Abstract 3241: Peptide Power: A PSMA-targeted CT20 Nanoparticle to Fight Prostate Cancer
Cancer research(2017)
摘要
Abstract Chemotherapeutic agents within targeted nanoparticles typically trigger cell death not only in tumors cells but also in normal cells that non-specifically uptake these nanoparticles. An alternative approach would be to target the delivery of a therapeutic agent that is toxic to cancer cells while less toxic to non-tumor cells. To accomplish this, a Bax-derived peptide (CT20) was developed as a selective cancer-targeting agent, and a folate-decorated hyperbranched polyester (HBPE) nanoparticle was employed to deliver the peptide to prostate-specific membrane antigen (PSMA) (+) prostate cancer cells. The receptor-targeting capability of folic acid towards PSMA (+) in prostate cancer was examined using a fluorescence activatable probe, folate-S-S-doxorubicin, and the PSMA inhibitor 2-PMPA. Additionally, a folate-decorated HBPE nanoparticle was utilized to targeted-deliver the CT20 peptide to prostate cancer cells in vitro as well as in athymic mice. CT20-encapsulated folate (folate-CT20) nanoparticles were used to determine cell cytotoxicity against PSMA-positive and -negative cells using flow cytometry. Furthermore, cytotoxicity of folate-CT20 nanoparticles towards murine macrophages was evaluated to determine the consequences of non-specific uptake; the FDA-approved doxorubicin was used for comparison. Cell death associated with CT20 was determined through a violet ratiometric membrane asymmetry probe combined with SYTOX AADvanced dead cell stain to evaluate membrane asymmetry and membrane permeability. Folate-CT20 nanoparticles’ tumor-targeting and tumor-killing efficacy was evaluated in athymic mice bearing PSMA (+) tumors and PSMA (-) tumors. Nanoparticles were delivered intravenously through the tail vein and the tumor size was assessed with calipers and ultrasound. Folate-S-S-Doxorubicin was uptaken specifically by PSMA (+) prostate cancer cells showing fluorescence within 12 hours and cell death within 24 hours. Cells that were preincubated with 2-PMPA followed by folate-S-S-Doxorubicin demonstrated no cell-associated fluorescence or cytotoxicity. Similarly, folate-decorated nanoparticles were only internalized by PSMA (+) cells. Cytotoxicity of folate-CT20 nanoparticles towards PSMA (+) cancer cells occurred within 48 hours, while no changes occurred in PSMA (-) cells. When murine macrophages were treated with PSMA-targeting nanocarriers and doxorubicin individually, significant cytotoxicity only occurred in doxorubicin-exposed cells. In vivo, folate-CT20 nanoparticles were capable of preventing further PSMA (+) tumor growth and caused PSMA (+) tumor regression in some cases. Moreover, minimal liver and spleen damage was observed. Herein, we demonstrate that the CT20 peptide is capable of displaying specific lethality towards PSMA (+) prostate cancer cells and that folate-CT20 nanoparticles are promising vehicles to deliver CT20 in vitro and in vivo. Citation Format: Orielyz Flores, Daniel Nierenberg, Ana C. Carr, Rania Bassiouni, Arati Limaye, Santimukul Santra, Charalambos Kaittanis, Annette Khaled, Jesus Manuel Perez. Peptide power: A PSMA-targeted CT20 nanoparticle to fight prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3241. doi:10.1158/1538-7445.AM2017-3241
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