Doxorubicin and CD‑CUR inclusion complex co‑loaded in thermosensitive hydrogel PLGA‑PEG‑PLGA localized administration for osteosarcoma.

Abstract

Combination therapy is a promising and prevalent strategy for osteosarcoma treatment. Curcumin (CUR), as a chemosensitizer, improves the antitumor effect of first-line chemotherapy drugs. However, due to its poor solubility and instability in physiological conditions, the bioavailability of CUR is limited. In order to improve the physicochemical properties of natural CUR, β-cyclodextrin was adopted to generate a β-cyclodextrin curcumin (CD-CUR) inclusion complex. A thermosensitive hydrogel, poly(D,L-lactide-co-glycolide)-poly(ethylene-glycol)-poly(D,L-lactide-co-glycolide), was selected and synthesized to co-deliver doxorubicin (DOX) and CD-CUR to tumor sites. The dual-drug delivery system (gel+DOX+CD-CUR) was prepared by mixing drugs with hydrogels and had a perfect sol-gel phase transition temperature (18.3°C for 20% concentration). Both DOX and CUR were released from hydrogels in a sustained manner in PBS (pH 7.4) medium. The combination therapy based on DOX+CD-CUR exhibited higher antitumor activity than monotherapies in vitro. Combined CD-CUR therapy significantly downregulated Bcl-2 expression and upregulated caspase-3 expression, suggesting that DOX combined with CD-CUR treatment has a higher apoptosis-inducing efficiency. The antitumor efficiency of the gel+DOX+CD-CUR strategy was evaluated in K-7 tumor-bearing mice, and this localized combination therapy demonstrated a higher antitumor efficiency compared with free DOX+CD-CUR or single-drug strategies. There were no significant differences in body weight and histological changes of major organs in each group. Therefore, the present combination treatment based on hydrogel may be a feasible approach to co-deliver DOX and CD-CUR to osteosarcoma tumor sites in clinical practice.