Prevention Of Local Cervical Cancer Recurrence After Surgery Using Electrospun Nanofibers Co-loaded With Cisplatin And Curcumin

Although the treatment of cervical cancer has been greatly improved these years,locoregional recurrence of cervical cancer following surgical resection remains a severe clinical problem. Cisplatin has long been the first-line chemotherapy drug against cervical cancer by systemic administration as an adjuvant to radiotherapy.However, it has been widely recognized that cisplatin-based combinations have significant toxicity and usually lead to many complications and side effects. In recent years, curcumin has wide concern as the adjunct drug to cancer chemotherapy for the purpose of reducing the risk of drug resistance, improving the efficacy and extenuating the drug toxicity. With these advantages, however, drawbacks associated with light sensitivity, low water solubility, and poor oral bioavailability restrict the therapeutic value of curcuminoids. Compared with the systematical and single agent chemotherapy, local-combination therapy has the advantages of enhancing drug concentration at target site, solubility and bioavailability, and achieves the goal of better efficacy and lower systemic toxicity, improving survival rate and quality. In various kinds of local drug delivery system, the electrospun nanofibers has been studied extensively in biomedicine as a drug delivery carrier with the advantages of high specific surface area, high drug loading and high porosity.Purpose:Therefore, in the present study, nanofibers co-loaded with cisplatin and curcumin,local, combination chemotherapy was investigated to prevent the local cervical cancer recurrence after surgery,in order to evaluate the efficacy and safety and investigate the potential use of polymer nanofibers of local combination chemotherapy in cervical cancer.Method: the article consists of the following three parts:1. The cytotoxicity of cisplatin, curcumin and their combination against He La cells and U14 cells was measured by the MTT assay in vitro. The apoptotic rates of He La cells after treatment were determined by flow cytometry using an Annexin V FITC / PI apoptosis kit2. Preparation and characterization of the PLA/PEO electrospun nanofibers co-loaded with cisplatin and curcumin. Then the in vitro release behaviors of both cisplatin and curcumin from this system were investigated in the release medium with or without the emulsifier.3. The in vivo biodistribution of cisplatin and curcumin was studied by ICP-MS and HPLC, respectively. Then the in vivo antitumor efficacy of cis-cur/fiber was studied in female KM mice bearing subcutaneous cervical cancer. The mice were grouped, the tumor recurrence rate,tumor volume, relative body weight and survival time were analyzed and tried to prove the superiority of nanofibers-based, local,combination chemotherapy to systemic, combination chemotherapy in vivo trails.Results:1. The combination of cisplatin and curcumin suppressed the proliferation of He La cells and U14 cells more effectively than each of them used alone, and achieved a synergetic effect when the drug dose radio was6:20. The combination chemotherapy markedly enhanced apoptosis of He La cells, which indicates that the application of curcumin significantly increased the effectiveness of cisplatin.2. Cisplatin and curcumin were successfully loaded into electrospun nanofibers, the fiber was smooth in appearance without drug crystals.The measured results showed that nanofibers had good hydrophilicity and mucoadhesiveness, and drugs were evenly distributed. In addition,the iv vitro drug release assay showed that a quick release of cisplatin and curcumin took place at the beginning, followed by a steadily release which inhibiting tumor cells continuously.3. Biodistribution assay showed that both cisplatin and curcumin released from the cis-cur/fiber mainly accumulated in the targeted armpit tissue and local drug delivery by nanofibers is favorable to reduce the drug distribution in important metabolic organs. When used in the prevention of U14 cervical cancer recurrence in mice, nanofibers-based local combination chemotherapy was more effective and less toxic than systemic combination chemotherapy, resulted in lower tumor recurrence rate, better survival time and quality. The tumor recurrence rate after nanofibers-based local combination chemotherapy was only 25% which was significantly different from those of the systemic combination chemotherapy or control group and the weight return well, which reflects the better efficacy and safety.Conclusion:In this text, we successfully prepare the PLA/PEO electrospun nanofibers co-loaded with cisplatin and curcumin, and proved it to be a good local chemotherapy dosage form. The effectiveness and system safety of cisplatin were significantly increased due to the addition of curcumin. Through the local implantation delivery system, achieved the enrichment of the drug in target site, and favorable to reduce the drug distribution in important metabolic organs such as liver and kidneys, thereby reduced unwanted side-effects. The nanofiber-based local drug delivery system has achieved a better balance between efficacy and systemic safety in chemotherapy. In short, nanofibers mat is a hopeful dosage form for local, combination chemotherapy as an auxiliary option to prevent local cervical cancer recurrence after surgical resection, which provides an encouraging prospect of preventing tumor recurrence,and also provides a feasible new way for the treatment of cervical or vaginal cancer.