A quantitative method for screening and identifying molecular targets for nanomedicine

• Published in: Journal of controlled release 2017-10, Vol.263, p.57-67
• Main Authors: Guo, Peng, Yang, Jiang, Bielenberg, Diane R., Dillon, Deborah, Zurakowski, David, Moses, Marsha A., Auguste, Debra T.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; antibodies; Antibodies, Monoclonal - administration & dosage; Antineoplastic Agents - administration & dosage; Cancer target; Cell Line, Tumor; Cell Movement - drug effects; cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Child; doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Drug delivery; encapsulation; Female; Flow Cytometry; Humans; ICAM-1; immunohistochemistry; Immunoliposome; intercellular adhesion molecule-1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - immunology; Male; Melanocytes; melanoma; Melanoma - genetics; Melanoma - metabolism; metastasis; Metastatic melanoma; Middle Aged; Molecular Targeted Therapy; Nanomedicine; neutralization; Polyethylene Glycols - administration & dosage; protein synthesis; quantitative analysis; screening; toxicity; Young Adult
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.03.030

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. [Display omitted]