Integration of sonosensitive nanomicelles and ultrasound for enhanced BBB penetration and targeted therapy against glioblastoma: intravenous injection vs. intranasal dripping

Abstract

The blood–brain barrier (BBB) is pivotal to protect the brain from external interference and to maintain homeostasis for normal physiological processes. However, it also becomes a vital obstacle for drug delivery across the BBB and undermines the efficiency of brain tumor therapies. In this study, an amphiphilic peptide with a cell-penetrating sequence and a hydrophilic targeting terminal (RGD) was self-assembled with encapsulation of Rose Bengal (RB) to generate functionalized nanomicelles (PRN). With active targeting capability, the integration of PRN and medical ultrasound was performed 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, the therapeutic efficacy of both intravenous injection and intranasal dripping of PRN was investigated, and a rationale for immune activation and multilateral cell death was 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 the BBB, and offers an inspiring vision with a cutting-edge DDFI modality for broader applications of disease-oriented treatments.