This project proposes to use tetrapyrrole-based conjugates to fluorescently label colorectal tumor foci. Colorectal cancer is the second 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 project we propose to synthesize and investigate new porphyrin and phthalocyanine fluorescent markers that selectively target colon cancer cells. Specifically our strategy involves the targeting of epidermal growth factor receptors (EGF-R) and human carcinoembryonic antigen (CEA), both over-expressed in colon cancer cells. Our proposed research is based on our preliminary investigations of a small library of porphyrin- and phthalocyanine-peptide conjugates and one phthalocyanine-CEA conjugate.
Our Specific Aims are: (1a) To synthesize a new series of porphyrins and Pc conjugated to EGF-R peptide ligands and anti-CEA MAb in order to enhance colon cancer targeting;(1b) to evaluate the new conjugates in vitro using human colon carcinoma cells;(2a) to expose promising conjugates to a organ culture of colon cancer with surrounding colon;(2b) to directly inject selected conjugates into colon tumors grown orthotopically in nude mice;and (2c) to instill topically onto rectal mucosa selected imaging agents and investigate their in vivo fluorescence emission and CRC tumor cell selectivity. 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. While naturally occurring porphyrin macrocycles absorb and emit within the 620-660 nm range, phthalocyanines absorb and emit further into the near-IR region (670-750 nm) where light penetrates deeper through tissues and interference from other molecules and autofluorescence is minimized. The proposed studies are of extremely high relevance 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 form the basis for 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 second 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 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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