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In vivo Antitumor and ametastatic efficacy of a polyacetal-based paclitaxel conjugate for prostate cancer therapy

Fernández, Yolanda, Movellan, Julie, Foradada, Laia, Giménez, Vanessa, García-Aranda, Natalia, Mancilla, Sandra, Armiñán, Ana, Borgos, Sven Even, Hyldbakk, Astrid, Bogdanska, Anna, Gobbo, Oliviero L., Prina-Mello, Adriele, Ponti, Jessica, Calzolai, Luigi, Zagorodko, Oleksandr, Gallon, Elena, Niño-Pariente, Amaya, Paul, Alison, Schwartz, Simó, Abasolo, Ibane and Vicent, María J. 2022. In vivo Antitumor and ametastatic efficacy of a polyacetal-based paclitaxel conjugate for prostate cancer therapy. Advanced Healthcare Materials 11 (7) , 2101544. 10.1002/adhm.202101544
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Abstract

Prostate cancer (PCa), one of the leading causes of cancer-related deaths, currently lacks effective treatment for advanced-stage disease. Paclitaxel (PTX) is a highly active chemotherapeutic drug and the first-line treatment for PCa; however, conventional PTX formulation causes severe hypersensitivity reactions and limits PTX use at high concentrations. In the pursuit of high molecular weight, biodegradable, and pH-responsive polymeric carriers, we conjugated PTX to a polyacetal-based nanocarrier to yield a tert-Ser-PTX polyacetal conjugate. tert-Ser-PTX conjugate provides sustained release of PTX over two weeks in a pH-responsive manner while also obtaining a degree of epimerization of PTX to 7-epi-PTX. Serum proteins stabilize tert-Ser-PTX, with enhanced stability in human serum vs. PBS (pH 7.4). In vitro efficacy assessments in PCa cells demonstrated IC50 values above those for the free form of PTX due to the differential cell trafficking modes; however, in vivo tolerability assays demonstrated that tert-Ser-PTX significantly reduced the systemic toxicities associated with free PTX treatment. tert-Ser-PTX also effectively inhibited primary tumor growth and hematologic, lymphatic, and coelomic dissemination, as confirmed by in vivo and ex vivo bioluminescence imaging and histopathological evaluations in mice carrying orthotopic LNCaP tumors. Overall, our results suggest the application of tert-Ser-PTX as a robust anti-tumor/antimetastatic treatment for PCa.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Wiley-VCH Verlag
ISSN: 2192-2640
Date of First Compliant Deposit: 28 October 2021
Date of Acceptance: 18 October 2021
Last Modified: 11 May 2022 22:55
URI: https://orca.cardiff.ac.uk/id/eprint/145148

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