Mbrs-53. Enhanced Efficacy of Nano-formulated Vismodegib Shows the Potential for Polyoxazoline Micelles to Improve Drug Delivery to Brain Tumors
Year: 2018
Type: article
Abstract: For the roughly 30% of medulloblastoma patients with SHH-subgroup tumors, drugs that disrupt SHH signaling offer the potential of improved efficacy with reduced toxicity compared to current, non-targeted treatment. The FDA-approved SMO inhibitor vismodegib, which targets SHH signaling at the cell membrane, has been shown to be safe and effective for the treatment of basal cell carcinoma. In SHH-subgroup medulloblastomas, however, initial responses to vismodegib, have been followed by resistance that develops during treatment. We hypothesized that improving the delivery of the drug across the blood-brain barrier would forestall the development of resistance. To test this hypothesis, we developed a novel, nanoparticle formulation of vismodegib, encapsulated in polyoxazoline micelles (POx-vismo). These nanoparticles showed high drug loading, and small, consistent particle size. We then compared the efficacy of POx-vismo to conventional vismodegib in mice genetically-engineered to develop medulloblastoma. We treated GFAP-cre/SmoM2 (G-Smo) mice with either POx-vismo or conventional vismodegib, administered by IP injection at postnatal days 12 and 13 and then every other day. Both formulations induced an initial response. However, POx-vismo-treated mice survived significantly longer than mice treated with conventional vismodegib. While no mice were cured by either formulation, our results show the superiority of POx-vismo and highlight the potential for polyoxazoline micelle drug delivery to increase the efficacy of approved and experimental agents for brain tumor therapy. The anti-tumor effect of vismodegib, optimized in POx-vismo is significant and may, in combination with additional treatments such as radiation, lead to new treatment approaches.
Source: Neuro-Oncology
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W2808992640