Tumor microenvironment-responsive injectable hydrogels for localized therapy of pancreatic cancer.

Abstract

To address the clinical need for localized therapy for pancreatic cancer, an injectable, self-healing nanocomposite hydrogel (GPPA-Mn@DOX) was rationally designed and developed. The hydrogel consists of phenylboronic acid-modified gelatin (Gel-PBA) and polyvinyl alcohol (PVA), which are crosslinked through dynamic boronate ester bonds and loaded with doxorubicin (DOX)-containing hollow mesoporous MnO2 (H-MnO2) nanocarriers. This integrated design enables tumor microenvironment (TME)-responsive drug release while facilitating in situ O2 generation. The resulting network exhibits a three-dimensional porous architecture, robust mechanical properties, and pronounced shear-thinning behavior. H-MnO2 catalyzes endogenous H2O2 to generate O2 and induces pH/ROS dual-responsive DOX release, resulting in a cumulative release of 76.71% within 48 h. The released DOX was efficiently internalized by BxPC-3 cells, thereby suppressing their migration and proliferation. In vivo, the hydrogel system significantly inhibited pancreatic tumor growth by promoting apoptosis, suppressing cellular proliferation, and alleviating hypoxia through downregulation of HIF-1α, while causing negligible systemic toxicity. Collectively, this platform represents a promising localized synergistic therapeutic strategy for pancreatic cancer.