2012.08.27,Professor Wang Jun Published a paper in Molecular Pharmaceutics,online

  • 2012.08.27,Professor Wang Jun Published a paper entitled:“Therapeutic Delivery of siRNA Silencing HIF-1 Alpha with Micellar Nanoparticles Inhibits Hypoxic Tumor Growth” in Molecular Pharmaceutics,online
    Author:Liu Xiqiu、Xiong Menghua、Shu Xiaotin、Tang Ruizhi、Wang Jun

    Abstract:The particular characteristics of the tumor microenvironment have the potential to stronglypromote tumor growth, metastasis, angiogenesis and induce drug resistance. Therefore, thedevelopment of effective, systemic therapeutic approaches specifically based on the tumormicroenvironment is highly desirable. Hypoxia-inducible factor-1α (HIF-1α) is an attractivetherapeutic target because it is a key transcription factor in tumor development and onlyaccumulates in hypoxic tumors. We report here that a cationic mixed micellar nanoparticle (MNP)consisted of amphiphilic block copolymers poly(ε-caprolactone)-block-poly(2-aminoethylethylene phosphate) (PCL29-b-PPEEA21) and poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL40-b-PEG45) was a suitable carrier for HIF-1α siRNA to treat hypoxictumors, which showed an average diameter of 58.0 ± 3.4 nm. The complex MNPsiRNA, formed bythe 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 (MNPsiHIF)blocked PC3 cell proliferation, suppressed cell migration and disturbed angiogenesis under invitro hypoxic mimicked condition. It was further demonstrated that systemic delivery ofMNPsiHIFeffectively inhibited tumor growth in a PC3 prostate cancer xenograft murine modelwithout activating innate immune responses. Moreover, delivery of MNPsiHIFsensitized PC3tumor cells to doxorubicin chemotherapy in vitro and in vivo by down-regulating MDR1 geneexpression which was induced by hypoxia. The underlying concept of use of MNPsiHIFto blockHIF-1α holds promise as an example of a clinical approach using specific siRNA therapy forcancer treatment aimed at the hypoxic tumor microenvironment.


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