Work

Pancreatic Cancer-Targeting Cascade Nanoamplifier Enables Self-Replenishing H2O2 Generation and Autophagy Disruption in Chemodynamic Therapy

Year: 2025

Type: article

Abstract: Background/Objectives: Conventional therapeutic strategies exhibit limited efficacy against pancreatic cancer, primarily due to its profoundly hypoxic tumor microenvironment and dense fibrotic stroma. Chemodynamic therapy (CDT) holds promise; however, its application in pancreatic cancer is restricted by insufficient endogenous hydrogen peroxide (H2O2) levels and the activation of protective autophagy in response to oxidative stress. Methods: To overcome these obstacles, we developed a tumor microenvironment-responsive, pancreatic cancer-targeted CDT nanoamplifier—H-MnO2/GOX&CQ-iRGD—comprising a hollow mesoporous MnO2 shell co-loaded with glucose oxidase (GOX) and chloroquine (CQ), and surface-functionalized with the tumor-penetrating peptide iRGD. GOX catalyzes glucose oxidation to generate H2O2, enhancing Fenton-like reactions. CQ suppresses autophagy induced by oxidative stress, thereby alleviating therapy resistance. The iRGD peptide targets integrin αvβ3, which is overexpressed on pancreatic cancer cells and tumor vasculature, promoting deep tumor penetration and enhanced delivery efficiency. Results: We comprehensively characterized the nanoplatform’s physicochemical properties, tumor microenvironment triggered degradation, controlled drug release, glucose-driven H2O2 generation, and hydroxyl radical production in vitro. Cellular studies assessed nanoparticle uptake, intracellular H2O2 production, autophagy inhibition, and cytotoxicity. In vivo experiments further demonstrated effective tumor targeting and significant therapeutic outcomes in pancreatic cancer models. Conclusions: This nanoplatform addresses major barriers of CDT—namely, insufficient H2O2 levels, autophagy-mediated resistance, and limited intratumoral penetration—offering a promising strategy for pancreatic cancer treatment.

Source: Pharmaceutics

DOI: 10.3390/pharmaceutics17091201