title: The effect of autophagy inhibitors on drug delivery using biodegradable polymer nanoparticles in cancer treatment.
abstract: Nanoparticles of biodegradable polymers (NPs) have been widely used for drug delivery. However, there has been little research on their fate after internalized into the cells. We show in this research by using docetaxel as a model anticancer drug, which is formulated in the cholic acid conjugated nanoparticles of poly(lactic-co-glycolic acid (PLGA NPs) that the NPs induce autophagy of the cancer cells and thus may hinder the advantages of the nanomedicine. Moreover, we show both in vitro and in vivo that co-administration of autophagy inhibitors such as 3-methyladenine (3-MA) and Chloroquine (CQ) could greatly enhance the therapeutic effects of the nanoparticle formulation. The IC50 values of the drug formulated in the PLGA NPs after 24 h treatment with no autophagy inhibitor or in combination with 10 mm 3-MA or 30 μm CQ are 38.27 ± 1.23, 6.7 ± 1.05, 4.78 ± 1.75 μg/mL, which implie 5.7 or 8,0 fold efficient by the autophagy inhibition respectively. Moreover, both the volume and the weight of the shrunk tumor of the mice after 20 day treatment with the PLGA NPs formulation combined with 3-MA or CQ are found to be only about a half in comparison with the treatment with the PLGA NPs formulation alone. In this research, we reported such a new mechanism of cancer cells to have PLGA NPs captured and degraded by auto-lysosomes. The findings provide advanced knowledge for development of nanomedicine for clinical application.
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
authors: Xudong
authors: X
authors: Zhang
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
authors: Yichen
authors: Y
authors: Dong
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
authors: Xiaowei
authors: X
authors: Zeng
authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, University of Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
authors: Xin
authors: X
authors: Liang
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
authors: Xiaoming
authors: X
authors: Li
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
authors: Wei
authors: W
authors: Tao
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
authors: Hongbo
authors: H
authors: Chen
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China.
authors: Yuyang
authors: Y
authors: Jiang
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: mei.lin@sz.tsinghua.edu.cn.
authors: Lin
authors: L
authors: Mei
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab - Shenzhen Key Laboratory of Chemical Biology, The Shenzhen Key Lab of Gene and Antibody Therapy, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China; Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore. Electronic address: chefss@nus.edu.sg.
authors: Si-Shen
authors: SS
authors: Feng
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000592:standards; D005260:Female; D006801:Humans; D015151:Immunoblotting; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016513:Mice, SCID; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C025946:3-methyladenine; D002738:Chloroquine; D000225:Adenine
keywords: 3-Methyladenine; Cancer nanotechnology; Chloroquine; Endocytosis; Nanomedicine; Pharmaceutical nanotechnology