Enhanced stability and efficacy of GEM-TOS prodrug by co-assembly with antimetastatic shell LMWH-TOS

Publication date: Available online 26 June 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Rong Guo, Yang Long, Zhengze Lu, Miao Deng, Penghui He, Man Li, Qin HeAbstractChemotherapy agents have been widely used for cancer treatment, while the insolubility, instability and toxicity seriously restrict their efficacy. Thus, prodrug strategy was devised. Since some prodrugs are still with poor solubility or stability, a synergy strategy is needed to enhance their efficacy. Gemcitabine (GEM) is a prescribed anticancer drug, however, the rapid clearance, growing resistance and serious side effects limit its clinical efficacy. Conjugating GEM with D-α-tocopherol succinate (TOS) is an effective solution, while the GEM-TOS (GT) is unstable in aqueous solution. D-α-Tocopherol polyethylene glycol succinate (TPGS) has been used to enhance the stability, but GT stabilized by TPGS (GTT) has limited effect on tumor metastases. Tumor metastases lead to high mortality in patients suffering from cancers. In order to further achieve antimetastatic effect, an amphiphilic polymer (LT) was synthesized by connecting low-molecular-weight heparin (LMWH) with TOS, and eventually obtained desired self-delivery micellar NPs (GLT) by co-assembly GT with LT. The GLT not only possessed excellent stability, but also inhibited the metastases by acting on different phases of the metastatic cascade. The hydrophobic TOS inhibited the secretion of matrix metalloproteinase-9 (MMP-9), the hydrophilic LMWH inhi...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research