In Vivo Antitumor and Antimetastatic Efficacy of a Polyacetal-Based Paclitaxel Conjugate for Prostate Cancer Therapy

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 pHresponsive 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.

FERNÁNDEZ Yolanda;  MOVELLAN Julie;  FORADADA Laia;  GIMENEZ Vanessa;  GARCIA-ARANDA Natalia;  MANCILLA Sandra;  ARMINAN Ana;  BORGOS Sven Even;  HYLDBAKK Astrid;  BOGDANSKA Anna;  GOBBO Oliviero L.;  PRINA-MELLO Adriele;  PONTI Jessica;  CALZOLAI Luigi;  ZAGORODKO Oleksandr;  GALLON Elena;  NINO-PARIENTE Amaya;  PAUL Alison;  SCHWARTZ JR. Simo;  ABASOLO Ibane;  VINCENT Maria J.; 

2022-11-09

WILEY

JRC126842

2192-2640 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC126842,   

10.1002/adhm.202101544 (online),