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 language||English (US)|
|Number of pages||13|
|Journal||International Journal of Radiation Oncology Biology Physics|
|State||Published - Mar 15 2004|
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging