title: Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth.
abstract: The particular characteristics of the tumor microenvironment have the potential to strongly promote tumor growth, metastasis and angiogenesis and induce drug resistance. Therefore, the development of effective, systemic therapeutic approaches specifically based on the tumor microenvironment is highly desirable. Hypoxia-inducible factor-1α (HIF-1α) is an attractive therapeutic target because it is a key transcription factor in tumor development and only accumulates in hypoxic tumors. We report here that a cationic mixed micellar nanoparticle (MNP) consisting of amphiphilic block copolymers poly(ε-caprolactone)-block-poly(2-aminoethylethylene phosphate) (PCL(29)-b-PPEEA(21)) and poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL(40)-b-PEG(45)) was a suitable carrier for HIF-1α siRNA to treat hypoxic tumors, which showed an average diameter of 58.0 ± 3.4 nm. The complex MNP(siRNA), formed by the interaction of MNP and siRNA, was transfected into PC3 prostate cancer cells efficiently, while the inhibition of HIF-1α expression by MNP loaded with HIF-1α siRNA (MNP(siHIF)) blocked PC3 cell proliferation, suppressed cell migration and disturbed angiogenesis under in vitro hypoxic mimicking conditions. It was further demonstrated that systemic delivery of MNP(siHIF) effectively inhibited tumor growth in a PC3 prostate cancer xenograft murine model without activating innate immune responses. Moreover, delivery of MNP(siHIF) sensitized PC3 tumor cells to doxorubicin chemotherapy in vitro and in vivo by downregulating MDR1 gene expression which was induced by hypoxia. The underlying concept of use of MNP(siHIF) to block HIF-1α holds promise as an example of a clinical approach using specific siRNA therapy for cancer treatment aimed at the hypoxic tumor microenvironment.
authors.affiliation: CAS Key Laboratory of Brain Function and Disease and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P. R. China.
authors.forename: Xi-Qiu
authors.initials: XQ
authors.lastname: Liu
authors.forename: Meng-Hua
authors.initials: MH
authors.lastname: Xiong
authors.forename: Xiao-Ting
authors.initials: XT
authors.lastname: Shu
authors.forename: Rui-Zhi
authors.initials: RZ
authors.lastname: Tang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D010316:Particle Size; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics*; D014162:Transfection / Q000379:methods; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008823:Micelles; D011108:Polymers; D034741:RNA, Small Interfering; D004317:Doxorubicin