| Background: Nowadays, chemotherapy has played an important role in the treatment of various cancers. However, systemic administration of chemotherapy agents usually has low efficiency and causes severe systemic toxicity due to the short circulation time and non-specific biodistribution. Additionally, because of the high compactness of most solid tumor, the chemotherapeutic drugs are hard to penetrate too far from the blood vessels and can only cause the partly regional apoptosis around the blood vessels. Moreover, the systemic applications of some hydrophobic drugs(e.g. paclitaxel, camptothecin, methotrexate and so on) are greatly hindered resulted from their poor water solubility. Therefore, the traditional administration of chemotherapeutic drugs is not enough for the development of chemotherapy. To achieve more efficient and safer delivery system, many researches have focused on localized delivery of chemotherapy agents using hydrogels as platforms, which is thought to improve both safety and efficacy compared to the systemic delivery. Moreover, due to the sustained release property, a single injection of the drug-loaded hydrogels can maintain the necessary therapeutic drug concentration for a long period of time, which is more convenient compared with the multiple injections of systemic administration. Thermo-sensitive hydrogels, which exist as fluid at low temperatures and become solid gel at body temperature, may be the most commonly biomedical materials applied in the localized drug delivery fields. Among all the thermo-sensitive hydrogels, the polypeptide-based hydrogels have a lot of advantages, such as no significant changes on the tissue microenvironment after degradation compared to the polyester-based hydrogels. More importantly, the gelation behavior of polypeptide-based copolymers can be easily adjusted by changing the amino acid monomers with different secondary structure or hydrophilicity. Apart from the revolution in the route of administration, the dosage forms also need great improvements. Single treatment of chemotherapy agents usually results in unsatisfying efficacy mainly because of drug resistant and tumor metastasis. Nowadays, the combination of anti-vascular agents and cytotoxic drugs is considered to have improved anticancer efficiency and can induce wholly regional apoptosis of tumors. Additionally, the sequence of administration is also important in the combination of DOX and CA4. On the one hand, if the blood vessels are destroyed by CA4 firstly, DOX could hardly be delivered to the center of the tumor and could not reach to a therapeutic concentration. On the other hand, the inhibited blood vessels induces the accumulation of hypoxia-inducible factor-1α(HIF1-α), which is related with increased tumor invasiveness and resistance to chemotherapy. To overcome these problems, the thermo-sensitive polypeptide hydrogels integrated with the localized and sequential delivery behavior may be an ideal platform for the combined administration of DOX and CA4.Method: In this work, a thermo-sensitive polypeptide hydrogel was firstly developed for the locally sequential delivery of doxorubicin(DOX, a cytotoxic agent) and combretastatin A4(CA4, a vascular disrupting drug). The polypeptide aqueous solution at low temperature could transform into hydrogel under the body temperature after subcutaneous injection and completely degrade after 4 weeks with excellent biocompatibility.Results: In this study, a novel strategy for locally sequential delivery of DOX and CA4 were implemented using an injectable and biodegradable thermo-responsive m PEG-b-PLAF hydrogel for two-pronged therapy of cervical cancer. The m PEG-b-PLAF solution at a concentration of 7 wt.% could transform into hydrogel at body temperature and could degrade gradually in the subcutaneous layer of mouse up to 4 weeks with great biocompatibility in vivo. More interesting, the quick release of DOX and sustained release of CA4 were observed owing to the difference of their water-solubility, which showed important features to the synergistic therapeutic effect. As predicted, after subcutaneous injection of the DOX and CA4 co-loaded hydrogel beside the xenografted U14 cervical tumor, the excellent inhibition of tumor growth was founded up to 28 days. The increased antitumor efficacy was owing to the synergistic effect of DOX and CA4, which was proved by PARP and CD31 staining of the tumors collected at the end of treatments. Moreover, the ex vivo H&E analyses of tumors showed the wholly regional apoptosis after the treatment of DOX and CA4 co-loaded hydrogel, while only the partly regional tumor apoptosis was founded in the single drug-treated groups,. All these results confirmed the excellent synergistic effect of DOX and CA4 co-loaded hydrogel. Additionally, no obvious damages toward normal organs were observed in the groups treated with the drugs-loaded hydrogels, indicating lower systemic toxicity of the localized treatments.Conclusion: DOX and CA4 were co-loaded into the hydrogel and exhibited sequential release behavior due to their difference in water solubility. The superior antitumor efficacy of DOX and CA4 co-loaded hydrogel was founded in the treatment of xenografted U14 cervical cancer compared with both free drugs and single drug-loaded hydrogels. In addition, the co-loaded hydrogel obtained the enhanced apoptosis of tumor cells, shutdown of blood vessels, and wholly regional tumor apoptosis, which indicated the eradication of solid tumor. Moreover, the treatment of the drug-loaded hydrogels showed decreased damage to normal tissues compared with free drug, suggesting their low systemic toxicity. In summary, the locally sequential delivery system had great potential for in situ synergistic chemotherapy. |
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