Biotin-Decorated Inulin-Based Polymeric Micelles Unveil Their Dual-Targeting Ability for the Potential Treatment of Glioblastoma Multiforme through the In Vitro and In Vivo Investigations

This study evaluated biotinylated-inulin vitamin E micelles (INVITE-BIO) as a carrier for the hydrophobic drug curcumin and their biotin-mediated dual-targeting ability to the Blood-Brain Barrier (BBB) and Glioblastoma Multiforme (GBM) cells by in vitro and in vivo studies. We previously demonstrated that INVITE-BIO micelles are long-circulating carriers upon i.v. administration, remaining in the body for up to 48 h, making these nanosystems potentially useful for receptor-mediated targeted drug delivery. Here, we first report the physicochemical characterization of curcumin-loaded INVITE-BIO micelles, which revealed a nanosized and spherical shape, as evaluated by DLS and TEM. Moreover, INVITE-BIO micelles showed high loading capacity and good ability to release the payloaded curcumin, which is located in the core of micelles, as demonstrated by 1H NMR study. The bioavailability of biotin on the micelle's surface was demonstrated by HABA/avidin binding assay. Second, in vitro biological studies on GBM U87MG cells indicated that empty micellar carriers did not reveal any significant cytotoxicity and that the encapsulation of curcumin within the carrier can enhance the curcumin's efficacy, potentially by improving its bioavailability. Furthermore, confocal microscopy and flow cytometry studies revealed that the presence of biotin moieties is pivotal to enhancing the cellular uptake and retention of the INVITE nanosystems. In conclusion, INVITE-BIO micelles enhanced both the crossing of BBB and drug accumulation in GBM tumor cells overexpressing the receptor for biotin through receptor-mediated endocytosis, demonstrating the great potential of biotinylated INVITE micelles as a promising dual-targeted approach for i.v. administration of antitumoral drugs for the treatment of Glioblastoma Multiforme.