Abstract 5288A: Multivalent fluorescent probes for in vivo tumor targeting

Conventional fluorescence probes are monovalent molecules that interact with cellular or extra-cellular target molecules through affinity binding. To improve the binding affinity and sensitivity of detection of the fluorescence probe, we describe a novel strategy for the synthesis designed to contain multiple targeting moieties and a near infrared fluorescent dye Iflour750 for optimal in vivo detection. In this study, we applied several multivalent probes to in vivo tumor targeting and monitored the targeting process using fluorescence imaging. Deoxyglucose based fluorescence probes have been applied to tumor labeling as the high metabolic rate of the tumor cells causes preferential labeling of the tumor mass. With a multivalent 2-deoxy-D- glucose Iflour750 (2-DG-IF750) probe, we demonstrated sensitive in vivo targeting as compared to a control mono-valent 2DG probe in several tumor models, including PC3M-luc2 prostate tumor cells, MDA-MB-231-luc2 mammary fat tumor cells as well as LL/2-luc and H460-luc2 lung cancer cells. Distinct tumor signal was visualized within a few hours after intravenous delivery and reached the peak of signal/background ratio between 6-24 hours. With a multivalent cyclooxygenase (COX) binding fluorescence probe Indomethacin-IF750, we observed an interesting targeting of COX2 negative colon tumor cells HCT116-luc2, but not the COX2 positive HT29-luc2, hypothetically due to selective binding to COX1. We also tested a multivalent RGD probe for targeting integrin avb3, the expression of which is associated with tumor angiogenesis and metastasis. With our iFlur750-(RGD)4 probe, we demonstrated in vivo targeting of U87-MG-luc2, HCT116-luc2 and HT29-luc2 tumor cells. Finally, we demonstrated that optical imaging was conveniently applied to evaluating the PK/PD profile of the probes. Our multivalent probes showed a fast clearance with a half life of less than 1 hour, which is a desirable feature for achieving maximal tumor/background contrast. In summary, we have developed a new class of multi-valent fluorescence probes with improved specificity and sensitivity of tumor targeting as compared to mono-valent analogs. Utility of this class of multivalent probes is likely to pass beyond pre-clinical models, as imaging guided tumor surgery is on the verge of clinical applications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; O