Salinomycin-loaded injectable thermosensitive hydrogels for glioblastoma therapy

Abstract

Local drug delivery approaches for treating brain tumors not only diminish the toxicity of systemic chemotherapy, but also circumvent the blood-brain barrier (BBB) which restricts the passage of most chemotherapeutics to the brain. Recently, salinomycin has attracted much attention as a potential chemotherapeutic agent in a variety of cancers. In this study, poly (ethylene oxide)/poly (propylene oxide)/poly (ethylene oxide) (PEO-PPO-PEO, Pluronic F127) and poly (dl-lactide-co-glycolide-b-ethylene glycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA), the two most common thermosensitive copolymers, were utilized as local delivery systems for salinomycin in the treatment of glioblastoma. The Pluronic and PLGA-PEG-PLGA hydrogels released 100% and 36% of the encapsulated salinomycin over a one-week period, respectively. While both hydrogels were found to be effective at inhibiting glioblastoma cell proliferation, inducing apoptosis and generating intracellular reactive oxygen species, the Pluronic formulation showed better biocompatibility, a superior drug release profile and an ability to further enhance the cytotoxicity of salinomycin, compared to the PLGA-PEG-PLGA hydrogel formulation. Animal studies in subcutaneous U251 xenograftednudemice also revealed that Pluronic + salinomycin hydrogel reduced tumor growth compared to free salinomycin- and PBS-treated mice by 4-fold and 6-fold, respectively within 12 days. Therefore, it is envisaged that salinomycin-loaded Pluronic can be utilized as an injectable thermosensitive hydrogel platform for local treatment of glioblastoma, providing a sustained release of salinomycin at the tumor site and potentially bypassing the BBB for drug delivery to the brain.

Keywords: Glioblastoma; PLGA-PEG-PLGA; Pluronic; Salinomycin; Thermosensitive injectable hydrogels.