Type II photodynamic therapy (PDT) is based on the photochemical reactions mediated through an interaction between a photosensitizer, ground-state oxygen ([O32]), and light excitation at an appropriate wavelength, which results in production of reactive singlet oxygen ([O12]rx). We use an empirical macroscopic model based on four photochemical parameters for the calculation of [O12]rx threshold concentration ([O12]rx,sh) causing tissue necrosis in tumors after PDT. For this reason, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-mediated PDT was performed interstitially on mice with radiation-induced fibrosarcoma (RIF) tumors. A linear light source at 665 nm with total energy released per unit length of 12 to 100 J/cm and source power per unit length (LS) of 12 to 150 mW/cm was used to induce different radii of necrosis. Then the amount of [O12]rx calculated by the macroscopic model incorporating explicit PDT dosimetry of light fluence distribution, tissue optical properties, and HPPH concentration was correlated to the necrotic radius to obtain the model parameters and [O12]rx,sh. We provide evidence that [O12]rx is a better dosimetric quantity for predicting the treatment outcome than PDT dose, which is proportional to the time integral of the products of the photosensitizer concentration and light fluence rate.
An appropriate expression for the oxygen supply rate (Γs) is required for the macroscopic modeling of the complex mechanisms of photodynamic therapy (PDT). It is unrealistic to model the actual heterogeneous tumor microvascular networks coupled with the PDT processes because of the large computational requirement. In this study, a theoretical microscopic model based on uniformly distributed Krogh cylinders is used to calculate Γs=g (1−[O32]/[O32]0) that can replace the complex modeling of blood vasculature while maintaining a reasonable resemblance to reality; g is the maximum oxygen supply rate and [O32]/[O32]0 is the volume-average tissue oxygen concentration normalized to its value prior to PDT. The model incorporates kinetic equations of oxygen diffusion and convection within capillaries and oxygen saturation from oxyhemoglobin. Oxygen supply to the tissue is via diffusion from the uniformly distributed blood vessels. Oxygen can also diffuse along the radius and the longitudinal axis of the cylinder within tissue. The relations of Γs to [3O2]/[3O2]0 are examined for a biologically reasonable range of the physiological parameters for the microvasculature and several light fluence rates (ϕ). The results show a linear relationship between Γs and [3O2]/[3O2]0, independent of ϕ and photochemical parameters; the obtained g ranges from 0.4 to 1390 μM/s.
The cell killing mechanism of benzoporphyrin derivative monoacid ring A (BPD) is known to be predominantly
apoptotic or vascular, depending on the drug-light interval (DLI). With a 3 hour DLI, necrosis develops secondary to
tumor cell damage, while with a 15 minute DLI, necrosis results from treatment-created vascular damage. The purpose
of this study is to examine if the different mechanisms of cell death will affect the photochemical parameters for the
macroscopic singlet oxygen model. Using the RIF model of murine fibrosarcoma, we determined the four photochemical
parameters (see manuscript) and the threshold singlet oxygen dose for BPD-mediated PDT through evaluation of the extent of
tumor necrosis as a function of PDT fluence rate and total fluence. Mice were treated with a linear source at fluence rates
from 12-150 mW/cm and total fluences from 24-135 J/cm. BPD was administered at 1mg/kg with a 15 minute DLI,
followed by light delivery at 690nm. Tumors were excised at 24 hours after PDT and necrosis was analyzed via HE
staining. The in-vivo BPD drug concentration is determined to be in the range of 0.05-0.30 μM. The determination of
these parameters specific for BPD and the 15 minute DLI provides necessary data for predicting treatment outcome in
clinical BPD-mediated PDT. Photochemical parameters will be compared between 1mg/kg DLI 3 hours and 1mg/kg DLI
15 minutes.
