Polysorbate-Based Carriers Encapsulating Oxygen-Deficient Nanoparticles for Targeted and Effective Chemo-Sonodynamic Therapy of Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with a high recurrence rate and mortality. A major obstacle to the effective treatment of GBM is the blood-brain barrier (BBB), which hinders the transfer of therapeutic cargo to the tumor lesion. Polysorbate-coated drug carriers are known to efficiently cross the BBB via apolipoprotein E (ApoE)-mediated transcytosis. In this study, we developed cancer-targeted nanocarriers using folic acid (FA)-conjugated polysorbate (Tween 80, T80) for safe and efficient chemo-sonodynamic combination therapy against GBM. T80-based nanocarriers effectively co-encapsulated doxorubicin (DOX, chemotherapeutic agent) and oxygen-deficient MnWOx nanoparticles (sonosensitizer). FA-conjugated T80 nanocarriers encapsulating DOX and MnWOx (FA-T-DOX@MnWOx) boosted the cellular uptake of DOX in human glioblastoma U87MG cells. The efficient ability of the T80-based drug carriers to cross the BBB was demonstrated using an in vitro transwell BBB model. In addition, sonosensitizer MnWOx nanoparticles in the T80-based carriers triggered GSH depletion, synergistically enhancing intracellular reactive oxygen species (ROS) generation in U87MG cells upon US irradiation. As a result, FA-T-DOX@MnWOx combined with US triggered significant apoptosis in U87MG cells. This study demonstrated that FA-conjugated, MnWOx-loaded, T80-based nanocarriers capable of crossing the BBB hold significant potential for treating GBM through a combined chemo-sonodynamic therapy.