Ultrasound‐Triggered In Situ Gelation to Overcome Tumor Hypoxia for Enhanced Photodynamic and Sustained Chemotherapy

Abstract The combination of photodynamic therapy (PDT) and chemotherapy (CT) has promising potential for cancer treatment in overcoming drug resistance and subsequently enhancing the therapeutic efficiency. However, the tumor hypoxia and premature release of drugs as well as off‐targeting of the established nanocarrier are still the major challenges. Herein, an ultrasound (US)‐triggered in situ hydrogel system is designed to overcome tumor hypoxia and combine PDT and CT (AIPH/PEGDA/DOX/CAT‐Ce6). After ultrasonic treatment, the 2,2′‐azobis[2‐(2‐imidazolin‐2‐yl) propane] dihydrochloride (AIPH) will decompose and release a large amount of alkyl radicals, which can activate the crosslink reaction of poly(ethylene glycol) double acrylate (PEGDA) through the amide bond to form the hydrogel structure. This system can achieve the long‐term immobilization of CAT‐Ce6 and doxorubicin (DOX) at tumor site. Owing to the long‐term retention of the hydrogel, the tumor hypoxia can be persistently relieved under the action of CAT and the effect of PDT can be greatly enhanced. Meanwhile, the sustained release of DOX from the hydrogel can achieve the long‐term chemotherapy. In vivo experiment demonstrates that the combination of repeatable PDT and sustained chemotherapy based on US‐triggered hydrogel system shows a synergistic effect in antitumor therapy without obvious side‐effect.