T.M. Baran, B.R. Giesselman, R. Hu, M.A. Biel, and T.H. Foster. Factors influencing tumor response to photodynamic therapy sensitized by intratumor administration of methylene blue. Lasers Surg. Med. 42, 728-735 (2010) [Erratum: Lasers Surg. Med. 43, 183 (2011)]. [Medline]
W.J. Cottrell, A.D. Paquette, K.R. Keymel, T.H. Foster, and A.R. Oseroff. Irradiance-dependent photobleaching and pain in delta-aminolevulinic acid-photodynamic therapy of superficial basal cell carcinomas. Clin. Cancer Res. 14, 4475-4483 (2008).
T.K. Lee, E.D. Baron, and T.H. Foster. Monitoring Pc 4-PDT in clinical trials of cutaneous T-cell lymphoma using noninvasive spectroscopy. J. Biomed. Opt. 13 , 030507 (2008).
W.J. Cottrell, A.R. Oseroff, andT.H. Foster. A portable instrument that integrates irradiation with fluorescence and reflectance spectroscopies during clinical photodynamic therapy of cutaneous disease. Rev. Sci. Instrum. 77, 064302-1 - 8 (2006).
J.C. Finlay and T.H. Foster. Hemoglobin oxygen saturations in phantoms and in vivo from measurements of steady state diffuse reflectance at a single, short source-detector separation. Med. Phys. 31, 1949-1959 (2004). [Medline]
Reflectance Spectroscopy in Tissue
Reflectance spectroscopy reports the absorption and scattering properties of tissue. Various strategies for separating the contributions of absorption and scattering in attenuation measurements have been proposed and evaluated. We have adopted broad band steady state methods that are based on either diffusion or P3 approximations to radiative transfer. Because of our interest in cancer and in photodynamic therapy in particular, we have been especially interested in monitoring hemoglobin oxygen saturation using reflectance techniques.
We have published on experimental methods for measuring spatially-resolved diffuse reflectance spectra and on characterizing laboratory phantoms that mimic optical properties of tissue. In M.G. Nichols et al. (1997) we described our first reflectance system and experimental results in model systems, which were based on a diffusion theory approximation method. These ideas were extended to a more realistic tissue-simulating phantom using intact red blood cells (Hull et al., Phys. Med. Biol. 1998), to phantoms containing red blood cells and mitochondria (Hull and Foster, Appl. Spectrosc. 2001), and to a rodent tumor model in vivo, where the effects of carbogen breathing on hemoglobin oxygen saturation were studied (Hull et al., Brit. J. Cancer 1999). An evaluation of the relationship between macroscopic, volume-averaged estimates of hemoglobin oxygen saturation reported by near infrared spectroscopy and microscopic heterogeneities in saturation assessed by cryospectroscopy was reported in D.L. Conover et al. (2000). During his thesis research, Ed Hull developed a method based on a higher order, P3 approximation to radiative transfer that recovers accurate absorption and scattering spectra in more highly absorbing media and at shorter source-detector separations (Hull and Foster, JOSA A 2001). The P3 approximation was applied in red blood cell phantoms and in a rodent tumor model in vivo by Jarod Finlay, who used it to develop a reflectance method based on a single, short source-detector separation. This enabled the use of probes much smaller than those typically used with techniques based on the diffusion theory approximation (Finlay and Foster, Med. Phys. 2004). Finlay and Foster (Opt. Lett. 2004) also described an important “pigment packaging” correction to reflectance spectra acquired at wavelengths corresponding to the Soret band of hemoglobin.
Fluorescence Photobleaching and Photoproduct Formation
Most photosensitizers used in photodynamic therapy are chemically modified by the photochemistry that they initiate. These modifications may take the form of photoproducts with fluorescence spectra that differ from that of the parent compound, and/or the irreversible photobleaching of the sensitizer, which gives rise to a progressive loss of fluorescence during irradiation. Thus, these modifications in fluorescence report something about the local photochemistry in the cells or tissue undergoing PDT. For this reason, monitoring sensitizer photobleaching and photoproduct accumulation during treatment has received some attention as a possible surrogate reporter of photodynamic dose deposition and biological response. We have been very active in this area during the past several years. In particular, we have been interested in the irradiance dependence of photobleaching/photoproduct formation because in a number of model systems the biological response to PDT shows a strong such dependence.
Spectra acquired in an intact spheroid incubated with h-ALA for 3 hours. Contributions from PpIX and photoproducts are shown for spectra acquired pre- and post-PDT in different regions of the spheroid.
Our work on sensitizer photobleaching has resulted in several publications. Jarod Finlay et al. reported on interesting irradiance-dependent features of the fluorescence spectra of ALA-induced PpIX and its photoproducts (2001) and on the irradiance dependence of the bleaching of mTHPC (2002), which does not form a photoproduct. Experiments with Photofrin revealed a complex situation, in which Photofrin bleaching in vivo and in multicell tumor spheroids was mediated by a “mixed” singlet-oxygen and excited-triplet-state mechanism. The irradiance dependence of the Photofrin photoproduct accumulation, however, was consistent with a singlet-oxygen-mediated mechanism (Finlay et al., 2004). Recently, we designed and built an instrument that integrates the delivery of PDT irradiation with the acquisition of fluorescence and reflectance spectra during therapy (Cottrell et al., 2006). This device is now part of a clinical trial of ALA-PDT in the treatment of human superficial basal cell carcinoma at nearby Roswell Park Cancer Institute. The fluorescence spectroscopy results of this study are critical in determining the choice of optimal irradiation parameters for a future trial of low-irradiance PDT in this patient population.