# Tumor-responsive PEGylated mesoporous nanoparticles achieve enhanced chemotherapy and reduced toxicity in prostate cancer

## TL;DR

A new nanoparticle system improves docetaxel delivery for prostate cancer by reducing toxicity and increasing drug effectiveness in tumors.

## Contribution

A redox-sensitive PEGylated mesoporous nanocarrier enables tumor-specific docetaxel release and reduced systemic toxicity.

## Key findings

- PEG–HMS–DTX showed minimal drug release under physiological conditions but rapid release in the presence of glutathione.
- In mice, PEG–HMS–DTX achieved over 70% tumor growth inhibition with minimal systemic toxicity.
- The nanocarrier increased apoptosis in tumor cells through elevated cleaved caspase-3 and reduced PCNA/Bcl-2 expression.

## Abstract

Docetaxel (DTX) remains the first-line chemotherapeutic for advanced prostate cancer, however, its therapeutic efficacy remains limited by poor aqueous solubility, rapid systemic clearance, and severe dose-dependent toxicity. To overcome these constraints, we developed a PEGylated, disulfide-bridged hierarchical mesoporous silica nanocarrier (PEG–HMS) as a redox-sensitive delivery system for DTX (PEG–HMS–DTX). The nanostructure was fabricated by integrating disulfide-containing organosilanes into the silica framework and conjugating thiol-reactive PEG chains, thereby combining long circulation stability with tumor-selective release. Comprehensive physicochemical characterization confirmed uniform spherical morphology, an optimal hydrodynamic size (∼40–50 nm), attenuated surface charge following PEGylation, and high colloidal stability in physiological media, while disulfide linkages enabled responsive structural changes under reductive conditions. Drug release was minimal under physiological conditions (<30% at 72 h) but markedly accelerated in the presence of glutathione (∼60% at 72 h). Compared with free DTX or non-PEGylated carriers, PEG-HMS-DTX exhibited stronger cellular uptake and enhanced cytotoxicity in RM-1 prostate cancer cells. In tumor-bearing mice, PEG-HMS-DTX achieved superior tumor accumulation (peak at ∼12 h), pronounced tumor growth inhibition (>70%), minimal systemic toxicity, and elevated apoptosis characterized by increased cleaved caspase-3 and reduced PCNA/Bcl-2 expression. Collectively, this “stable-in-circulation, trigger-in-tumor” platform substantially improves intratumoral DTX delivery and apoptosis-driven antitumor efficacy, while maintaining systemic safety. These findings highlight PEG-HMS-DTX as a promising and generalizable strategy for prostate cancer chemotherapy, warranting further pharmacokinetic, immunogenicity, and GLP toxicology studies to support translational advancement.

A tumor-responsive PEGylated mesoporous silica nanoplatform (PEG–HMS–DTX) integrates a stealth PEG corona with an internally disulfide-crosslinked structure to achieve “stable in circulation, trigger in tumor” delivery of docetaxel. The nanosystem exhibits prolonged systemic persistence, preferentially accumulates at prostate tumor sites, and undergoes glutathione-mediated disassembly in the reductive tumor microenvironment, resulting in on-site drug release. This mechanism enhances apoptotic killing of cancer cells, markedly inhibits tumor growth, and reduces off-target toxicity compared with free docetaxel.Unlabelled Image