CADD-06. VISMODEGIB LOADED POLYOXAZOLINE (POx) MICELLES ENHANCE EFFICACY OF VISMODEGIB AND PROLONG MICE SURVIVAL, EMPHASIZE POTENTIAL OF POx MICELLES TO IMPROVE DRUG DELIVERY TO BRAIN TUMORS
Year: 2018
Type: conference-abstract
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, 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. We developed a novel, nanoparticle formulation of vismodegib, encapsulated in polyoxazoline micelles (POx-vismo). These nanoparticles showed high drug loading, and consistent, nanometer-scale particle size. We treated medulloblastoma bearing GFAP-cre/SmoM2 (G-Smo) mice with either POx-vismo or conventional vismodegib, administered by IP injection at postnatal days 12 and 13 (P12, P13) and then every other day. Both formulations induced an initial response. However, G-Smo mice treated with conventional vismodegib quickly progressed despite therapy. In contrast, POx-vismo-treated mice survived significantly longer than untreated mice or mice treated with conventional vismodegib. Our results show the superiority of POx-vismo and highlight the potential for POx micelles 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: W2900346958