Integration of Sonosensitive Nanomicelles and Ultrasound for Enhanced BBB Penetration and Targeted Therapy against Glioblastoma: Intravenous Injection vs. Intranasal Dripping

The blood brain barrier (BBB) is pivotal to protect brain from external interferences and to maintain homeostasis for normal physiological processes. However, it also becomes a vital obstacle for drug delivery across BBB and undermines efficiency of brain tumor therapies. In this study, an amphiphilic peptide with cell-penetrating sequence and hydrophilic targeting terminal (RGD) was self-assembled with encapsulation of Rose Bengal (RB) to generate the functionalized nanomicelles (PRN). With active target capacity, the integration of PRN and medical ultrasound was applied to enhance BBB penetration and achieve consecutive glioblastoma-targeted sonodynamic therapy. The temporary BBB opening and penetration enhancement have been validated in vitro and in vivo under US irradiation, and the efficacious tumor growth inhibition and lesion elimination were evidenced by a mechanism of in situ ROS-induced tumor cell apoptosis. Meanwhile, therapeutic efficacies by both intravenous injection and intranasal dripping of PRN were investigated, and a rationale of immune-actuation and multilateral cell death were proposed for this therapeutic modality of drug-device-field integration (DDFI). This research has provided an advanced glioblastoma treatment by different administrations and delivery pathways across BBB, and outlook an inspiring vision with a cutting-edge DDFI modality for broader applications of disease-oriented treatments.