A quantitative method for screening and identifying molecular targets for nanomedicine

J Control Release. 2017 Oct 10;263:57-67. doi: 10.1016/j.jconrel.2017.03.030. Epub 2017 Mar 22.

Abstract

Identifying a molecular target is essential for tumor-targeted nanomedicine. Current cancer nanomedicines commonly suffer from poor tumor specificity, "off-target" toxicity, and limited clinical efficacy. Here, we report a method to screen and identify new molecular targets for tumor-targeted nanomedicine based on a quantitative analysis. In our proof-of-principle study, we used comparative flow cytometric screening to identify ICAM-1 as a potential target for metastatic melanoma (MM). We further evaluated ICAM-1 as a MM targeting moiety by characterizing its (1) tumor specificity, (2) expression level, (3) cellular internalization, (4) therapeutic function, and (5) potential clinical impact. Quantitation of ICAM-1 protein expression on cells and validation by immunohistochemistry on human tissue specimens justified the synthesis of antibody-functionalized drug delivery vehicles, which were benchmarked against appropriate controls. We engineered ICAM-1 antibody conjugated, doxorubicin encapsulating immunoliposomes (ICAM-Dox-LPs) to selectively recognize and deliver doxorubicin to MM cells and simultaneously neutralize ICAM-1 signaling via an antibody blockade, demonstrating significant and simultaneous inhibitory effects on MM cell proliferation and migration. This paper describes a novel, quantitative metric system that identifies and evaluates new cancer targets for tumor-targeting nanomedicine.

Keywords: Cancer target; Drug delivery; ICAM-1; Immunoliposome; Metastatic melanoma; Nanomedicine.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / administration & dosage*
  • Antineoplastic Agents / administration & dosage*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Child
  • Doxorubicin / administration & dosage
  • Doxorubicin / analogs & derivatives*
  • Female
  • Flow Cytometry
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / immunology*
  • Male
  • Melanocytes
  • Melanoma / genetics
  • Melanoma / metabolism
  • Middle Aged
  • Molecular Targeted Therapy
  • Nanomedicine
  • Polyethylene Glycols / administration & dosage
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • liposomal doxorubicin
  • Intercellular Adhesion Molecule-1
  • Polyethylene Glycols
  • Doxorubicin