title: An effective tumor-targeting strategy utilizing hypoxia-sensitive siRNA delivery system for improved anti-tumor outcome.
abstract: Hypoxia is a feature of most solid tumors, targeting hypoxia is considered as the best validated yet not extensively exploited strategy in cancer therapy. Here, we reported a novel tumor-targeting strategy using a hypoxia-sensitive siRNA delivery system. In the study, 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazole (AI) through bioreduction under hypoxic conditions, was conjugated to the alkylated polyethyleneimine (bPEI1.8k-C6) to form amphiphilic bPEI1.8k-C6-NI polycations. bPEI1.8k-C6-NI could self-assemble into micelle-like aggregations in aqueous, which contributed to the improved stability of the bPEI1.8k-C6-NI/siRNA polyplexes, resulted in increased cellular uptake. After being transported into the hypoxic tumor cells, the selective nitro-to-amino reduction would cause structural change and elicit a relatively loose structure to facilitate the siRNA dissociation in the cytoplasm, for enhanced gene silencing efficiency ultimately. Therefore, the conflict between the extracellular stability and the intracellular siRNA release ability of the polyplexes was solved by introducing the hypoxia-responsive unit. Consequently, the survivin-targeted siRNA loaded polyplexes shown remarkable anti-tumor effect not only in hypoxic cells, but also in tumor spheroids and tumor-bearing mice, indicating that the hypoxia-sensitive siRNA delivery system had great potential for tumor-targeted therapy.
  
  
  
  Hypoxia is one of the most remarkable features of most solid tumors, and targeting hypoxia is considered as the best validated strategy in cancer therapy. However, in the past decades, there were few reports about using this strategy in the drug delivery system, especially in siRNA delivery system. Therefore, we constructed a hypoxia-sensitive siRNA delivery system utilizing a hypoxia-responsive unit, 2-nitroimidazole, by which the unavoidable conflict between improved extracellular stability and promoted intracellular siRNA release in the same delivery system could be effectively solved, resulting in enhanced siRNA silencing efficiency in tumor cells. To our knowledge, the described work is the first demonstration of a siRNA delivery system using a hypoxia trigger for regulation of siRNA release, which represents a new strategy for tumor-targeted therapy, and it is expected that this meaningful strategy must be widely applied in the future.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Mingji
authors.initials: M
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: zggao@imm.ac.cn.
authors.forename: Zhonggao
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000818:Animals; D016923:Cell Death; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D004705:Endocytosis; D005260:Female; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D008156:Luciferases / Q000235:genetics; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D010316:Particle Size; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D034741:RNA, Small Interfering; D011094:Polyethyleneimine; D008156:Luciferases
keywords: 2-Nitroimidazole; Hypoxia; Polyethyleneimine; Tumor; siRNA delivery