Glycosylated paclitaxel mixed nanomicelles: Increasing drug brain accumulation and enhancing its in vitro antitumoral activity in glioblastoma cell lines

Glioblastoma multiforme (GBM) is the most common, most aggressive and lethal of brain cancers. Patients with GBM exhibit a survival between 12 and 15 months. Unfortunately, intravenous chemotherapy for GBM is very limited due to the poor penetration of the drugs through the blood brain barrier. In this framework, we expand the potential of a nanoformulation based in mixed micelles of polyvinyl caprolactam-polyvinylacetatepolyethylene glycol graft copolymer (Soluplus (R)) and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) loaded with paclitaxel (PTX). The nanoformulation was surface-decorated with glucose moieties as an attempt to optimize its anticancer performance and the PTX accumulation in the central nervous system. Soluplus (R) glycosylation was produced using a ring-opening reaction assisted by microwave. Hence, a multifunctional nanocarrier employing Soluplus(Glu) and TPGS (5:1 wt ratio) loaded with PTX (4 mg/mL) was investigated. Its micellar size before lyophilization, after lyophilization, drug loading content and encapsulation efficiency were 119.3 +/- 41.8 nm, 140.0 +/- 70.2 nm, 6.16 +/- 0.06% and 98.5%, respectively. The colloidal dispersions were also characterized in terms of morphology and in vitro PTX release. Glycosylated PTX-loaded system demonstrated an enhanced (similar to 4.5-fold) in vitro anti-glioma efficacy than its glucose-free counterpart in U251 human glioblastoma cells. Further, in vivo assays revealed that our nanoformulation improved PTX pharmacokinetic parameters after i.v. administration. Interestingly, brain drug accumulation was improved (> 8 fold) for the polymeric micelles in comparison with the PTX solution in Wistar rats. Overall, our micellar system represents a feasible nanotechnological platform for the potential improvement of glioma chemotherapy.