title: Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells.
abstract: 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 ALDH(hi) cells of breast cancer cell line MDA-MB-231. We further proved that nanoparticle-mediated autophagy inhibition promoted the efficacy of chemotherapeutics against ALDH(hi) 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 ALDH(hi) 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.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Sun
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Song
authors.initials: S
authors.lastname: Shen
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Yun-Jiao
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Cong-Fei
authors.initials: CF
authors.lastname: Xu
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Zhi-Ting
authors.initials: ZT
authors.lastname: Cao
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Long-Ping
authors.initials: LP
authors.lastname: Wen
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China; CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China; High Magnetic Field Laboratory of CAS, University of Science and Technology of China, Hefei, Anhui 230026, PR China; Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, Anhui 230027, PR China. Electronic address: jwang699@ustc.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: Autophagy inhibition; Breast cancer; Cancer stem cells; Chemotherapeutics; Combination therapy; Nanoparticles