Surgical resection and postoperative adjuvant chemotherapy have enhanced the outlook for
breast cancer patients, yet tumor relapse and chemotherapy side effects 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 pH sensitive nanogels (DOX-NG) and combretastatin A۴ (CA۴) loaded liposomes which undergo rapid disassembly in cancer cells. CA۴ prevents tubulin polymerization and thus inhibits angiogenesis by binding to vascular endothelial tubulin. Methods: Doxorubicin-loaded nanogels were fabricated by a single emulsion technique and CA۴ loaded liposome was created using the thin film hydration method. Physicochemical properties of the nanogels and liposomes such as particle size, zeta potential, loading efficiency, and the release profile were studied. Cell viability assays of the treated cells were performed using the MTT assay. Anti-tumor effect and biosafety of dox-loaded dual sensitive nanogel and CA۴ loaded liposome were evaluated in vivo in bulb-c mice. Results: The results showed that DOX-NGs were negatively charged and ۲۳۴.۶±۱.۱۵ nm in size. Besides, the size of CA۴ loaded liposomes were ۱۰۲.۳۵±۴.۲۲ nm and were negatively charged. Encapsulation efficiency of DOX-NGs and CA۴ loaded liposomes were ۹۸% and ۸۹%, respectively. After loading into the hydrogel structure, doxorubicin and CA۴ were gradually released from the composite hydrogel for up to ۲۱ days. DOX-NGs and CA۴ loaded liposomes showed a dose-dependent cytotoxic effect against ۴T۱
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 ۱۱۷ mm۳ to ۶۷mm۳) with negligible organ damage, while showed lower cardiotoxicity in ۲۸ days. Conclusion: In conclusion, our results revealed that injectable composite dextran-based hydrogel incorporated with DOX-NG and CA۴ loaded liposomes can be used for the delivery of combination therapies and for the treatment of other solid tumors.