title: Targeting ETS1 with RNAi-based supramolecular nanoassemblies for multidrug-resistant breast cancer therapy.
abstract: Overexpression of erythroblastosis virus E26 oncogene homolog 1 (ETS1) gene is correlated with both tumor progression and poor response to chemotherapy in cancer treatment, and the exploitation of RNA interference (RNAi) technology to downregulate ETS1 seems to be a promising approach to reverse multidrug-resistant cancer cells to chemotherapy. Hence, the RNAi-based nanomedicine which is able to simultaneously downregulate ETS1 expression and to deliver chemotherapeutic agents may improve multidrug-resistant cancer therapy synergistically. In this study, we developed a supramolecular nanoassembly that could deliver siRNA targeting ETS1 (siETS1) and doxorubicin (DOX) as an effective nanomedicine to achieve successful chemotherapy towards multidrug-resistant breast cancer. The nanotherapeutic system was prepared by loading adamantane-conjugated doxorubicin (AD) into polyethyleneimine-modified (2-hydroxypropyl)-γ-cyclodextrin (HP) through the supramolecular assembly to form AD-loaded HP (HPAD), followed by electrostatically-driven self-assembly between siETS1 and HPAD. When the HPAD/siETS1 nanoassemblies were delivered into drug-resistant MCF-7/ADR cells, the drug efflux was significantly reduced as a result of simultaneous silencing of ETS1 and MDR1 genes. Importantly, the HPAD/siETS1 nanoassembly could enhance drug residence time at tumor site, and effectively inhibit drug-resistant tumor growth due to the inhibition of angiogenesis and necrosis in tumor tissues. Western blot analysis indicated that the gene expression of both ETS1 and MDR1 in vivo was considerably downregulated after the drug-resistant tumor-bearing mouse was treated with HPAD/siETS1 nanoassemblies. This study offers a new therapeutic delivery strategy targeting ETS1 for the effective multidrug-resistant chemotherapy.
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China; Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China.
authors.forename: Xingang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China; Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China; Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
authors.forename: Qinglian
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Chu
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China; Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China. Electronic address: tangguping@zju.edu.cn.
authors.forename: Guping
authors.initials: G
authors.lastname: Tang
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore. Electronic address: pingyuan7@gmail.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ping
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011094:Polyethyleneimine / Q000737:chemistry; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D047368:Tumor Burden; D047408:gamma-Cyclodextrins / Q000737:chemistry
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D034741:RNA, Small Interfering; D047408:gamma-Cyclodextrins; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D011094:Polyethyleneimine; C000612223:(2-hydroxypropyl)-gamma-cyclodextrin
keywords: 1,1′-Carbonyldiimidazole (PubChem CID: 68263); Acetic acid (PubChem CID: 176); Adamantanecarboxylic acid (PubChem CID: 13235); DAPI (PubChem CID: 2954); Dimethyl sulfoxide (PubChem CID: 679); Doxorubicin; Doxorubicin hydrochloride (PubChem CID: 443939); Drug delivery; Erythroblastosis virus E26 oncogene homolog 1; Ethanol (PubChem CID: 702); Multidrug resistance; Nanomedicine; Sodium hydroxide (PubChem CID: 14798); Thiazolyl Blue (PubChem CID: 64965); Triethylamine (PubChem CID: 8471); siRNA