Sustained release of lipophilic gemcitabine from an injectable polymeric hydrogel for synergistically enhancing tumor chemoradiotherapy

•A long-acting delivery system was developed based on Gem derivative and thermogel.•The sustained release of Gem played a dual role in chemoradiotherapy.•The delivery system achieved synergistically enhanced chemoradiotherapy effect. Gemcitabine (Gem), an analogue of deoxycytidine, has potent antitumor activities against various solid tumors and is an excellent radiosensitizer as well. However, Gem has a very short half-life, making it difficult to achieve the long-term synergies between chemotherapy and radiotherapy. Herein, we developed a long-acting Gem delivery system using a palmityl modified Gem derivative (GemC16) as the drug and an injectable and thermosensitive hydrogel as the vehicle, and then combined with multiple radiation therapy for the synergistic treatment of tumors. The thermosensitive hydrogel that exhibited a temperature-responsive sol–gel transition was composed of two poly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers with different PLGA/PEG ratios. Such a physical hydrogel formed an internal structure of percolated micelle network, in which the polymeric micelles played a reservoir role in effectively solubilizing lipophilic GemC16 in water. In vitro tests manifested that the entrapped GemC16 was, in the form of micelles and micellar aggregates, released out of the hydrogel depot in a sustained pattern for over one month. In vitro cellular assays demonstrated that GemC16 mediated by the polymeric micelles was rapidly internalized to tumor cells via endocytosis. After a single peritumoral administration of the hydrogel system combined with local multiple X ray exposures, the sustained release of GemC16 exerted a long-acting chemotherapy effect and afforded a durable radiosensitization, thereby synergistically enhancing chemoradiotherapy efficacy, inhibiting metastasis and ameliorating complications.