title: One-Step Microfluidic Synthesis of Nanocomplex with Tunable Rigidity and Acid-Switchable Surface Charge for Overcoming Drug Resistance.
abstract: Multidrug resistance (MDR), is the key reason accounting for the failure of cancer chemotherapy, remains a dramatic challenge for cancer therapy. In this study, the one-step microfluidic fabrication of a rigid pH-sensitive micellar nanocomplex (RPN) with tunable rigidity and acid-switchable surface charge for overcoming MDR by enhancing cellular uptake and lysosome escape is demonstrated. The RPN is composed of a poly(lactic-co-glycolic acid) (PLGA) core and a pH-sensitive copolymer shell, which is of neutral surface charge during blood circulation. Upon internalization of RPN by cancer cells, the pH-responsive shell dissociates inside the acidic lysosomes, while the rigid and positively charged PLGA core improves the lysosomal escape. The cellular uptake and nuclear uptake of doxorubicin (Dox) from Dox-loaded RPN are 1.6 and 2.4 times higher than that from Dox-loaded pH-sensitive micelles (PM) using a Dox-resistant cancer model (MCF-7/ADR, re-designated NCI/ADR-RES) in vitro. Dox-loaded RPN significantly enhances the therapeutic efficacy (92% inhibition of tumor growth) against MCF-7/ADR xenograft tumor in mice, while Dox-loaded PM only inhibits the tumor growth by 36%. RPN avoids the use of complicated synthesis procedure of nanoparticle and the necessary to integrate multiple components, which can facilitate the clinical translation of this novel nanostructure.
authors.affiliation: Beijing Engineering Research Center for BioNanotechnology and CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.|University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, P. R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Beijing Engineering Research Center for BioNanotechnology and CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.|University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
authors.forename: Xuanyu
authors.initials: X
authors.lastname: Li
authors.affiliation: Beijing Engineering Research Center for BioNanotechnology and CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Beijing Engineering Research Center for BioNanotechnology and CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.|University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
authors.forename: Jiashu
authors.initials: J
authors.lastname: Sun
authors.affiliation: University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.|CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Shi
authors.affiliation: University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.|CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.
authors.forename: Baoquan
authors.initials: B
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, P. R. China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, P. R. China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Beijing Engineering Research Center for BioNanotechnology and CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.|University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000143:Acids / Q000737:chemistry*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008823:Micelles; D044085:Microfluidics / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D000143:Acids; D008823:Micelles; D004317:Doxorubicin
keywords: drug delivery; micellar nanocomplex; microfluidics; multidrug resistance; pH-sensitive