Singlet oxygen (1O2) is the major cytotoxic species producing PDT effects, but it is difficult to monitor in vivo due to its short life time in real biological environments. Mathematical models are then useful to calculate 1O2 concentrations for PDT dosimetry. Our previously introduced macroscopic model has four PDT parameters: ξ, σ, β and g describing initial oxygen consumption rate, ratio of photobleaching to reaction between 1O2 and cellular targets, ratio of triplet state (T) phosphorescence to reaction between T and oxygen (3O2), and oxygen supply rate to tissue, respectively. In addition, the model calculates a fifth parameter, threshold 1O2 dose ([1O2]rx,sd). These PDT parameters have been investigated for HPPH using radiation-induced fibrosarcoma (RIF) tumors
in an in-vivo C3H mouse model. In recent studies, we additionally investigated these parameters in human non-small cell lung carcinoma (H460) tumor xenografts, also using HPPH-mediated PDT. In-vivo studies are performed with nude female mice with H460 tumors grown intradermally on their right shoulders. HPPH (0.25 mg/kg) is injected i.v. at 24 hours prior to light delivery. Initial in vivo HPPH concentration is quantified via interstitial HPPH fluorescence measurements after correction for tissue optical properties. Light is delivered by a linear source at various light doses (12-50 J/cm) with powers ranging from 12 to 150 mW per cm length. The necrosis radius is quantified using ScanScope after tumor sectioning and hematoxylin and eosin (H and E) staining. The macroscopic optimization model is used to fit the results and generate four PDT parameters. Initial results of the parameters for H460 tumors will be reported and compared with those for the RIF tumor.
Macroscopic modeling of singlet oxygen (1O2) is of particular interest because it is the major cytotoxic agent causing
biological effects for type II photosensitizers during PDT. We have developed a macroscopic model to calculate reacted
singlet oxygen concentration ([1O2]rx for PDT. An in-vivo RIF tumor mouse model is used to correlate the necrosis
depth to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and
photosensitizer concentrations. Inputs to the model include 4 photosensitizer specific photochemical parameters along
with the apparent singlet oxygen threshold concentration. Photosensitizer specific model parameters are determined for
several type II photosensitizers (Photofrin, BPD, and HPPH). The singlet oxygen threshold concentration is
approximately 0.41 - 0.56 mM for all three photosensitizers studied, assuming that the fraction of singlet oxygen
generated that interacts with the cell is (f = 1). In comparison, value derived from other in-vivo mice studies is 0.4 mM
for mTHPC. However, the singlet oxygen threshold doses were reported to be 7.9 and 12.1 mM for a multicell in-vitro
EMT6/Ro spheroid model for mTHPC and Photofrin PDT, respectively. The sensitivity of threshold singlet oxygen
dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanism on the
singlet oxygen threshold dose is discussed using the BPD with different drug-light intervals 3 hrs vs. 15 min. The
observed discrepancies between different experiments warrant further investigation to explain the cause of the
difference.
Mathematic models were developed to simulate the complex dynamic process of photodynamic therapy (PDT). Macroscopic or microscopic modeling of singlet oxygen (1O2) is particularly of interest because it is the major cytotoxic agent causing biological effects during PDT. Our previously introduced macroscopic PDT model incorporates the diffusion equation for the light propagation in tissue and the macroscopic kinetic equations for the production of the 1O2. The distance-dependent distribution of 3O2 and reacted 1O2 can be numerically calculated using finite-element method (FEM). We recently improved the model to include microscopic kinetic equations of oxygen diffusion from uniformly distributed blood vessels and within tissue. In the model, the cylindrical blood capillary has radius in the range of 2-5 μm and a mean length of 300 μm, and supplies oxygen into tissue. The blood vessel network is assumed to form a 2-D square grid perpendicular to a linear light source. The spacing of the grid is 60 μm. Oxygen can also diffuse along the radius and the longitudinal axial of the cylinder within tissue. The oxygen depletion during Photofrin-PDT PDT can be simulated using both macroscopic and microscopic approaches. The comparison of the simulation results have reasonable agreements when velocity of blood flow is reduced during PDT.
Pleural photodynamic therapy (PDT) has been used as an adjuvant treatment with lung-sparing surgical treatment for
mesothelioma with remarkable results. In the current intrapleural PDT protocol, a moving fiber-based point source is
used to deliver the light and the light dose are monitored by 7 detectors placed in the pleural cavity. To improve the
delivery of light dose uniformity, an infrared (IR) camera system is used to track the motion of the light sources. A
treatment planning system uses feedback from the detectors as well as the IR camera to update light fluence distribution
in real-time, which is used to guide the light source motion for uniform light dose distribution. We have improved the
GUI of the light dose calculation engine to provide real-time light fluence distribution suitable for guiding the surgery to
delivery light more uniformly. A dual-correction method is used in the feedback system, so that fluence calculation can
match detector readings using both direct and scatter light models. An improved measurement device is developed to
automatically acquire laser position for the point source. Comparison of the effects of the guidance is presented in
phantom study.
