Enhanced Treatment of Glioblastoma through Controlled Drug Release from a Novel Nano-Carrier

Carmustine (BCNU) is an FDA-approved anti-cancer drug for the treatment of certain types of brain tumors including glioblastoma. Unfortunately, to reach the necessary therapeutic levels in the brain, BCNU needs to be administrated intravenously at a high dosage to compensate for its accumulation in various nonspecific organs, leading to severe adverse side effects, such as bone marrow suppression, pulmonary fibrosis, and hepatic toxicity. Gliadel® wafers are biodegradable polymer constructs loaded with BCNU for surgically implanted directly at the brain tumor site, thus potentially reducing the side effects associated with intravenous delivery. However, multiple critical complications can arise from the invasive surgery, including seizures, cerebral edema, and impaired neurosurgical wound healing. Therefore, there is an urgent need to develop a drug delivery system that can effectively deliver BCNU across the blood-brain barrier (BBB) with minimal side effects. To address the unmet demand, we will develop a novel drug delivery system based on a uniquely engineered, nanoscale metal-organic framework (nMOF). nMOFs represent a new generation of nanoporous, hybrid, crystalline materials, which are unparalleled in terms of their tunable sizes, uniform pore structures, and large surface areas. A multi-functional nano-device with a unique core-shell structure will be developed by utilizing an nMOF as the shell and a magnetic nanoparticle as the core.  The size and surface properties of the nano-device will be optimized for efficient delivery of BCNU through a blood-tumor barrier model to be developed on a microfluidic chip. High drug payload will be obtained and the controlled release of the loaded drugs will be achieved via a magnetothermol effect by applying an alternating magnetic field on the magnetic core. In addition, we will further demonstrate that the proposed nano-device can act as an efficient catalyst to generate O2 continuously to overcome resistance in chemotheropy treatment reduced by cancer hypoxia.