This revised project proposes to use near-IR conjugates to fluorescently label colorectal tumor foci. Colorectal cancer (CRC) is the third most common solid internal malignancy and over 50,000 deaths in the U.S. are attributable to this disease. Since the early disease lacks outward signs or symptoms, sensitive recognition of early cancers is key to preventative screening. Current screening techniques, primarily colonoscopy, identify large adenomatous lesions but often miss at least two forms of early colorectal cancer: small adenomas (<5 mm) and flat lesions. Confocal laser endomicroscopy is currently being used for in situ histology as a complement to endoscopy. However up to one-third of adenomas are still missed using this technique, because the fluorescent imaging agents currently in use non-selectively stain normal as well as neoplastic mucosal tissue. In this revised project we propose to design and develop fluorescent markers with high selectivity for colon cancer cells. Specifically our strategy involves the targeting of epidermal growth factor receptors (EGFR) and human carcinoembryonic antigen (CEA), both over-expressed in colon cancer cells. Our proposed research is based on our preliminary investigations conducted during funding of 5R21 CA139385, that show that near-IR absorbing/emitting phthalocyanines (Pcs) conjugated to EGFR peptide ligands and to anti-CEA, show large increases in cancer cell targeting, up to 37-fold higher than unconjugated Pc, and low toxicity.
Our Specific Aims are: (1) To design and synthesize near-IR Pc and BODIPY bioconjugates that selectively target two antigens commonly associated with the surface of CRC: CEA and EGFR; and (2) To evaluate the conjugates both in vitro and in vivo to investigate their toxicity and specificity for CRC-targetin. Porphyrins have been used for over 100 years as labels for biomolecules and as treatment agents by photodynamic therapy, but currently known porphyrins are not tumor-targeted and absorb and emit within the 620-660 nm range. On the other hand Pc and BODIPYs absorb and emit further into the near-IR region (>700 nm) where light penetrates deeper through tissues and interference from other molecules and autofluorescence is minimized. The proposed studies are highly relevant since they could lead to a much more effective early detection of CRC which could greatly reduce the incidence and mortality of CRC. Furthermore, these studies could lead to the development of more efficient tumor-targeted imaging agents and chemotherapeutics.
Our proposed program is of great relevance to public health since cancer is still the second most common cause of death in the Nation and, in particular colorectal cancer, is the third most common solid internal malignancy. The effective early detection of tumors as well as tumor infiltrative areas and tumor metastasis will have an enormous impact on diagnosis, treatment planning, tumor response to treatment and overall treatment outcome, will increase the success of cancer treatment with minimal cost, and will increase the patient's quality of life.
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|Xuan, Sunting; Zhao, Ning; Ke, Xiangyi et al. (2017) Synthesis and Spectroscopic Investigation of a Series of Push-Pull Boron Dipyrromethenes (BODIPYs). J Org Chem 82:2545-2557|
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|Zhao, Ning; Xuan, Sunting; Fronczek, Frank R et al. (2017) Enhanced Hypsochromic Shifts, Quantum Yield, and ?-? Interactions in a meso,?-Heteroaryl-Fused BODIPY. J Org Chem 82:3880-3885|
|Zhao, Ning; Williams, Tyrslai M; Zhou, Zehua et al. (2017) Synthesis of BODIPY-Peptide Conjugates for Fluorescence Labeling of EGFR Overexpressing Cells. Bioconjug Chem 28:1566-1579|
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|Zhao, Ning; Xuan, Sunting; Byrd, Brandon et al. (2016) Synthesis and regioselective functionalization of perhalogenated BODIPYs. Org Biomol Chem 14:6184-8|
|Jinadasa, R G Waruna; Zhou, Zehua; Vicente, M Graça H et al. (2016) Syntheses and cellular investigations of di-aspartate and aspartate-lysine chlorin e(6) conjugates. Org Biomol Chem 14:1049-64|
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