Different wavelength light sources are used in photodynamic therapy (PDT) of the skin to treat different conditions. Clinical studies show inconsistent results for the effectiveness of aminolevulinic acid (ALA)-PDT performed at different wavelengths. In order to understand the effect of treatment wavelength, a theoretical study was performed to calculate time-resolved depth-dependent distributions of PDT components including ground-state oxygen, sensitizer, and reacted singlet oxygen for different treatment wavelengths (405, 523, and 633 nm) using a numerical model of ALA-PDT of human skin. This model incorporates clinically relevant features of the PDT process including light attenuation, photobleaching, oxygen consumption, and diffusion, as well as tissue perfusion. The calculations show that the distributions of these quantities are almost independent of the treatment wavelength to a depth of about 1 mm. In this surface region, PDT-induced hypoxia is the dominant process. At greater depths, the production of singlet -oxygen is governed by the penetration of the treatment light. Two noninvasive PDT dosimetry approaches: the cumulative singlet oxygen luminescence (CSOL) and the fractional fluorescence bleaching metric, were investigated and compared for all three wavelengths. Although CSOL was more robust, both metrics provided correlations with the singlet oxygen dose in the upper dermis that were almost independent of treatment wavelength. This relationship breaks down at greater depths because light penetration depends on wavelength.
Photosensitizer fluorescence photobleaching and Singlet Oxygen (1O2) Luminescence Dosimetry (SOLD) are
being studied as potential dosimetric tools for ALA-PDT of skin diseases. However, the correlation of both
SOLD data and PpIX fluorescence to 1O2 distribution is difficult to interpret because of the temporal and spatial
variations of the PDT parameters (light fluence rate, photosensitizer concentration and oxygen concentration).
This work used our dynamic model to investigate both dosimetry approaches for varied PpIX concentration
and distribution, and three commonly used treatment wavelengths. The results show that SOLD is much less
dependent upon the treatment parameters, which implies it has better potential as a "gold standard" dosimetric
tool for clinical PDT.
Both photosensitizer fluorescence photobleaching and singlet oxygen luminescence (SOL) have been measured
during ALA-PDT of skin in attempts to estimate PDT dose. However, the relationship of these detected signals
to singlet oxygen (1O2) dose in a given volume and to its depth distribution are not well understood and difficult
to verify experimentally because of the temporal and spatial variations of the essential parameters in PDT. A
model for ALA-PDT of normal human skin was developed to simulate the dynamic progress of PDT. The model
incorporates Monte Carlo simulations of excitation light fluence and both SOL and PpIX fluorescence signals,
1O2-mediated photobleaching mechanism, ground-state oxygen (3O2) diffusion and perfusion, a cumulative 1O2-dependent threshold vascular response and any initial distribution of PpIX. The simulated
time-resolved evolution
of the instantaneous PpIX fluorescence photobleaching and cumulative SOL signals are examined as functions
of irradiance and related to both the time-resolved distribution of cumulative 1O2 production at various depths
and the average dose in the dermis. The simulations used a green light source at 523 nm. The correlation of SOL
signals with the average dose was found to be less
irradiance-dependent than that of fluorescence photobleaching,
which indicates the great potential of SOL as a clinical dosimetric tool in PDT.
Singlet Oxygen (1O2) Luminescence Dosimetry (SOLD) and fluorescence photobleaching are being investigated
as dosimetric tools for clinical PDT. Both have been applied during superficial ALA-PDT of normal skin and
skin cancers. The interpretation of fluorescence and SOLD data is complicated by the non-uniform distribution
and bleaching of PpIX and the absorption and scattering of light in the skin. The aim of the present work was
to tackle these challenges using Monte Carlo (MC) simulations. Skin was modeled as a three-layer semi-infinite
medium with uniform optical properties in each layer. The initial depth-dependent distribution of PpIX was an
exponential decay and, after the delivery of each treatment fluence increment, standard photochemical reaction
kinetics were used to update the distribution of sensitizer and reacted singlet oxygen. Oxygen depletion due to
photochemical consumption or vascular shutdown was also incorporated in the model. The adjoint method was
applied to calculate the PpIX fluorescence and 1270 nm singlet oxygen luminescence reaching the skin surface
in each time increment. The time-resolved evolution of the fluorescence and cumulative SOLD signals during
treatment were compared to the time-resolved volume-averaged distribution of reacted singlet oxygen in the
dermis layer for typical clinical PDT conditions. Approximate linear relationships were observed over most of
the treatment time.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.