Analysis and modeling of noninvasive measurement of tissue chromophores by the Optical Pharmacokinetic System.

摘要

Efficient design of anti-cancer treatments involving radiation- and photo-sensitizing therapeutics requires knowledge of tissue-specific drug concentrations. This dissertation investigates the utility of the Optical Pharmacokinetic System (OPS), a fiber-optic based elastic-scattering spectroscopy device, to noninvasively quantitate concentrations of sensitizing compounds and hemoglobin within tissue in vivo.;The OPS was used to quantitate concentrations of motexafin gadolinium (MGd), in mouse tissues in vivo and in situ. An algorithm was developed to quantify MGd absorbance by integration of the MGd peak absorbance area, thereby relaxing the requirement that the extinction coefficient be known a priori. Concentrations measured by OPS were well-correlated with measurements by high-performance liquid chromatography (HPLC).;Compartmental pharmacokinetic models were developed from tissue-specific MGd concentrations measured by OPS and HPLC. Models predicted both rapid initial distribution and slow elimination of MGd in plasma, fast transport of MGd out of the skin, and MGd retention at long times in the tumor. In vivo tumor MGd concentrations measured by the OPS were estimated by a linear combination of the plasma, tumor, and skin PK profiles.;A theoretical analysis of the OPS measurement of tissue was conducted using a Monte Carlo (MC) model of light transport through tissue that included discrete blood vessels. Simulation results motivated extensions to a previous analysis algorithm, including: (1) a novel analytic functionality between mean photon path length and total absorption coefficient; and (2) incorporation of a vessel correction factor to account for the pigment packaging effect of discrete vessels on the OPS-estimated absorption coefficient. These extensions improved OPS-estimates of both silicon phthalocyanine (Pc4) and hemoglobin concentration in a mouse xenograft in vivo following photodynamic therapy (PDT).;Mathematical models were utilized to investigate in silico the sensitivity of the OPS to chronically and acutely hypoxic regions within tumor tissue. PDT-induced acute hypoxia occurred via simulation of the photodynamic reaction. Subsequent simulation of the OPS measurement suggested that the OPS may be sensitive to the presence of chronically hypoxic vessels (an OPS-estimated hemoglobin saturation of ≥57% indicated 6% of vessels hypoxic), but may have limited application to detection of acute hypoxia following PDT.