Injectable Hydrogel Delivery System with Nintedanib and Chloroquine Triggers Apoptosis and Inhibits Protective Autophagy

Abstract

The hydrogel drug delivery system has demonstrated significant potential in addressing the limitations of chemotherapeutic medicines and tumor-targeted treatment. Nintedanib, an FDA-approved potent triple vascular kinase inhibitor, has exhibited effective antitumor activity in a variety of malignancies, although its underlying mechanism remains elusive. In this investigation, an innovative sustained-release hydrogel delivery system for medication was established using the Michael addition reaction of the polyethylene glycol diacrylate and 4-arm poly(ethylene glycol)-thiol (4 Arm PEG-SH). It was discovered that the nintedanib@PEG hydrogel induced cell apoptosis and inhibited tumor progression. Subsequently, analysis revealed that nintedanib caused apoptosis in colon cancer cells by upregulating PUMA (p53 upregulated modulator of apoptosis) expression while also activating protective autophagy. Mechanistically, nintedanib inhibited Akt/mTOR (mechanistic target of rapamycin kinase) pathway activation, thereby inducing PUMA-dependent apoptosis and triggering protective autophagy. Moreover, the combination of nintedanib and CQ (chloroquine, an autophagy inhibitor) contained in the hydrogel delivery system showed a synergistically antitumor effect both in vitro and in vivo. Consequently, an in situ-targeted, long-term, effective, and safe antitumor strategy using an innovative injectable hydrogel delivery system combined with complementary medication. These findings propose a promising therapeutic approach for clinical patients, particularly in the realm of colon cancer therapy, thereby illuminating potential avenues for further research and clinical application.