PDT Dose Research Articles

Reactive Oxygen Species Explicit dosimetry for Pleural PDT

SignificancePreclinical studies show improved prediction of treatment outcome using [ROS]rx than light fluence rate or PDT dose. We demonstrate ROSED in a clinical setting. ApproachExplicit dosimetry of light fluence, photosensitizer concentration, and oxygen concentration is used to quantify the reactive oxygen species explicit dosimetry (ROSED) during Photofrin-mediated pleural PDT. Light fluence and photosensitizer concentration were measured by a customized multi-channel PDT dose dosimeter system. Diffuse correlation spectroscopy (DCS) contact probes were sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (BFI) during intraoperative PDT treatment. Tissue oxygen concentration can be determined by utilizing tumor blood flow measured by DCS. ResultsLarge inter- and intra-patient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J/cm2 was prescribed to all patients. ConclusionsThis study summarizes the current results of ROSED for a Phase II pleural PDT clinical trial.

Investigating the effects of a temperature dependent photodynamic dose: A numerical study

SignificancePhotodynamic therapy (PDT) and photothermal therapy (PTT) show promise as cancer treatments, but challenges in generating large ablative volumes for deep-seated tumours persist. Using simulations, this study investigates combined PDT and PTT to increase treatment volumes, including the impact of a temperature-dependent PDT dose on the treatment volume radius. ApproachA finite-element model, using the open-source SfePy package, was developed to simulate combined interstitial photothermal and photodynamic treatments. Results compared an additive dose model to a temperature-dependent dose model with enhanced PDT dosimetry and examined typical clinical scenarios for possible synergistic effects. ResultsFindings revealed that the temperature-dependent dose model could significantly expand the damage radius compared to the additive model, depending on the tissue and drug properties. ConclusionsCharacterizing synergistic effects of PDT and PTT could enhance treatment planning. Future work is ongoing to implement additional variables, such as photosensitizer photobleaching, and spatial and temporally varying oxygenation.

Photodynamic therapy outcome modelling for patients with spinal metastases: a simulation-based study

Spinal metastases often occur in the advanced stages of breast, lung or prostate cancer, resulting in a significant impact on the patient’s quality of life. Current treatment modalities for spinal metastases include both systemic and localized treatments that aim to decrease pain, improve mobility and structural stability, and control tumour growth. With the development of non-toxic photosensitizer drugs, photodynamic therapy (PDT) has shown promise as a minimally invasive non-thermal alternative in oncology, including for spinal metastases. To apply PDT to spinal metastases, predictive algorithms that optimize tumour treatment and minimize the risk of spinal cord damage are needed to assess the feasibility of the treatment and encourage a broad acceptance of PDT in clinical trials. This work presents a framework for PDT modelling and planning, and simulates the feasibility of using a BPD-MA mediated PDT to treat bone metastases at two different wavelengths (690 nm and 565 nm). An open-source software for PDT planning, PDT-SPACE, is used to evaluate different configurations of light diffusers (cut-end and cylindrical) fibres with optimized power allocation in order to minimize the damage to spinal cord or maximize tumour destruction. The work is simulated on three CT images of metastatically involved vertebrae acquired from three patients with spinal metastases secondary to colorectal or lung cancer. Simulation results show that PDT at a 565 nm wavelength has the ability to treat 90% of the metastatic lesion with less than 17% damage to the spinal cord. However, the energy required, and hence treatment time, to achieve this outcome with the 565 nm is infeasible. The energy required and treatment time for the longer wavelength of 690 nm is feasible ({sim },40 min), but treatment aimed at 90% of the metastatic lesion would severely damage the proximal spinal cord. PDT-SPACE provides a simulation platform that can be used to optimize PDT delivery in the metastatic spine. While this work serves as a prospective methodology to analyze the feasibility of PDT for tumour ablation in the spine, preclinical studies in an animal model are ongoing to elucidate the spinal cord damage extent as a function of PDT dose, and the resulting short and long term functional impairments. These will be required before there can be any consideration of clinical trials.

Death Pathways Associated with Photodynamic Therapy.

This report describes studies involving ER vs. lysosomal targeting and is designed to assess the initiation of different death pathways as a function of subcellular targeting and PDT dose. Photodamage directed at mitochondria or lysosomes initiates apoptosis, a death pathway generally considered to be irreversible. Photodamage that involves the ER can lead to another death pathway termed paraptosis. This does not involve caspase activation, can eradicate cell types with impaired apoptosis; at high levels of irradiation, apoptosis and necrosis were observed. Autophagy has a cytoprotective function unless lysosomes are targeted; loss of lysosomal integrity can interfere with the autophagic recycling processes.

