Showing papers by "Thomas H. Foster published in 2008"

Irradiance-Dependent Photobleaching and Pain in δ-Aminolevulinic Acid-Photodynamic Therapy of Superficial Basal Cell Carcinomas

Abstract: Purpose: In superficial basal cell carcinomas treated with photodynamic therapy with topical δ-aminolevulinic acid, we examined effects of light irradiance on photodynamic efficiency and pain. The rate of singlet-oxygen production depends on the product of irradiance and photosensitizer and oxygen concentrations. High irradiance and/or photosensitizer levels cause inefficient treatment from oxygen depletion in preclinical models. Experimental Design: Self-sensitized photobleaching of protoporphyrin IX (PpIX) fluorescence was used as a surrogate metric for photodynamic dose. We developed instrumentation measuring fluorescence and reflectance from lesions and margins during treatment at 633 nm with various irradiances. When PpIX was 90% bleached, irradiance was increased to 150 mW/cm2 until 200 J/cm2 were delivered. Pain was monitored. Results: In 33 superficial basal cell carcinomas in 26 patients, photobleaching efficiency decreased with increasing irradiance above 20 mW/cm2, consistent with oxygen depletion. Fluences bleaching PpIX fluorescence 80% (D80) were 5.7 ± 1.6, 4.5 ± 0.3, 7.5 ± 0.8, 7.4 ± 0.3, 12.4 ± 0.3, and 28.7 ± 7.1 J/cm2, respectively, at 10, 20, 40, 50, 60 and 150 mW/cm2. At 20-150 mW/cm2, D80 doses required 2.5-3.5 min; times for the total 200 J/cm2 were 22.2-25.3 min. No significant pain occurred up to 50 mW/cm2; pain was not significant when irradiance then increased. Clinical responses were comparable to continuous 150 mW/cm2 treatment. Conclusions: Photodynamic therapy with topical δ-aminolevulinic acid using ∼40 mW/cm2 at 633 nm is photodynamically efficient with minimum pain. Once PpIX is largely photobleached, higher irradiances allow efficient, rapid delivery of additional light. Optimal fluence at a single low irradiance is yet to be determined.

Light Delivery over Extended Time Periods Enhances the Effectiveness of Photodynamic Therapy

Abstract: Purpose: The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high-irradiance treatments, recent preclinical and clinical studies have focused on low-irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose, and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model. Experimental Design: Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations was evaluated. Magnetic resonance imaging and oxygen tension measurements were done along with the Evans blue exclusion assay to assess vascular response, oxygenation status, and tumor necrosis. Results: In contrast to high-incident laser power (150 mW), low-power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens using treatment times of 120 to 240 min showed marked reduction in signal intensity in T2-weighted magnetic resonance images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared with short-duration (6-11 min) regimens. Significantly greater reductions in pO 2 were observed with extended exposures, which persisted after completion of treatment. Conclusions: These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor, and suggest that duration of light treatment (time) may be an important new treatment variable.

Photodynamic dose does not correlate with long-term tumor response to mTHPC-PDT performed at several drug-light intervals.

Abstract: Meso-tetra-hydroxyphenyl-chlorin (mTHPC, Foscan registered ), a promising photosensitizer for photodynamic therapy (PDT), is approved in Europe for the palliative treatment of head and neck cancer. Based on work in mice that investigated optimal tumor accumulation, clinical protocols with Foscan registered typically employ an interval of 96 h between systemic sensitizer administration and irradiation. However, recent studies in mouse tumor models have demonstrated significantly improved long-term tumor response when irradiation is performed at shorter drug-light intervals of 3 and 6 h. Using a previously published theoretical model of microscopic PDT dosimetry and informed by experimentally determined photophysical properties and intratumor sensitizer concentrations and distributions, we calculated photodynamic dose depositions following mTHPC-PDT for drug-light intervals of 3, 6, 24, and 96 h. Our results demonstrate that the singlet oxygen dose to the tumor volume does not track even qualitatively with tumor responses for these four drug-light intervals. Further, microscopic analysis of simulated singlet oxygen deposition shows that in no case do any subpopulations of tumor cells receive a threshold dose. Indeed, under the conditions of these simulations more than 90% of the tumor volume receives a dose that is approximately 20-fold lower than the threshold dose for mTHPC. Thus, in this evaluationmore » of mTHPC-PDT at various drug-light intervals, any PDT dose metric that is proportional to singlet oxygen creation and/or deposition would fail to predict the tumor response. In situations like this one, other reporters of biological response to therapy would be necessary.« less

Respiratory deficiency enhances the sensitivity of the pathogenic fungus Candida to photodynamic treatment.

