Integrin-mediated targeting of drug delivery to irradiated tumor blood vessels.
The objective of this study was to target drug delivery to radiation-induced neoantigens, which include activated receptors within the tumor vasculature. These responses include posttranslational changes in pre-existing proteins, which can be discovered by phage-displayed peptide libraries administered to mice bearing irradiated tumors. Phage-displayed peptides recovered from irradiated tumors included the amino acid sequence RGDGSSV. This peptide binds to integrins within the tumor microvasculature. Immunohistochemical staining of irradiated tumors showed accumulation of fibrinogen receptor alpha(2b)beta(3) integrin. We studied tumor targeting efficiency of ligands to radiation-induced alpha(2b)beta(3). Radiopharmaceuticals were localized to irradiated tumors by use of alpha(2b)beta(3) ligands conjugated to nanoparticles and liposomes. Fibrinogen-conjugated nanoparticles bind to the radiation-activated receptor, obliterate tumor blood flow, and significantly increase regression and growth delay in irradiated tumors. Radiation-guided drug delivery to tumor blood vessels is a novel paradigm for targeted drug delivery.
Hallahan
Dennis
D
Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. dennis.hallahan@mcmail.vanderbilt.edu
Geng
Ling
L
Qu
Shimian
S
Scarfone
Christopher
C
Giorgio
Todd
T
Donnelly
Edwin
E
Gao
Xiang
X
Clanton
Jeff
J
D000418:Albumins / Q000008:administration & dosage; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D017123:Bacteriophage T7; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems; D005340:Fibrinogen / Q000008:administration & dosage; D005910:Glioma / Q000098:blood supply / Q000378:metabolism; D016023:Integrins / Q000378:metabolism* / Q000528:radiation effects; D007457:Iodine Radioisotopes; D008081:Liposomes; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D036103:Nanotechnology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000532:radiotherapy*; D010455:Peptides / Q000378:metabolism; D016499:Radioimmunotherapy / Q000379:methods*; D012039:Regional Blood Flow / Q000187:drug effects; D014407:Tumor Cells, Cultured; D018608:Ultrasonography, Doppler
D000418:Albumins; D000951:Antigens, Neoplasm; D004337:Drug Carriers; D016023:Integrins; D007457:Iodine Radioisotopes; D008081:Liposomes; D010455:Peptides; D005340:Fibrinogen