Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity.

Abstract

We report a nanoparticle formulation of the SHH-pathway inhibitor vismodegib that improves efficacy for medulloblastoma, while reducing toxicity. Limited blood-brain barrier (BBB) penetration and dose-limiting extitle/citraneural toxicities complicate systemic therapies for brain tumors. Vismodegib is FDA-approved for SHH-driven basal cell carcinoma, but implementation for medulloblastoma has been limited by inadequate efficacy and excessive bone toxicity. To address these issues through optimized drug delivery, we formulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo in transgenic mice that develop SHH-driven medulloblastomas with native vasculature and tumor microenvironment. POx-vismo improved CNS pharmacokinetics and reduced bone toxicity. Mechanistically, the nanoparticle carrier did not enter the CNS, and acted within the vascular compartment to improve drug delivery. Unlike conventional vismodegib, POx-vismo extended survival in medulloblastoma-bearing mice. Our results show the broad potential for non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to improve vismodegib therapy for SHH-driven cancers.

• Authors: Duhyeong Hwang, Taylor Dismuke, Andrey Tikunov, Elias P Rosen, John R Kagel, Jacob D Ramsey, Chaemin Lim, William Zamboni, Alexander V Kabanov, Timothy R Gershon, Marina Sokolsky-Papkov PhD
• Journal: Nanomedicine : nanotechnology, biology, and medicine (Nanomedicine) Vol. 32 Pg. 102345 (02 2021) ISSN: 1549-9642 [Electronic] United States
• PMID: 33259959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anilides
• Drug Carriers
• HhAntag691
• Micelles
• Oxazoles
• Pyridines
• Serum Albumin
• poly(2-oxazoline)

Topics

• Anilides (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Animals
• Biological Availability
• Central Nervous System (pathology)
• Cerebellar Neoplasms (drug therapy)
• Disease Models, Animal
• Drug Carriers (chemistry)
• Drug Delivery Systems
• Medulloblastoma (drug therapy)
• Mice
• Micelles
• Nanoparticles (chemistry)
• Oxazoles (chemistry)
• Particle Size
• Protein Binding
• Pyridines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Serum Albumin (metabolism)