Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer

Longjiang Shao, Nermin Kahraman, Ge Yan, Jianghua Wang, Bulent Ozpolat, Michael Ittmann

    Research output: Contribution to journalArticlepeer-review

    20 Scopus citations

    Abstract

    Background: The TMPRSS2/ERG (TE) fusion gene is present in half of the prostate cancers (PCas). The TMPRSS2 and ERG junction of the fusion messenger RNA (mRNA) constitutes a cancer-specific target. Although docetaxel-based chemotherapy is the second line of therapy following development resistance to androgen ablation therapies, it is not curative. Therefore, the development of nontoxic novel monotherapies for targeting TE mRNA in PCa patients and for increasing the clinical efficacy of docetaxel treatment are needed. Methods: We evaluated multiple approaches to enhance the delivery of TE small interfering RNA (siRNA) containing liposomes including PEGylation, topical treatment with nitroglycerin (NG) to increase permeability and retention, and three different PEG modifications: folate, RGD cyclic peptide, and a bFGF fibroblast growth factor receptor-targeting peptide. The efficacy of the optimized TE siRNA liposome in combination with docetaxel was then evaluated in vivo with or without topical NG in vivo using a VCaP xenograft model. TE fusion protein knockdown in residual tumors was assessed using Western blotting and immunohistochemistry. Results: In vivo therapeutic targeting of TE fusion gene by systemic delivery of RGD-peptide-coated liposomal siRNA nanovectors led to sustained target silencing, suppressed tumor growth in xenograft models and enhanced the efficacy of docetaxel chemotherapy. Simultaneous application of the vasodilator NG to the skin further increased tissue the delivery of siRNA and enhanced target knockdown. Conclusion: TE-targeted gene silencing therapy using liposomal nanovectors is a potential therapeutic strategy as a monotherapy and to enhance the efficacy of chemotherapy in patients with advanced PCa.

    Original languageEnglish (US)
    Pages (from-to)65-73
    Number of pages9
    JournalProstate
    Volume80
    Issue number1
    DOIs
    StatePublished - Jan 1 2020

    Keywords

    • TMPRSS2/ERG fusion gene
    • docetaxel
    • liposomes
    • prostate cancer

    ASJC Scopus subject areas

    • Oncology
    • Urology

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