Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature

D. E. Hallahan, L. Geng, A. J. Cmelak, A. B. Chakravarthy, W. Martin, C. Scarfone, A. Gonzalez

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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 β3 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 β3 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 β3. β3-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 β3 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 α2bβ3 (fibrinogen). Peptides within fibrinogen that bind to α2bβ3 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.

Original languageEnglish
Pages (from-to)183-191
Number of pages9
JournalJournal of Controlled Release
Volume74
Issue number1-3
DOIs
StatePublished - Jul 6 2001
Externally publishedYes

Keywords

  • Drug delivery
  • Liposomes
  • Peptides
  • Radiation
  • Tumor targeting

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    Hallahan, D. E., Geng, L., Cmelak, A. J., Chakravarthy, A. B., Martin, W., Scarfone, C., & Gonzalez, A. (2001). Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature. Journal of Controlled Release, 74(1-3), 183-191. https://doi.org/10.1016/S0168-3659(01)00335-2