Research in our group focuses on the development of new and improved fluorescent tools for in vivo cancer diagnosis. Our research projects integrate molecular design, organic synthesis, heterocyclic chemistry, supramolecular chemistry, photochemistry, and spectroscopy to address the current problems in fluorescence bioimaging: selectivity, sensitivity, and resolution.
I. New fluorophores for in vivo bioimaging. Fluorophores for in vivo applications need to have absorption and emission wavelength between 700-900 nm, high brightness, large Stokes shift (~50 nm), high chemical and photochemical stability, low cytotoxicity, water solubility, cell permeability, etc. In addition, it is highly desirable to have fluorophores with narrow (10-20 nm) emission band, which is beneficial for simultaneous, multicolor detection of various factors. Our group focuses on the design, synthesis and characterization of tetrapyrrolic macrocycles (chlorins and bacteriochlorins) for application in fluorescent bioimaging. Chlorins and bacteriochlorins exhibit intense, narrow emission band in the optimal spectral window for in vivo application (650-850 nm). Our efforts focus on the preparation of water soluble, target-specific, tetrapyrrolic derivatives with improved photochemical properties (high qantum yield of fluorescence, large Stokes shift, and low photocytotoxicity).
II. Fluorescent probes for in vivo ratiometric protease assay and their application for cancer bioimaging. The long-term objective of this project is to develop highly integrated, sensitive, and specific molecular probes for ratiometric protease assay and to utilize them for bioimaging of tumor formation, growth, and metastasis, as well as to monitor the effect of cancer therapy. Proteases are convenient markers for cancer detection, and can also be used for monitoring the cancer progression, invasiveness, and metastasis. In our strategy for protease assay we will utilize the fluorescence energy transfer in molecular arrays containing two fluorophores linked by a peptide. The probe emits at two different wavelengths, depending on the presence or absence of target proteases. Measurement of the ratio of the intensity of both emissions enables ratiometric detection of a given protease. The proteases of interest include those which are reported to be important for tumor formation, growth, and metastasis, i.e., matrix metalloproteinases and cathepsins.
III. Synthesis of libraries of small molecules as matrix metalloproteinases inhibitors and fluorophores for bioimaging of tumor angiogenesis. Matrix metalloproteinases (MMPs) are a class of zinc-dependent, proteolytic enzymes which participate in tumor angiogenesis and metastasis. Our goal is to develop new, potent, and selective matrix metalloproteinases inhibitors for therapeutic applications. We prepare the libraries of analogs of naturally occurring, highly fluorescent alkaloids and evaluate them as potential MMPs inhibitors and probes for in vivo imaging of angiogenesis.