Systemically administered chemotherapeutic drugs are often ineffective in the treatment of invasive brain tumors due to poor therapeutic index. Within gliomas, despite the presence of heterogeneously leaky microvessels, dense extracellular matrix and high interstitial pressure generate a “blood-tumor barrier” (BTB), which inhibits drug delivery and distribution. Meanwhile, beyond the contrast MRI-enhancing edge of the tumor, invasive cancer cells are protected by the intact blood-brain barrier (BBB). In this project, we are investigating whether highly PEGylated drug-loaded brain-penetrating nanoparticles (BPN) loaded with a chemotherapeutic agent, cisplatin (CDDP), can be delivered across both the blood-tumor and blood-brain barriers with MR image-guided focused ultrasound (MRgFUS), and whether this treatment can control glioma growth and invasiveness. To this end, we have established that MRgFUS is capable of significantly enhancing the delivery of ~60 nm fluorescent tracer BPN across the blood-tumor barrier in both the 9L (6-fold improvement) gliosarcoma and invasive F98 (28-fold improvement) glioma models. We’ve also shown that a CDDP loaded BPN formulation (CDDP-BPN), composed of a blend of polyaspartic acid (PAA) and heavily PEGylated polyaspartic acid (PAA-PEG), may be delivered from the systemic circulation into orthotopic F98 gliomas using MRgFUS. This treatment elicits a significant reduction in tumor invasiveness and growth, as well as improved animal survival.