A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles

Lingyun Li, Charles A. Wartchow, S. Narasimhan Danthi, Zhimin Shen, Neal Dechene, John Pease, H. Steven Choi, Tina Doede, Pauline Chu, Shoucheng Ning, Daniel Y. Lee, Mark D. Bednarski, Susan J. Knox

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

Purpose Integrin αvβ3 and vascular endothelial growth factor receptor 2 (Flk-1) have been shown to be involved in tumor-induced angiogenesis. Selective targeting of upregulated α vβ3 and Flk-1 on the neovasculature of tumors is a novel antiangiogenesis strategy for treating a wide variety of solid tumors. In the studies described here, we investigated the potential therapeutic efficacy of two three-component treatment regimens using two murine tumor models. Methods and materials The treatment regimens used nanoparticle (NP) based targeting agents radiolabeled with 90Y. The small molecule integrin antagonist (IA) 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]-benzoyl-2- (5)-aminoethylsulfonylamino-β-alanine, which binds to the integrin αvβ3, and a monoclonal antibody against murine Flk-1 (anti-Flk-1 MAb) were used to target the NPs. Murine tumor models K1735-M2 (melanoma) and CT-26 (colon adenocarcinoma) were used to evaluate the treatment efficacy. Results In K1735-M2 and CT-26 tumors, a single treatment with IA-NP-90Y (14.2 μg/g IA, 5 or 6 μCi/g 90Y) caused a significant tumor growth delay compared to untreated control tumors, as well as tumors treated with IA, IA-NP, and NP-90Y, respectively (p < 0.025, Wilcoxon test). In K1735-M2 tumors, a single treatment with anti-Flk-1 MAb-NP-90Y (0.36 μg/g anti-Flk-1 MAb, 5 μCi/g 90Y) also caused a significant tumor growth delay (p < 0.05, Wilcoxon test) compared to untreated tumors, as well as tumors treated with anti-Flk-1 MAb, anti-Flk-1 MAb-NP, and conventional radioimmunotherapy with 90Y-labeled anti-Flk mAb. Anti-CD31 staining showed a marked decrease in vessel density in tumors treated with anti-Flk-1 MAb-NP- 90Y, which was associated with a high level of apoptotic death in these tumors, as shown by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. Conclusions The present studies provide proof of principle that targeted radiotherapy works using different targeting agents on a nanoparticle, to target both the integrin αvβ 3 and the vascular endothelial growth factor receptor. These encouraging results demonstrate the potential therapeutic efficacy of the IA-NP-90Y and anti-Flk-1 MAb-NP-90Y complexes as novel therapeutic agents for the treatment of a variety of tumor types.

Original languageEnglish (US)
Pages (from-to)1215-1227
Number of pages13
JournalInternational Journal of Radiation Oncology Biology Physics
Volume58
Issue number4
DOIs
StatePublished - Mar 15 2004

Keywords

  • Flk-1
  • Integrin
  • Nanoparticle
  • Radiotherapy

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

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