Targeted drug distribution in tumor extracellular fluid of GD2-expressing neuroblastoma patient-derived xenografts using SN-38-loaded nanoparticles conjugated to the monoclonal antibody 3F8

J Control Release. 2017 Jun 10:255:108-119. doi: 10.1016/j.jconrel.2017.04.016. Epub 2017 Apr 12.

Abstract

Neuroblastoma is a pediatric solid tumor with high expression of the tumor associated antigen disialoganglioside GD2. Despite initial response to induction therapy, nearly 50% of high-risk neuroblastomas recur because of chemoresistance. Here we encapsulated the topoisomerase-I inhibitor SN-38 in polymeric nanoparticles (NPs) surface-decorated with the anti-GD2 mouse mAb 3F8 at a mean density of seven antibody molecules per NP. The accumulation of drug-loaded NPs targeted with 3F8 versus with control antibody was monitored by microdialysis in patient-derived GD2-expressing neuroblastoma xenografts. We showed that the extent of tumor penetration by SN-38 was significantly higher in mice receiving the targeted nano-drug delivery system when compared to non-targeted system or free drug. This selective penetration of the tumor extracellular fluid translated into a strong anti-tumor effect prolonging survival of mice bearing GD2-high neuroblastomas in vivo.

Keywords: GD2-targeted nanoparticles; Intratumor drug distribution; Irinotecan (PubChem CID: 60838).; Irinotecan/SN-38; Microdialysis; Neuroblastoma; PDX models; SN-38 (PubChem CID: 104842); Tumor extracellular fluid.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemistry
  • Camptothecin / pharmacokinetics
  • Cell Line, Tumor
  • Child, Preschool
  • Drug Liberation
  • Extracellular Fluid / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoglobulin G / administration & dosage*
  • Immunoglobulin G / chemistry
  • Irinotecan
  • Male
  • Mice, Nude
  • N-Acetylgalactosaminyltransferases / antagonists & inhibitors*
  • N-Acetylgalactosaminyltransferases / genetics
  • N-Acetylgalactosaminyltransferases / immunology
  • N-Acetylgalactosaminyltransferases / metabolism
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism*
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • 3F8 antibody
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, Neoplasm
  • Antineoplastic Agents, Phytogenic
  • Immunoglobulin G
  • Irinotecan
  • N-Acetylgalactosaminyltransferases
  • (N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase
  • Camptothecin