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

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...

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Veröffentlicht in:Nanomedicine 2021-02, Vol.32, p.102345-102345, Article 102345
Hauptverfasser: Hwang, Duhyeong, Dismuke, Taylor, Tikunov, Andrey, Rosen, Elias P., Kagel, John R., Ramsey, Jacob D., Lim, Chaemin, Zamboni, William, Kabanov, Alexander V., Gershon, Timothy R., Sokolsky-Papkov PhD, Marina
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Sprache:eng
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Zusammenfassung: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. We present a nanoparticle formulation of the SHH-pathway inhibitor vismodegib in poly(2-oxazoline) micelles (POx-vismo) that improves drug delivery into CNS tumors. We tested POx-vismo using mice genetically engineered to develop medulloblastoma as a preclinical model. POx-vismo showed improved pharmacokinetics, reduced toxicity and increased efficacy. Conventional vismodegib produced no survival benefit while POx-vismo treated mice live significantly longer. These findings show the potential of POx micelle drug delivery to improve medulloblastoma therapy and more broadly, brain tumor treatment. [Display omitted]
ISSN:1549-9634
1549-9642
DOI:10.1016/j.nano.2020.102345