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Research Articles: Therapeutics, Targets, and Development

In vivo optical imaging of human lymphoma xenograft using a library-derived peptidomimetic against 4β1 integrin

Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis Cancer Center, Sacramento, California

Requests for reprints: Kit S. Lam, Division of Hematology and Oncology, University of California Davis Cancer Center, 4501 X Street, Sacramento, CA 95817. Phone: 916-734-8012; Fax: 916-734-7946. E-mail: Kit.Lam{at}ucdmc.ucdavis.edu

Abstract

Increasing literature suggests that cell adhesion molecule 4β1 integrin plays a pivotal role in autoimmune diseases and cancer development. Noninvasive visualization of 4β1 integrin in vivo will facilitate the understanding of its involvement in disease progression and development of targeted therapies. Due to the lack of high-affinity targeting ligands, molecular imaging of 4β1 integrin is much less explored than that of vβ3 and vβ5 integrins. We have recently reported using the one bead–one compound combinatorial library method to identify a peptidomimetic, LLP2A, that preferentially binds to activated 4β1 integrin. Here, we described the use of LLP2A-Cy5.5 conjugate as an in vivo optical imaging probe in a human lymphoma xenograft model. This univalent LLP2A-Cy5.5 conjugate retained the binding activity and specificity to 4β1 integrin as shown by cell binding assays using 4β1-positive Molt-4 T-leukemia cells. The subcutaneous Molt-4 tumor was clearly visualized from 1 to 24 h after tail vein injection of the conjugate. Direct imaging and confocal microscopic examination of excised tumors and organs confirmed the accumulation of LLP2A in tumors and revealed very little or no uptake in normal organs except for lymph nodes. Kidney uptake was high when the whole organ was scanned but it was negative when examined microscopically, suggesting that LLP2A bound to the renal tubules loosely. Tumor uptake of LLP2A-Cy5.5 conjugate was blocked by excess unlabeled LLP2A. This study showed that the combinatorial chemical library-derived peptidomimetic LLP2A can be easily developed into an optical imaging probe for noninvasively monitoring of activated 4β1 integrin in vivo. [Mol Cancer Ther 2008;7(2):432–7]

Grant support: NIH R33 CA86364, NIH R33 CA99136, NCI NCDDG U19 CA113298, and NSF CHE-0302122. The 500-MHz nuclear magnetic resonance spectrometer was purchased in part with the grant NSF 9724412.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 8/20/07; revised 11/ 5/07; accepted 12/20/07.