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

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, one conjugates PTX to a polyacetal-based nanocarrier to yield a tert-Ser-PTX polyacetal conjugate. tert-Ser-PTX conjugate provides sustained release of PTX over 2 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 versus PBS (pH 7.4). In vitro efficacy assessments in PCa cells demonstrate IC50 values above those for the free form of PTX due to the differential cell trafficking modes; however, in vivo tolerability assays demonstrate that tert-Ser-PTX significantly reduces the systemic toxicities associated with free PTX treatment. tert-Ser-PTX also effectively inhibits 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, the results suggest the application of tert-Ser-PTX as a robust antitumor/antimetastatic treatment for PCa.

Category

Academic article

Language

English

Author(s)

  • Yolanda Fernández
  • Julie Movellan
  • Laia Foradada
  • Vanessa Giménez
  • Natalia García-Aranda
  • Sandra Mancilla
  • Ana Armiñán
  • Sven Even Borgos
  • Astrid Hyldbakk
  • Anna Bogdanska
  • Oliviero L. Gobbo
  • Adriele Prina-Mello
  • Jessica Ponti
  • Luigi Calzolai
  • Oleksandr Zagorodko
  • Elena Gallon
  • Amaya Niño-Pariente
  • Alison Paul
  • Simó Schwartz Jr
  • Ibane Abasolo
  • María J. Vicent

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • Trinity College Dublin, the University of Dublin
  • European Commission - Joint Research Centre
  • Spain
  • Autonomous University of Barcelona
  • Cardiff University

Year

2021

Published in

Advanced Healthcare Materials

ISSN

2192-2640

View this publication at Norwegian Research Information Repository