Abstract 5737: Development of targeted imaging agents for Cholecystokinin 2 receptor expressing cancers

Autor: Philip S. Low, Charity Wayua
Rok vydání: 2012
Předmět:
Zdroj: Cancer Research. 72:5737-5737
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2012-5737
Popis: The use of conventional chemotherapeutics is limited by their indiscriminate accumulation in both cancer and healthy cells. Ligand-targeted therapies that can deliver cytotoxic agents selectively to malignant cells, avoiding uptake by healthy cells, constitute attractive alternatives to non targeted therapies. Indeed, folate-targeted therapies have shown great promise for treatment of ovarian and lung cancers.1 The Cholecystokinin 2 Receptor (Gastrin / CCK2R) is reported to be ectopically expressed or over expressed in a variety of cancers, including medullary thyroid and hepatocellular carcinomas, and gastric, colorectal, pancreatic and small cell lung cancers2-6. In order to selectively target these pathologic cells, we elected to use a small molecule antagonist that has a sub-nanomolar affinity to the CCCK2R and excellent selectivity over CCK1R7 as a targeting ligand. A ligation site on the antagonist that could be chemically modified without altering its binding affinity to the receptor, was then identified and several linkers attached. The optimal linker, a peptidoglycan spacer found to improve the conjugate's water solubility, was then attached to a Technetium99m chelating moiety. The radio imaging conjugate (CW1809-99mTc) was found to bind CCK2R expressing cells (HEK-293 CCK2R cell line) with nanomolar affinity (KD =30 nM). Binding was quantitatively inhibited by competition with 100 fold excess of the unlabeled conjugate. We evaluated the specificity of the CW1809-99mTc in vivo by intravenous injection into athymic nu/nu mice bearing CCK2R tumors. Imaging and biodistribution studies revealed that CW1809-99mTc localizes primarily to HEK-293 CCK2R tumor cell xenografts in nu/nu mice (14.25% Injected dose/gram of tissue at 2hrs post injection; tumor: muscle ratio of 35:1). Similar specificity was observed with a targeted Near Infra red dye conjugated to this antagonist. Blockade of tumor targeting upon administration of excess unlabelled conjugate and the absence of targeting to CCK2R-negative tumors confirmed the specificity of each of the above targeted reagents for CCK2R. The data from these studies are designed to lead to new targeted therapeutic and companion diagnostic agents for radio imaging, fluorescence-guided surgery and treatment of CCK2R expressing cancers. This tandem use of an imaging and therapeutic agent targeted to the same receptor could allow for detection, staging, monitoring and treatment of CCK2R cancers with improved accuracy and efficacy. References 1. Curr. Opin. Invest. Drugs 2010, 11, 1423-33 2.J. Cell Mol. Med. 2010, 14, 4, 933-943 3. Cancer Res. 1997, 57, 1377-1387 4. J. Cancer Res. Clin. Oncol. 2006, 132, 85-91 5. Eur. J. of Clin. Investig. 2001, 31, 812-820 6. J. of Surg. Res. 2005, 129, 313-321 7. Reg. Peptides 2008, 146, 46-57 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5737. doi:1538-7445.AM2012-5737
Databáze: OpenAIRE
Externí odkaz: