title: Cancer-targeted MDR-1 siRNA delivery using self-cross-linked glycol chitosan nanoparticles to overcome drug resistance.
abstract: P-glycoprotein (Pgp) mediated multi-drug resistance (MDR) is a major cause of failure in chemotherapy. In this study, small interfering RNA (siRNA) for Pgp down-regulation was delivered to tumors to overcome MDR in cancer. To achieve an efficient siRNA delivery in vivo, self-polymerized 5'-end thiol-modified siRNA (poly-siRNA) was incorporated in tumor targeting glycol chitosan nanoparticles. Pgp-targeted poly-siRNA (psi-Pgp) and thiolated glycol chitosan polymers (tGC) formed stable nanoparticles (psi-Pgp-tGC NPs), and the resulting nanoparticles protected siRNA molecules from enzymatic degradation. The psi-Pgp-tGC NPs could release functional siRNA molecules after cellular delivery, and they were able to facilitate siRNA delivery to Adriamycin-resistant breast cancer cells (MCF-7/ADR). After intravenous administration, the psi-Pgp-tGC NPs accumulated in MCF-7/ADR tumors and down-regulated P-gp expression to sensitize cancer cells. Consequently, chemo-siRNA combination therapy significantly inhibited tumor growth without systemic toxicity. These psi-Pgp-tGC NPs showed great potential as a supplementary therapeutic agent for drug-resistant cancer.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yhee
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Seungyong
authors.initials: S
authors.lastname: Song
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: So Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Sung-Gurl
authors.initials: SG
authors.lastname: Park
authors.affiliation: Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Ki-Suk
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Myung Goo
authors.initials: MG
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Sejin
authors.initials: S
authors.lastname: Son
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Heebeom
authors.initials: H
authors.lastname: Koo
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea; KU-KIST School, Korea University, 1 Anam-dong, Seongbuk-gu, Seoul 136-701, Republic of Korea.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Seo Young
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea. Electronic address: sunkim@kist.re.kr.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, Republic of Korea. Electronic address: kim@kist.re.kr.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000008:administration & dosage*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D034741:RNA, Small Interfering; C118638:glycol-chitosan; D004317:Doxorubicin; D048271:Chitosan
keywords: Glycol chitosan; Multi-drug resistance; Nanoparticles; Polymerized siRNA; siRNA delivery