Methotrexate sustained-release implants for delay of sarcoma recurrence in mice

LIU Xiu-xiu; GAO Li; XIA Lun-yang; XU Jian-jian; LIAO Chen-zhong

Abstract：Objective:In this study,methotrexate sustained-release implants were prepared and investigated for their potential usage for cancer treatment.The degradation ration and cumulative release in vitro and in vivo of the sustained-release implants were determined separately.The effect of methotrexate sustained-release implants on delayed sarcoma recurrence was explored.The methotrexate sustained-release implants made herein were compared with traditional delivery system to explore their clinical superiority and advantages.Methods:PLGA and PEG4000 were used as excipients and hot-melting extrusion method was applied to fabricate methotrexate sustained-release implants,whose cumulative release ratio in vitro and in vivo were measured by UV and HPLC,respectively.HPLC was also applied to determine the drug actual contents in the produced implants.KM mice were inoculated subcutaneously with Sarcoma 180 cells at the axillary region to simulate postoperative residual lesions.Adjuvant chemotherapy after radical operation model was fabricated and the effect of local administration of methotrexate sustained-release implants on delayed sarcoma recurrence was evaluated.Results:Yellow uniform methotrexate sustained-release implants with a diameter of 0.88 mm were successfully fabricated by hot-melting extrusion method.Further characterization results demonstrated that drug actual content was up to (8.34 ± 0.65) ％,which was consistent with theoretical content.Methotrexate sustained-release implants we made herein could maintain a sustained and controlled release up to 7 d in vitro release and 15 d in vivo release respectively.Compared with traditional delivery system,methotrexate sustained-release implants prepared in this research were more effective in delaying tumor recurrence and prolonging the survival of mice and the implants could avoid some adverse effects.Conclusion:Hot-melting extrusion method can be applied successfully to fabricate methotrexate sustained-release implants,which have the advantages such as controlled slow-release and long-acting,and then can overcome some shortcomings and defects of the administration method of methotrexate,and might be a promising formulation for delaying local tumor recurrence.