Abstract: Mucosal infections caused by the pathogenic fungus Candida are a significant infectious disease problem and are often difficult to eradicate because of the high frequency of resistance to conventional antifungal agents. Photodynamic treatment (PDT) offers an attractive therapeutic alternative. Previous studies demonstrated that filamentous forms and biofilms of Candida albicans were sensitive to PDT using Photofrin as a photosensitizer. However, early stationary phase yeast forms of C. albicans and Candida glabrata were not adversely affected by treatment. We report that the cationic porphyrin photosensitizer meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP-1363) is effective in PDT against yeast forms of C. albicans and C. glabrata. Respiratory-deficient (RD) strains of C. albicans and C. glabrata display a pleiotropic resistance pattern, including resistance to members of the azole family of antifungals, the salivary antimicrobial peptides histatins and other types of toxic stresses. In contrast to this pattern, RD mutants of both C. albicans and C. glabrata were significantly more sensitive to PDT compared to parental strains. These data suggest that intact mitochondrial function may provide a basal level of anti-oxidant defense against PDT-induced phototoxicity in Candida, and reveals pathways of resistance to oxidative stress that can potentially be targeted to increase the efficacy of PDT against this pathogenic fungus.

Monitoring Pc 4 photodynamic therapy in clinical trials of cutaneous T-cell lymphoma using noninvasive spectroscopy

Abstract: Silicon phthalocyanine Pc 4 photodynamic therapy (Pc 4-PDT) has emerged as a potentially effective treatment for cutaneous T-cell lymphoma (CTCL). Noninvasive reflectance and fluorescence spectroscopy before, during, and after PDT may provide useful dose metrics and enable therapy to be tailored to individual lesions. We present the design and implementation of a portable bedside spectroscopy system for initial clinical trials of Pc 4-PDT of CTCL. Reflectance and fluorescence spectra were obtained from an early stage CTCL patient throughout the course of the PDT treatment. Preliminary patient data show a significant effect of Pc 4 on the tissue absorption, modest Pc 4 photobleaching, and heterogeneity of Pc 4 within and between the lesions.

Antibody-labeled fluorescence imaging of dendritic cell populations in vivo

Abstract: We report an optical molecular imaging technique that exploits local administration of fluorophore-conjugated antibodies and confocal fluorescence microscopy to achieve high-contrast imaging of host cell populations in normal and tumor tissue in living mice. The method achieves micron-scale spatial resolution to depths greater than 100 mum. We illustrate the capabilities of this approach by imaging two dendritic cell populations in the skin and normal and tumor vasculature in vivo.

Feedback-controlled method for delivering photodynamic therapy and related instrumentation

Abstract: A method for delivering photodynamic therapy (PDT) while performing dose metric monitoring and treatment feedback-driven control is presented. Photodynamic therapy is initiated with irradiation of light at a first irradiance. A set of fluorescence and reflectance spectroscopic measurements are taken at prescribed intervals during the therapy of the treatment region. Spectra are analyzed to determine dose metrics of the therapy such as fluorescence photobleaching of the sensitizer and blood oxygen status and optical properties of the treatment region. This information is then used to determine an optimal fluence rate given those parameters and the region is irradiated with a second irradiance. This process is continued until either the entire prescribed fluence is delivered to the region or a predetermined extent of photosensitizer bleaching is achieved.

Erratum: "A comprehensive mathematical model of microscopic dose deposition in photodynamic therapy" [Med. Phys. 34, 282-293 (2007)].