Paraptosis and Photodynamic Therapy: A Progress Report.

Photodamage to the endoplasmic reticulum (ER) can initiate a death pathway termed paraptosis. The "canonical" model of paraptosis, initiated by certain drugs and other stimuli, requires a brief interval of protein synthesis, involves the action of MAP kinases and can be followed by biochemical markers. The latter include changes in expression of AIP-1/Alix and IGF-1R proteins and translocation of HMGB-1 from nucleus to plasma membrane. There is also a report indicating that an enhanced level of autophagy can impair death by paraptosis. The pathway to paraptosis follows the canonical pathway when ER photodamage is minor (<LD50 ). When the extent of ER photodamage approaches LD90 levels, there are deviations from the "canonical" pathway: interfering with protein synthesis does not prevent paraptosis nor does a brief chilling of cells after irradiation, MAP kinases are not involved, and stimulation of autophagy was not cytoprotective. We had previously speculated that ER protein cross-linking might potentiate paraptosis (Photochem. Photobiol. 95, 2019, 1239) but this appears to be incorrect. At higher PDT doses, substantial cross-linking of a typical ER protein (BiP, binding immunoglobin protein, an HSP chaperone) was detected and paraptosis was impaired. This may relate to decreased mobility of cross-linked proteins. Other pathways to cell death were then observed.

Pathways to Paraptosis After ER Photodamage in OVCAR-5 Cells.

A death mode termed paraptosis is initiated by photodamage to the endoplasmic reticulum (ER). This is characterized by an extensive pattern of cytoplasmic vacuole formation and leads to a gradual loss of cytoplasm and of viability. Many photosensitizers in clinical use target sub-cellular organelles that include the ER and can, therefore, invoke paraptosis as well as apoptosis. In this study, we explore pathways to paraptosis in OVCAR-5, an ovarian cancer cell line of human origin. At low PDT doses, the route to paraptosis follows the pattern that occurs after chemotherapy, that is, a pattern of vacuole formation that can be suppressed by MAPK antagonists or inhibition of new protein synthesis. At PDT doses clinically pertinent for tumor eradication, the pathway to paraptosis appears to be independent of these factors. In addition to morphologic changes, translocation of the nuclear protein HMGB1(high mobility group protein B1) to the cell periphery has been described as a potential marker for drug-induced paraptosis. This occurs to only a very minor extent after a lethal PDT dose that targets the ER. It appears that a lethal level of ER photodamage can initiate a different pathway to paraptosis, perhaps associated with ER protein cross-linking.

Modeling PpIX effective light fluence at depths into the skin for PDT dose comparison.

Daylight-activated PDT has seen increased support in recent years as a treatment method for actinic keratosis and other non-melanoma skin cancers. The inherent variability observed in broad-spectrum light used in this methodology makes it difficult to plan and monitor light dose, or compare to lamp light doses. The present study expands on the commonly used PpIX-weighted effective surface irradiance metric by introducing a Monte Carlo method for estimating effective fluence rates into depths of the skin. The fluence rates are compared between multiple broadband and narrowband sources that have been reported in previous studies, and an effective total fluence for various treatment times is reported. A dynamic estimate of PpIX concentration produced during pro-drug incubation and treatment is used with the fluence estimates to calculate a photodynamic dose. Even when there is up to a 5x reduction between the effective surface irradiance of the broadband light sources, the effective fluence below 250 μm depth is predicted to be relatively equivalent. An effective threshold fluence value (0. 70Jeff/cm2) is introduced based on a meta-analysis of previously published ALA-PpIX induced cell death. This was combined with a threshold PpIX concentration (50 nM) to define a threshold photodynamic dose of 0.035 u M Jeff/cm2. The threshold was used to generate lookup tables to prescribe minimal treatment times to achieve depth-dependent cytotoxic effect based on incubation times and irradiance values for each light source.

Effect of aminolevulinic acid-based photodynamic therapy on the expression of protein kinase D1 and its phosphorylation sites in a cutaneous squamous cell carcinoma cell line A431

