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 IC 50 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.

Recent Progress of Paclitaxel Delivery Systems: Covalent and Noncovalent Approaches

“…synthesized a tert ‐Ser‐PTX polyacetal conjugate which release PTX in a pH‐responsive manner for over 2 weeks. [ 172 ] For PTX labeled via esterification, while many reports claimed a more rapid drug release at lower pH due to hydrolyzed ester bonds, here they observed the accelerated release of PTX at higher pH. Implying that acid‐catalyzed hydrolysis of ester is a reversible reaction but it becomes irreversible with base catalysts.…”

Identification and validation of a novel anoikis‐related prognostic model for prostate cancer

“…SB‐743921 is a selective kinesin spindle protein inhibitor, which is being investigated in ongoing clinical trials for the treatment of myeloma, leukemia, and solid tumors (Good et al., 2013 ; Talapatra et al., 2013 ). The microtubule‐interfering agent paclitaxel is a clinically well‐established and highly effective chemotherapeutic drug used to treat advanced tumors, including prostate, breast, ovarian, and non‐small cell lung cancer (Fernandez et al., 2022 ). GSK461364 is a Polo‐like kinase 1 (PLK1) inhibitor that has shown promising results in preclinical studies for the treatment of various cancer types (Ferrarotto et al., 2016 ).…”

In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate

“…Moreover, the rate of release of the active moiety can be controlled by careful selection of linker chemistry through which the drug is conjugated to the dendrimer ( Gupta et al, 2017 , Kratz et al, 2008 , Martin et al, 1972 , Caminade et al, 2005 , Ulaszewska et al, 2013 , Cutler, 2008 ). Owing to their ability to improve both physicochemical and pharmacokinetic properties of drugs, dendrimers have been explored in many therapeutic and biomedical applications ( Anselmo and Mitragotri, 2016 , Tran et al, 2017 , Fernández et al, 2021 , Mignani et al, 2020 ).…”