Polymeric micelle nanocarriers for targeted epidermal delivery of the hedgehog pathway inhibitor vismodegib: formulation development and cutaneous biodistribution in human skin

Expert Opin Drug Deliv. 2019 Jun;16(6):667-674. doi: 10.1080/17425247.2019.1609449. Epub 2019 Apr 26.

Abstract

Background: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions. Methods: VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin in vitro with quantification by UHPLC-MS/MS. Results: The optimal micelle solution (Zav 20-30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 μg/cm2, respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120-200 μm, were ˃3800- and ˃2300-fold greater than the IC50 reported for hedgehog signaling pathway inhibition in vitro. Conclusion: Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.

Keywords: Vismodegib; basal cell carcinoma; nanocarriers; polymeric micelle; topical delivery.

MeSH terms

  • Administration, Cutaneous
  • Anilides / administration & dosage*
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Drug Carriers / chemistry
  • Drug Delivery Systems*
  • Epidermis / metabolism
  • Hedgehog Proteins / metabolism*
  • Humans
  • Micelles
  • Particle Size
  • Polymers / chemistry*
  • Pyridines / administration & dosage*
  • Skin / metabolism
  • Skin Absorption
  • Swine
  • Tandem Mass Spectrometry
  • Tissue Distribution

Substances

  • Anilides
  • Antineoplastic Agents
  • Drug Carriers
  • Hedgehog Proteins
  • HhAntag691
  • Micelles
  • Polymers
  • Pyridines