An oxygen-enriched thermosensitive hydrogel for the relief of a hypoxic tumor microenvironment and enhancement of radiotherapy.

ABSTRACT

The rapid proliferation of tumor cells and tortuous vasculature in solid tumors often bring about a hypoxic tumor microenvironment, which renders tumor cells more resistant to many cancer treatments, including radiotherapy. In this study, an injectable and thermosensitive composite hydrogel composed of perfluorooctanoic acid (PFOA) modified monomethoxy poly(ethylene glycol)-poly(D,L-lactide-co-glycolide) (mPEG-PLGA-PFOA) and perfluorooctyl bromide (PFOB) that presented a thermoreversible sol-gel transition upon heating was developed to deliver exogenous oxygen for the relief of tumor hypoxia and enhancement of radiotherapy. The fluorinated modification of copolymers significantly increased the stability of PFOB in the mPEG-PLGA-PFOA aqueous solution owing to the fluorophilic interaction between PFOB and PFOA-modified copolymers. The introduction of PFOB not only efficiently heightened the oxygen loading capacity of the composite hydrogel, but also endowed it with excellent X-ray opacity, allowing the visual observation of the hydrogel via micro-CT imaging. After peritumoral injection of the oxygen-enriched composite hydrogel, the continuous supply of oxygen effectively relieved tumor hypoxia and down-regulated the expression of hypoxia-inducible factor-1α. Profiting from this, the hyposensitivity of tumor cells to radiation was successfully reversed, and the tumor growth in mice was significantly suppressed and the survival of mice was prolonged when combined with multiple X-ray exposure. As a result, the oxygen-enriched composite hydrogel shows a great potential for radiosensitization to improve the radiotherapeutic efficacy.