杂志将正式发表中国科学技术大学的研究成果，发现借助纳米颗粒运输系统将自噬抑制药物和化疗药物联合使用可以有效杀伤乳腺癌细胞和乳腺癌干细胞，该研究为解决因乳腺癌干细胞导致的治疗抵抗及复发等问题提供了一个新的治疗方法。 癌症干细胞在肿瘤起始、进展和转移、复发以及药物抵抗过程中扮演了重要角色。过去十年，癌症干细胞概念迅速发展，得到了越来越多关注。同时消灭数量庞大的肿瘤细胞和数量稀少的癌症干细胞亚群可能会产生良好的治疗效果，并最终导致癌症病情的缓解。越来越多的证据表明自噬在癌症干细胞维持，可塑性和存活方面发挥重要功能。 该研究对自噬如何影响乳腺癌干细胞对化疗药物的易感性进行了分析，首先从乳腺癌细胞系MDA-MB-231中分选出ALDHhi细胞，用自噬抑制剂氯喹对细胞自噬过程进行抑制，结果发现乳腺癌干细胞干性下降，对化疗药物多柔比星和多西他赛的易感性增加。 近些年纳米医学领域也取得了长足发展，特别是借助纳米颗粒运输系统进行药物输送已经在多种疾病的治疗中得到证明。该研究进一步证明在体外培养条件下纳米颗粒介导的自噬抑制能够促进化疗药物对乳腺癌MDA-MB-231细胞株ALDHhi细胞的疗效。通过纳米药物运输系统给药可以显著延长多柔比星和多西他赛这两种药物的循环半衰期，增加药物在肿瘤组织和ALDHhi细胞中的富集。更加重要的是，利用MDA-MB-231细胞株建立的肿瘤正位小鼠模型进行研究发现，与单药治疗相比，将分别装载氯喹和多柔比星的纳米颗粒联合使用以及将两种药物包装在同一个纳米运输系统中能够同时清除肿瘤细胞和癌症干细胞，展现出更加有效和持续的肿瘤生长抑制作用。 因此，该研究表明借助纳米颗粒药物运输系统将自噬抑制药物和化疗药物同时送达肿瘤部位能够有效地发挥杀伤作用，是治疗乳腺癌的一种有效策略。 Biomaterials. 2016 Aug;103:44-55. Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells. Sun R, Shen S, Zhang YJ, Xu CF, Cao ZT, Wen LP, Wang J. University of Science and Technology of China, Hefei, Anhui, PR China. Cancer stem cells (CSCs) have garnered increasing attention over the past decade, as they are believed to play a crucial role in tumor initiation, progression and metastasis, relapse and drug resistance. Therapeutic strategies which simultaneously exterminate both bulk tumor cells and the rare CSC subpopulation may produce striking response and result in long-term tumor remission. Accumulating evidence provides insight into the function of autophagy in maintenance, plasticity and survival of CSCs. The role of autophagy in the susceptibility of breast CSCs to chemotherapeutics was investigated in the present work, reduced 'stemness' and increased susceptibility to chemotherapy drugs (doxorubicin, DOX and docetaxel, DTXL) were observed after chloroquine (CQ)-mediated autophagy inhibition in sorted ALDHhi cells of breast cancer cell line MDA-MB-231. We further proved that nanoparticle-mediated autophagy inhibition promoted the efficacy of chemotherapeutics against ALDHhi MDA-MB-231 cells in vitro. Administration of drug delivery systems significantly prolonged the circulation half-life and augmented enrichment of two different drugs in tumor tissues and ALDHhi cells. More importantly, compared with single treatment, the combined delivery systems NPCQ/NPDOX and NPCQ/DOX (NPCQ/NPDTXL and NPCQ/DTXL) showed most effective and persistent tumor growth inhibitory effect by eliminating bulk tumor cells as well as CSCs (p < 0.01) in an MDA-MB-231 orthotopic tumor murine model. Therefore, our research provides new insights into the nanoparticle-facilitated combination of autophagy inhibition and chemotherapy for effective therapy of breast cancer. KEYWORDS: Autophagy inhibition; Breast cancer; Cancer stem cells; Chemotherapeutics; Combination therapy; Nanoparticles PMID: 27376558 DOI: 10.1016/j.biomaterials.2016.06.038
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