A quantitative method for screening and identifying molecular targets for nanomedicine.
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.
Department of Biomedical Engineering, The City College of New York, 160 Convent Avenue, New York, NY 10031, United States; Vascular Biology Program, Boston Children's Hospital, 1 Blackfan Circle, Boston, MA 02115, United States; Department of Surgery, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States.
Peng
P
Guo
Vascular Biology Program, Boston Children's Hospital, 1 Blackfan Circle, Boston, MA 02115, United States; Department of Surgery, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States.
Jiang
J
Yang
Vascular Biology Program, Boston Children's Hospital, 1 Blackfan Circle, Boston, MA 02115, United States; Department of Surgery, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States.
Diane R
DR
Bielenberg
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.
Deborah
D
Dillon
Department of Anesthesia, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States.
David
D
Zurakowski
Vascular Biology Program, Boston Children's Hospital, 1 Blackfan Circle, Boston, MA 02115, United States; Department of Surgery, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States.
Marsha A
MA
Moses
Department of Biomedical Engineering, The City College of New York, 160 Convent Avenue, New York, NY 10031, United States. Electronic address: dauguste@ccny.cuny.edu.
Debra T
DT
Auguste
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology*; D008297:Male; D008544:Melanocytes; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D050997:Nanomedicine; D011092:Polyethylene Glycols / Q000008:administration & dosage; D055815:Young Adult
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D018799:Intercellular Adhesion Molecule-1; D011092:Polyethylene Glycols; D004317:Doxorubicin
Cancer target; Drug delivery; ICAM-1; Immunoliposome; Metastatic melanoma; Nanomedicine