Abstract: Recently, we published an improved mathematical model of photodynamic therapy (PDT) dose deposition on length scales corresponding to intercapillary distances.1 This model describes the spatial and temporal dynamics of oxygen (O23) consumption and transport and microscopic singlet oxygen (O21) dose deposition during PDT treatment. It also enables simulation of volume-averaged quantities like hemoglobin oxygen saturation (SO2) and photosensitizer fluorescence photobleaching, which are accessible experimentally. In a subsequent modeling study of the kinetics of the recovery of SO2 following the interruption of PDT irradiation, we were troubled by what appeared to be physically unreasonable simulation results. The origin of these erroneous results was a sign error in one of the terms buried deep in the original code, which had the effect of creating a tumor microenvironment that was more hypoxic that we had specified as an initial condition. We emphasize that in our previously published article on this model, there were no errors in what was described, but the plots presented in that article were quantitatively affected by this sign error. Specifically, this error was in the numerator of Eq. (2) of Wang et al.,1 which was correct in the text; the error was only in the code. In this erratum, we show the revised figures generated by using the same photophysical and physiological parameters described previously.1 We also use this occasion to describe a few relatively minor improvements to the model. The oxygen transport equation in the capillary is revised slightly from the original and is now written (1+S)∂Ccap∂t=Dcap[1r∂∂r(r∂Ccap∂r)]+Dcap∂2Ccap∂z2−V(1+S)∂Ccap∂z,0⩽r⩽Rc, (1) where S=CsatnC50nCcapn−1(C50n+Ccapn)2. (2) Here, we include a new term, (1+S), on the left-hand side of the transport equation for the capillary [Eq. 1], which more correctly provides for the dynamic unloading of O23 from hemoglobin.2 Further, the revised code uses Michaelis–Menten kinetics to describe the rate of metabolic O23 consumption not only in the calculation of the time-dependent state, as was done previously, but also in the calculation of the steady-state with axial diffusion. The equation for the tissue region remains as previously described ∂Ctiss∂t=Dtiss[1r∂∂r(r∂Ctiss∂r)]+Dtiss∂2Ctiss∂z2−Γ,Rc⩽r⩽b. (3) The definitions and the values of the parameters were previously described. Using the corrected code and implementing the above modifications to the model, we repeated the simulations for the case of a 130 μm intercapillary spacing. Figure ​Figure11 shows the revised computed spatial distributions of O23 concentration, [O23](r,z), for (a) 0 J cm−2 and mTHPC-PDT conducted at irradiances of (b) 10 mW cm−2 for a fluence of 50 J cm−2, (c) 100 mW cm−2 for a fluence of 3 J cm−2, and (d) for a fluence of 50 J cm−2, assuming a nonuniform initial sensitizer distribution 3 h after i.v. injection. The anoxic regions shown in Figs. ​Figs.3b,3b, ​,3c,3c, ​,3d3d of our original article,1 which do not appear in these corrected results, were a result of the sign error in the code. Figure 1 Calculated axial and radial distributions of the O23 concentration [O23](r,z) for (a) 0 J cm−2 and mTHPC-PDT conducted at irradiances of (b) 10 mW cm−2 for a fluence of 50 J cm−2, (c) 100 mW cm−2 for a fluence of 3 J cm ... Figure 3 Computed spatial distributions of O21 dose, [O21](r,z), deposited during mTHPC-PDT at irradiances of 10 and 100 mW cm−2 for a fluence of 50 J cm−2, assuming initially uniform [(a1) and (a2)] and nonuniform [(b1), and (b2)] sensitizer distributions. ... Revised numerical calculations of volume-averaged hemoglobin O23 saturation, ⟨SO2⟩, within the capillary versus irradiation time, the normalized, volume-averaged ground state sensitizer concentration, ⟨[S0]⟩, versus fluence, and the volume-averaged O21 dose, ⟨[O21]⟩, versus fluence for two fluence rates, 10 and 100 mW cm−2, assuming nonuniform initial sensitizer distribution are shown in Figs. ​Figs.2a,2a, ​,2b,2b, ​,2c,2c, respectively. The initial decrease in ⟨SO2⟩ in Fig. ​Fig.2a2a is not as significant as shown in Fig. 4(b) of Wang et al.1 Compared to Figs. 5(a) and 7(a) of our previous article, the rates of photobleaching and dose deposition for the 10 and 100 mW cm−2 cases in Figs. 2(b) and 2(c) are more rapid, and for a given fluence, the differences in the extent of sen-sitizer degradation and dose deposition between these two fluence rate cases are smaller. The differences between these and our previous results originate from greater oxygen availability in the tumor region after correcting the sign error. Figure 2 (a) Computed ⟨SO2⟩ within the capillary vs irradiation time (s), (b) computed normalized ⟨[S0]⟩ vs fluence (J cm−2), and (c) computed ⟨[O21]⟩ vs fluence (J cm−2) for two fluence rates, 10 ... Figure ​Figure33 shows the computed spatial distributions of O21 dose, [O21](r,z), deposited during mTHPC-PDT at irradiances of 10 and 100 mW cm−2 for a fluence of 50 J cm−2, assuming initially uniform [(a1) and (a2)] and nonuniform [(b1), and (b2)] sensitizer distributions. Compared to our previously published Fig. 8,1 the axial gradients in [O21] are now less severe. The corrected MATLAB code is available, and interested readers should contact the authors for the updated version.

Integrated Spectroscopy and PDT Delivery for Various Treatment Geometries

Abstract: We present the design of portable instrumentation that integrates spectroscopy with PDT delivery. The flexibility of the system accommodates probes for various surface and interstitial PDT geometries.

Molecular Imaging of Tumor Responses to Photodynamic Therapy in vivo

Abstract: Photodynamic therapy (PDT) elicits significant molecular and host responses, which are understood to be important to long-term tumor control. We demonstrate the ability to image these responses using confocal fluorescence in superficial tumors in vivo.

Method for controlling photodynamic therapy irradiation and related instrumentation

Abstract: In a first embodiment, there is no monitoring, and instead light is delivered according to a predetermined 'recipe.' In a second embodiment, the instrumentation provides a means for making the reflectance measurements during therapy without requiring the brief interruption. This device may therefore allow more accurate measurement of treatment-induced changes to the reflectance measurement. In a third embodiment, an adjustable aperture is used to constrict the area of a treatment beam.