SBIR-STTR Award

The rapid developments in non-invasive approaches to cancer detection now afford remarkable contrasts between cancers and normal tissues. Molecular beacons studied in four cooperating laboratories identify tumor specific enzymes and receptors which are used to bind, to alter the structures, etc. of delivery vehicles so that fluorescent signals are accumulated or converted from quenched to radiant forms. Tumors are also distinguished by metabolic parameters that can be distinguished by intrinsic signals of mitochondrial origin, NADH and flavoprotein and by a novel intrinsic beacon, fluorescent glucose. Angiogenesis is a third key indicator of tumorigenesis and is evaluated by quantitation of the hemoglobin content. This application proposes the high resolution co-localization and quantitation of these tumor markers in the same pixel of the tumor 3-D image, and thereby an objective test of their efficacy in cancer detection. The localization of well known metabolic signals of cancer and site directed molecular beacons require images at cellular resolution in solid tissues with preservation of metabolic state, glucose uptake and Hb concentrations and at the same time image specific tissue markers of cancer in several cm depths. This is a formidable task and one which at present requires invasive freeze trapping, in order to avoid motion artifacts and requires low temperatures to trap metabolic activities and to enhance absorption bands and fluorescence quantum yields. The functional diagram of Fig. 8 illustrates our plan to provide a complete evaluation of tumor characteristics of hypermetabolism, angiogenesis and glucose uptake (metabolic images) and cancer identification by the molecular beacons. The diagram demonstrates innovative instrument development of a Multi-wavelength Multi-channel Fluorescence/Absorption Imager for high resolution cancer detection in tissues. PROPOSED COMMERCIAL APPLICATION: The 40x40x10 micron pixel of 3D resolution of over 4 specific tumor characteristics creates a unique niche in cancer detection of animal models and of biopsy material for human cancers and is expected to afford a high throughput customated device and is expected to open a market niche in detection of early cancers in animal models (Phase I) and eventually (Phase II) in biopsy material.

Thesaurus Terms:
biomarker, cryoscopy, diagnosis design /evaluation, fluorescent dye /probe, image processing, imaging /visualization /scanning, neoplasm /cancer diagnosis, structural biology, structural model angiogenesis, flavoprotein, glucose metabolism, hemodynamics, hemoglobin, neoplasm /cancer blood supply, nicotinamide adenine dinucleotide bioimaging /biomedical imaging

The maturation of molecular imaging of cancers emphasizes the high tumor tissue ratios above ten which, when approved by FDA, are expected to revolutionize the sensitivity/specificity of, for example, breast and prostate cancer detection. The development of molecular beacons from collaborating laboratories has provided the two key types of beacons, one being the affinity binding, for example somatostatin, LDL, folate and the stealth or silent beacons (Cathepsin B, etc.) that depend upon recognition and unmasking of the fluorochrome attached to the beacon. Most recently, a fluorescent glucose generally applicable to all rapidly growing cancers has incorporated a NIR fluorochrome. While the NADH and flavoprotein signals are the gold standard of recognition of cancer by the greater glycolytic flow and enhanced reduction state of the tumor, these markers can be greatly enhanced by multi-photon technologies. In addition, the time shared wavelengths characteristically include reflectance spectophotometry of deoxy and total hemoglobin affording a direct links to hypermetabolism and angiogenesis. However, the most important aspect of the technology is its 3-D capability since ice crystal formation which characterizes the freeze trap state, impedes penetration of light through the highly scattering crystal matrix is very limited and fluorescent signals deeper than tens of microns do not interfere with planar images. Finally, fiber optic technology will permit reduction of the size of the voxel from 50 x 50 x 10 to 30 x 30 x 10 mu or even smaller depending upon the light guide construction. As a result of Phase I funding, a greatly improved, simplified and more economical design of the 3-D light pen imager has been completed. A vastly improved system which employs a time multiplex LED source system and silicon diode detector system which will permit a much greater throughput because of the increased duty cycle from roughly 20% to 75%. The operation is automatic and its authenticity is validated by the experiments carried out under Phase I support. Finally, a timetable and milestone exhibit assures production of the second phase model within 8 months at the funding of Phase II and exhaustive validation tests and tech transfer to occur in the remaining 16 months of the Phase II study.

Thesaurus Terms:
biomarker, diagnosis design /evaluation, fluorescent dye /probe, image processing, imaging /visualization /scanning, neoplasm /cancer diagnosis, structural biology, three dimensional imaging /topography angiogenesis, cryoscopy, fiber optics, flavoprotein, glucose metabolism, hemodynamics, hemoglobin, infrared radiation, neoplasm /cancer blood supply, nicotinamide adenine dinucleotide, structural model animal tissue, bioimaging /biomedical imaging