111 In-Labeled Glycoprotein Nonmetastatic b (GPNMB) Targeted Gemini Surfactant-Based Nanoparticles against Melanoma: In Vitro Characterization and in Vivo Evaluation in Melanoma Mouse Xenograft Model

Mol Pharm. 2019 Feb 4;16(2):542-551. doi: 10.1021/acs.molpharmaceut.8b00831. Epub 2019 Jan 18.

Abstract

Melanoma is a devastating form of skin cancer with high tendency to metastasis. This work addresses the development of new targeted nanoparticles that can be used for single-photon emission computed tomography (SPECT) imaging of melanoma. Melanoma-specific glycoprotein nonmetastatic b (GPNMB) antigen targeted and nontargeted gemini nanoparticles were prepared, characterized, and radiolabeled with 111In. 111In-labeled nanoparticles were composed of gemini surfactant grafted with monoclonal antibody Fab fragment that targeted GPNMB. Specific uptake of GPNMB-Fab was studied in six melanoma cell lines using flow cytometry. In vitro cellular uptake and internalization were studied using flow cytometry, confocal laser scanning microscopy, and radiometric techniques. Specific uptake of anti-GPNMB targeted nanoparticles was observed in GPNMB expressing cells, which was higher than low expressing or control cells. In vitro studies showed that conjugation of GPNMB targeted nanoparticles led to enhanced intracellular uptake of the nanodelivery system, which is critical for drug delivery. In vivo distribution of the nanoparticles was studied by microSPECT/CT imaging and ex vivo biodistribution. Tumor uptake was significantly higher ( p < 0.05) in nontargeted nanoparticles (5.47 ± 0.46%IA/cc) compared to GPNMB targeted nanoparticles (1.87 ± 0.27% ID/cc), which might be attributed to the high spleen uptake of the targeted formulation. These findings demonstrated that the radiolabeled gemini nanoparticles are promising for image-guided radiotherapy of melanoma. Formulation optimization is needed to improved tumor uptake and in vivo intracellular delivery for radiotherapeutic applications.

Keywords: 111Indium; GPNMB nanoparticles; gemini; imaging; melanoma; theranostics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitriol / analogs & derivatives*
  • Calcitriol / chemistry
  • Calcitriol / therapeutic use
  • Cell Line, Tumor
  • Drug Delivery Systems
  • Eye Proteins / metabolism*
  • Humans
  • Indium / chemistry*
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Nanoparticles / chemistry*
  • Surface-Active Agents / chemistry*
  • Surface-Active Agents / therapeutic use*
  • Tomography, Emission-Computed, Single-Photon

Substances

  • 1,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3)
  • Eye Proteins
  • Gpnmb protein, mouse
  • Membrane Glycoproteins
  • Surface-Active Agents
  • Indium
  • Calcitriol