Thermo-sensitive polypeptide hydrogel for locally sequential delivery of two-pronged antitumor drugs

In the synergistic treatment with cytotoxic drug and vascular disrupting agent, the order of drug release shows great importance to enhance the antitumor efficacy. When vascular disrupting agent is firstly administrated, the reduced blood supply and overexpressed hypoxia-inducible factor-1α greatly limit the efficiency of chemotherapy. In this work, an injectable thermo-sensitive polypeptide hydrogel was firstly developed for the locally sequential delivery of hydrophilic doxorubicin (DOX, a cytotoxic agent) and hydrophobic combretastatin A4 (CA4, a vascular disrupting drug). The aqueous solution of polypeptide at low temperature transformed into hydrogel under the body temperature after subcutaneous injection and completely degraded after four weeks with excellent biocompatibility. DOX and CA4 were co-loaded into the hydrogel, and the release of DOX showed much faster than that of CA4 due to their difference in water solubility. The superior inhibition of tumor volume after treatment with DOX and CA4 co-loaded hydrogel occurred in the treatment of grafted mouse U14 cervical tumor compared with both free drugs and single drug-loaded hydrogels. In addition, the co-loaded hydrogel obtained enhanced apoptosis of tumor cells, significant shutdown of blood vessels, and wholly regional tumor apoptosis, which indicated the eradication of solid tumor. Moreover, treatments with the drug-loaded hydrogels showed negligible damage to normal tissues, suggesting their low systemic toxicity. The locally sequential delivery system had great potential for in situ synergistic chemotherapy.

The release order makes great difference in the synergistic efficacies of cytotoxic drug and vascular disrupting agent. When cytotoxic drug is administrated before vascular disrupting agent, an eradication of tumor might be obtained. On the contrary, the antitumor efficiency will be greatly hindered by limited penetration of later cytotoxic drug and drug resistant induced by vascular disrupting agent. Therefore, the adjustment of the delivery behaviors of such two-pronged agents in one platform was significant for their efficiently synergistic chemotherapy. The present study originally provides a convenient strategy and an advanced sample for sequential administration of cytotoxic drug and vascular disrupting agent in one platform based on their water solubility to achieve upregulated efficacy and safety.