title: Multifunctional polyamidoamine-modified selenium nanoparticles dual-delivering siRNA and cisplatin to A549/DDP cells for reversal multidrug resistance.
abstract: Multidrug resistance (MDR) is a major barrier against effective cancer treatment. Dual-delivering a therapeutic small interfering RNA (siRNA) and chemotherapeutic agents has been developed to reverse drug resistance in tumor cells. In this study, amine-terminated generation 5 polyamidoamine (PAMAM) dendrimers (G5.NH2)-modified selenium nanoparticles (G5@Se NP) were synthesized for the systemic dual-delivery of mdr1 siRNA and cisplatin (cis-diamminedichloroplatinum-(II), DDP), which was demonstrated to enhance siRNA loading, releasing efficiency and gene-silencing efficacy. When the mdr1 siRNA was conjugated with G5@Se NP via electrostatic interaction, a significant down-regulation of P-glycoprotein and multidrug resistance-associated protein expression was observed; G5@Se-DDP-siRNA arrested A549/DDP cells at G1 phase and led to enhanced cytotoxicity in A549/DDP cells through induction of apoptosis involving the AKT and ERK signaling pathways. Interestingly, G5@Se-DDP NP were much less reactive than DDP in the reactions with both MT and GSH, indicating that loading of DDP in a nano-delivery system could effectively prevent cell detoxification. Furthermore, animal studies demonstrated that the new delivery system of G5@Se-DDP-siRNA significantly enhanced the anti-tumor effect on tumor-bearing nude mice, with no appreciable abnormality in the major organs. These results suggest that G5@Se NP could be a potential platform to combine chemotherapy and gene therapy technology in the treatment of human disease.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Cao
authors.affiliation: Department of Biology, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Chuping
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. Electronic address: tliuliu@jnu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D012643:Selenium / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D050091:Dendrimers; D053769:Nanocapsules; C104700:PAMAM Starburst; D034741:RNA, Small Interfering; D012643:Selenium; D002945:Cisplatin
keywords: Dual-delivering; Multidrug resistance; Polyamidoamine; Selenium nanoparticles; Small interfering RNA