Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature.
Radiation can be used to guide drugs to specific sites such as neoplasms or aberrant blood vessels. When blood vessels are treated with ionizing radiation, they respond by expressing a number of cell adhesion molecules and receptors that participate in homeostasis. Examples of radiation-induced molecules in blood vessels include ICAM-1, E-selectin, P-selectin and the beta(3) integrin. We have observed that the endothelium and blood components respond to oxidative stress in a similar, if not identical manner in all tumor models. Although we have identified several other radiation-induced molecules within tumor blood vessels, the beta(3) target for drug delivery achieves the greatest site-specific peptide binding within irradiated tumor blood vessels. We have focused on peptides and antibodies that bind to integrin beta(3). beta(3)-binding proteins have been conjugated to fluorochromes and radionuclides to study the site specificity and microscopic distribution. We have found immunofluorescent and immunohistochemical staining of beta(3) within the lumen of blood vessels immediately following irradiation. To determine whether it is feasible to guide drug delivery to irradiated tumors, we studied ligands to alpha(2b)beta(3) (fibrinogen). Peptides within fibrinogen that bind to alpha(2b)beta(3) includes the dodecapeptide, HHLGGAKQAGDV and the RGD peptide. We utilized 131I conjugation to these ligands to study the biodistribution in tumor bearing mice. Our clinical trial consists of the RGD peptidomimetic, biapcitide, labeled with 99mTc. This study shows that it is feasible to guide drugs to human neoplasms by use of radiation-guided peptides. These studies have shown that peptides that bind to these integrins bind to tumors following exposure to ionizing radiation.
Hallahan
D E
DE
Departments of Radiation Oncology, Biomedical Engineering and Radiology, Vanderbilt University, Nashville, TN 37232-5671, USA. dennis.hallahan@mcmail.vanderbilt.edu
Geng
L
L
Cmelak
A J
AJ
Chakravarthy
A B
AB
Martin
W
W
Scarfone
C
C
Gonzalez
A
A
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology*; D016503:Drug Delivery Systems; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008163:Luminescent Measurements; D008833:Microcirculation; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply / Q000276:immunology* / Q000532:radiotherapy*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects / Q000378:metabolism; D016499:Radioimmunotherapy / Q000379:methods*; D012039:Regional Blood Flow / Q000502:physiology; D013667:Technetium
D000951:Antigens, Neoplasm; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013667:Technetium