The goal of this work is the development of an optical instrument and method for measuring in real time, and with site-specificity, the absolute concentrations of drugs or other compounds in tissue. New computational methods, incorporating Mie theory into a Monte Carlo transport code, for modeling of photon transport in tissue, will for the first time allow determination of the effective path histories of photons over varying distances in tissue. Analysis of the optical spectra will enable the separation of the optical scattering and absorption co-efficients of the tissue, and permit determination of the drug concentrations. Fiber-optic probes will permit such measurements to be conducted directly or through endoscopes. The concentrations and kinetics of drugs at specific tissue locations in the body are generally difficult to determine, given only the administered dosage or blood serum measurements. For chemotherapy, it is the difference between the dose-response curves of normal tissue and tumor tissue that must be exploited during treatment. The ability to rapidly, quantitatively and non-invasively measure the concentration of specific drugs and other compounds, especially chemotherapy agents, at specific organ sites, would provide succinct benefits to the study of pharmacokinetics and to clinical pharmacology in general. There does not currently exits a non-invasive method of measuring drug concentrations in the target tissue, and even invasive methods, such as microdialysis, have limited application. We will demonstrate an instrument and a diagnostic method which invokes elastic scattering spectroscopy for measurements through fiber-optic probes, over a broad range of wavelengths from the near-ultraviolet to the near-infrared. Improved spectrometers will be assembled, and the computational codes will be used to model the photon transport, enabling improved designs of fiber-optic probes. The algorithms to analyze the spectra and deduce drug concentrations will be refined. The instrumentation will be applied to pharmacokinetic studies of selected chemotherapy and photodynamic-therapy agents in laboratory animals. Optical measurements will be compared with standard invasive assay results, generally HPLC, for purposes of calibration.
