Enhanced delivery of low-density lipoprotein-based nanoparticles to the mouse glioblastoma using focused ultrasound as a novel therapy.

Abstract

Glioblastoma (GBM) is a highly invasive and infiltrative primary brain tumor with a poor prognosis. This tumor avidly acquires cholesterol from its environment through the low-density lipoprotein receptor (LDLR) to facilitate their aggressive and rapid proliferative phenotype. The blood-brain barrier (BBB) remains a major challenge for drug delivery to GBM as it restricts the entry of most therapeutics limiting their treatment efficacy. Focused ultrasound (FUS) with microbubbles is a non-invasive and safe method to transiently open the BBB to improve the delivery of the therapeutic agents to the brain. In this study, we aim to establish a facile and effective drug delivery strategy to GBM that integrates FUS-mediated BBB disruption and LDLR targeted delivery. Herein, an invasive intracranial mouse model of GBM was developed with the PS5A cell line. GBM bearing mice received intravenous injection of low-density lipoprotein (LDL) nanoparticles loaded with oleic acid and carbocyanine fluorescent dye with and without pulse FUS sonication in the tumor region of the brain. Tumor bearing mice without LDL nanoparticle or FUS intervention served as untreated controls. Initial confirmation of tumor progression and BBB opening was evaluated by magnetic resonance Imaging (MRI). Fluorescent imaging of the brain tissues post treatment revealed a markedly higher fluorescent signal in the sonicated tumor area when compared to the contralateral hemisphere, groups receiving LDL nanoparticle alone or untreated controls. The combination of LDLR targeting and FUS enabled enhanced intracellular delivery of LDL nanoparticles to GBM cells in the bulk tumor and surrounding peritumor regions in the striatum. These findings indicate that drug delivery can be achieved not only to bulk tumor but also to tumor cells infiltrating surrounding brain tissue behind the BBB. In summary, the current study establishes a foundational framework for the combination of FUS and receptor-targeted delivery of LDL nanoparticles to GBM.