Smart release injectable hydrogel co-loaded with liposomal combretastatin A4 and doxorubicin nanogel for local combinational drug delivery: A preclinical study.

Surgical resection and postoperative adjuvant chemotherapy have enhanced the outlook for breast cancer patients. However, tumor relapse and serious side effects of chemotherapy continue to impact patients' quality of life. Designing injectable composite hydrogel made of biodegradable polymers providing sustained release of antiangiogenic and chemotherapeutic agents might play a vital role in elimination of cancer cells. In this regard, we developed dextran based composite hydrogel incorporating doxorubicin-loaded dual-sensitive pH-redox nanogels (DOX-DSNG) and combretastatin A4 (CA4) loaded liposomes which undergo rapid disassembly in cancer cells. CA4 prevents tubulin polymerization and thus inhibits angiogenesis by binding to vascular endothelial tubulin. The results showed that DOX-DSNGs were negatively charged and 144.8 ± 0.85 nm in size. Besides, the size of CA4 loaded liposomes were 102.35 ± 4.22 nm and were negatively charged. Encapsulation efficiency of DOX-DSNGs and CA4 loaded liposomes were 100 % and 89 %, respectively. After loading into the hydrogel structure, doxorubicin and CA4 were gradually released from the composite hydrogel for up to 21 days. DOX-DSNGs and CA4 loaded liposomes showed a dose-dependent cytotoxic effect against 4 T1 breast cancer cells. Thereafter, the anti-neoplastic effect and survival study of the composite hydrogel was evaluated in vivo in tumor-bearing mice. The composite hydrogel significantly reduced tumor volume (from 116 mm to 38 mm) with negligible organ damage, while showed lower cardiotoxicity in 28 days. In conclusion, our results revealed that injectable composite dextran-based hydrogel incorporated with DOX-DSNG and CA4 loaded liposomes could be used as an efficient delivery platform for combination therapies in treatment of solid tumors.