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Cited by 53Nanoparticle-Based Drug DeliveryGlioma Diagnosis and TreatmentAdvanced Drug Delivery Systems

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

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Hwang, Duhyeong, Dismuke, Taylor, Tikunov, Andrey, Rosen, Elias P., Kagel, John R., Ramsey, Jacob D., Lim, Chaemin, Zamboni, William +3 more·2021·Nanomedicine: Nanotechnology, Biology and Medicine
DOI 10.1016/j.nano.2020.102345PMC PMC8160025

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Abstract

Abstract We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and dose-limiting extraneural toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHH- subgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and bone toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.

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  • The POx-vismodegib formulation showed a 1.6-times increase in tumor AUC and overall improved delivery to the brain.

    “The POx-vismodegib formulation showed a 1.6-times increase in tumor AUC and overall improved delivery to the brain.”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [113]

    The Results section, “POx micelles improve the brain and tumor delivery of vismodegib without penetrating CNS” (page unavailable), reports significantly higher tumor AUC and improved distribution across the blood–brain barrier with POx-vismodegib. Our copy does not give a 1.6-times increase in tumor AUC; the numerical comparison it provides here is the tumor-to-plasma AUC ratio, 0.569 versus 0.439. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • POx A-B-A triblock copolymers with a hydrophobic PBuOx block and two hydrophilic PMeOx blocks have shown very high loading for many poorly soluble drugs.

    “Triblock A-B-A copolymers of POx consisting of hydrophobic PBuOx block with two flanking hydrophilic PMeOx blocks, PMeOx-b-PBuOx-b-PMeOx, have shown unprecedentedly high loading for many poorly soluble drugs [22, 45, 113, 114].”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [113]

  • A study from the authors' lab showed improved pharmacokinetic profile of vismodegib when encapsulated in a POx micelle for treatment of pediatric brain tumor medulloblastoma.

    “Recently, a study from our lab showed the improved PK profile of the drug vismodegib when encapsulated in a POx micelle for treatment of a pediatric brain tumor – medulloblastoma [113].”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [113]

  • The micelle formulation also resulted in a lower volume of distribution, which could lead to fewer off-target effects than the conventional formulation's less than ideal distribution to peripheral tissues.

    “The micelle formulation also resulted in a lower Vd which could lead fewer off-target affects than the conventional formulation’s less than ideal distribution to peripheral tissues [113].”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [113]

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Cited by

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Authors
Hwang, D., Dismuke, T., Tikunov, A., Rosen, E. P., Kagel, J. R., Ramsey, J. D., Lim, C., Zamboni, W., Kabanov, A. V., Gershon, T. R., & Sokolsky-Papkov PhD, M.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Gershon, Timothy R.
ORCID
Venue
Nanomedicine: Nanotechnology, Biology and Medicine
Publisher
Elsevier BV
Published
2021-02
Volume
32
Pages
102345
ISSN
1549-9634 (ISSN-L)
DOI
10.1016/j.nano.2020.102345
PMC
PMC8160025
OpenAlex
W3107716592
Cited by
53
References
5
Citations by year
2026: 8 · 2025: 6 · 2024: 7 · 2023: 9 · 2022: 13 · 2021: 8 · 2020: 2
FWCI
2.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Nanomedicine Nanotechnology Biology and Medicine (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • St. Baldrick's Foundation
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
vismodegib, medulloblastoma, poly(2-oxazoline), block copolymer micelles, nanoparticle drug delivery, sonic hedgehog pathway, blood-brain barrier penetration, bone toxicity, systemic toxicity, brain tumor therapy, transgenic mouse model
MeSH terms
Anilides, Animals, Biological Availability, Central Nervous System, Cerebellar Neoplasms, Disease Models, Animal, Drug Carriers, Medulloblastoma, Micelles, Oxazoles, Particle Size, Protein Binding, Pyridines, Serum Albumin, Drug Delivery Systems, Mice, Nanoparticles

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