One of the most challenging problems for camptothecin (CPT) family anticancer drugs (i.e. topotecan (TPT)) is the conversion of the active lactone ring into an inactive toxic carboxylate form under physiological conditions (pH = 7.4) in the body. Therefore, a simple platform based on thermosensitive PLLA-mPEG gels was designed to maintain TPT and CPT in lactone form, especially for brain tumor therapies. A high stabilization of the lactone species CPT and TPT within gel (>95%), efficient versatile homogenous drug loadings at 0.015%, 1%, and 10%, and the sustained-release of CPT and TPT over three weeks were all successful. The stabilization mechanism of drugs with gel was elucidated by ATR-FTIR, confocal and light microscopy. The cytotoxic efficacy of TPT in the PLLA-mPEG platform (PLLA-mPEG-TPT) was evaluated on LLC-1 and 4T1 cancer cell lines. In vivo, the administration of PLLA-mPEG-TPT to mice with breast tumors resulted in a significant reduction in tumor size and better survival percentages.