Localized controlled release of bevacizumab and doxorubicin by thermo-sensitive hydrogel for normalization of tumor vasculature and to enhance the efficacy of chemotherapy

Abstract

In a malignant tumor, overexpression of pro-angiogenic factors like vascular endothelial growth factor (VEGF) provokes the production of pathologic vascular networks characterized by leaky, chaotically organized, immature, thin-walled, and ill-perfused. As a result, hostile tumor environment would be developed and profoundly hinders anti-cancer drug activities and fuels tumor progression. In this study, we develop a strategy of sequential sustain release of anti-angiogenic drug, Bevacizumab (BVZ), and anti-cancer drug, Doxorubicin (DOX), using poly (d, l-Lactide)- Poly (ethylene glycol) -Poly (d, l-Lactide) (PDLLA-PEG-PDLLA) hydrogel as a local delivery system. The release profiles of the drugs from the hydrogel were investigated in vitro which confirmed that relatively rapid release of BVZ (73.56 ± 1.39%) followed by Dox (61.21 ± 0.62%) at pH 6.5 for prolonged period. The in vitro cytotoxicity test revealed that the copolymer exhibited negligible cytotoxicity up to 2.5 mg ml^-1 concentration on HaCaT and HeLa cells. Likeways, the in vitro degradation of the copolymer showed 41.63 ± 2.62% and 73.25 ± 4.36% weight loss within 6 weeks at pH 7.4 and 6.5, respectively. After a single intratumoral injection of the drug-encapsulated hydrogel on Hela xenograft nude, hydrogel co-loaded with BVZ and Dox displayed the highest tumor suppression efficacy for up to 36 days with no noticeable damage on vital organs. Therefore, localized co-delivery of anti-angiogenic drug and anti-cancer drug by hydrogel system may be a promising approach for enhanced chemotherapeutic efficacy in cancer treatment.

Keywords: Anti-angiogenesis; Chemotherapy; Controlled release; Thermo-sensitive hydrogel.