Objective To evaluate the effect of aminolevulinic acid-based photodynamic therapy (ALA-PDT) on the expression of protein kinase D1 (PKD1) in a cutaneous squamous cell carcinoma cell line A431, and to explore the mechanism underlying ALA-PDT-induced apoptosis of A431 cells. Methods A431 cells were cultured in vitro, and cell counting kit-8 (CCK-8) assay was performed to select the optimal combination of ALA concentration and PDT dose with the strongest proliferation inhibitory effect. A431 cells at exponential growth phase were randomly divided into 4 groups: control group receiving no treatment, ALA group treated with ALA solution alone, PDT group treated with PDT alone, and ALA-PDT group treated firstly with ALA solution and then with PDT. After 12-, 24-, 36- and 48-hour additional culture, CCK-8 assay was conducted to evaluate the cellular proliferation inhibition, and the apoptosis rate at the time point of the strongest proliferation inhibitory effect was measured by flow cytometry. RT-PCR was performed to determine the expression of protein kinase D1 gene (PRKD1) in A431 cells at different time points after the ALA-PDT treatment, and Western blot analysis to measure protein expression of PKD1 and its phosphorylation at Tyr463 (pTyr463) and Ser916 (pSer916) in A431 cells. Results The combi-nation of ALA at the concentration of 1.5 mmol/L with PDT at an irradiation dose of 2 J/cm2 was optimal due to its strongest proliferation inhibitory effect. After 12-, 24-, 36- and 48-hour additional culture, there were significant differences in the proliferation inhibition rate among the 4 groups (F= 39.56, P 0.05) . No significant difference in the Ser916-phosphorylated PKD1 expression was found among the 4 groups (F= 1.53, P > 0.05) , while there were significant differences in the expression of PKD1 and Tyr463-phosphorylated PKD1 among the 4 groups (F= 10.04, 8.27, both P < 0.05) . Additionally, the ALA-PDT group showed significantly lower expression of PKD1 and Tyr463-phosphorylated PKD1 compared with the control group, ALA group and PDT group (all P < 0.05) . Conclusion PKD1 may be involved in the photochemical process of A431 cell apoptosis induced by ALA-PDT, and may promote the occurrence of squamous cell carcinoma by Tyr463 phosphorylation. Key words: Photochemotherapy; Aminolevulinic acid; Neoplasms, Squamous Cell; Protein kinases; Primary cell culture; A431 cell

The effect of in vitro photodynamic therapy on increase of osteopontin and heat shock protein 70 expression in squamous cell and colon carcinoma

The aim of the study was investigating whether the 5-ALA-mediated-photodynamic therapy may cause an increase in osteopontin expression in malignant cells, and whether this was accompanied by a parallel increase in an expression of Heat Shock Protein 70. The heat shock proteins belong to highly conserved stress proteins widely expressed in different cells and playing specific important roles. Osteopontins have been associated with the progression of numerous types of cancer. SCC-4 and SW480 cells were exposed to 3 and 6 mM of 5-aminolevulinic acid for 5 h. Two different light sources were used: first, a halogen lamp; and second, the diode laser. The viability of SCC-4 and SW480 cells following treatment was determined by MTT assay. Protein expression was assessed by immunocytochemistry and Western blot analysis. The apoptosis rate after treatment with different light sources was measured by flow cytometry. Immunocytochemical stainings showed distinct increase of HSP70 and osteopontin protein expression in both cancer cell lines after PDT by means of either halogen lamp or laser light. The effects of a photodamage can both promote cell death and enhance metastasis. This will emphasize the rationale for providing sufficient PDT doses to eradicate malignant cells since a suboptimal dose may have an adverse effect on cancer control.

Photodynamic inactivation of methicillin-resistant Staphylococcus aureus by indocyanine green and near infrared light

Abstract Background Antimicrobial photodynamic therapy (APDT) has become a potential regimen to treat multidrug-resistant bacterial infections. Limited data showed indocyanine green (ICG), a safe and inexpensive contrast medium for eye angiography and hepatic function examination, is an effective photosensitizer in APDT to kill methicillin-resistant Staphylococcus aureus (MRSA) after excitation with laser. Objective We investigated the potentials of ICG-APDT with an inexpensive, non-coherent commercial near infrared (NIR) lamp against MRSA. Methods The inhibition of MRSA was studied after exposing bacteria to NIR with different light doses and concentrations of ICG. The selectivity on MRSA was examined on human fibroblasts. Bacterial virulence including the activities of coagulase and enterotoxin was investigated. The effects of singlet oxygen scavengers (tryptophan and ascorbic acid) and H2O2 on cell survival were evaluated. The morphology of bacteria after PDT was observed by transmission electron microscopy. Results ICG-PDT inhibited the growth of bacteria by 5 log (99.999% inhibition) with 200 J/cm2 at 65.5 mW/cm2 in the presence of 100 μg/mL ICG. Adding 0.1% H2O2 at a lower PDT dose (25 μg/mL ICG and 100 J/cm2) increased its efficacy by 5 log. This PDT dose was not toxic to human fibroblasts. PDT significantly reduced the level of bacterial virulence factors. The inhibition effects were decreased by tryptophan and ascorbic acid suggested singlet oxygen involved in the process. TEM showed severe non-selective cell destruction immediately after irradiation. Conclusion The study reveals ICG-PDT has the potential to treat MRSA by using a clinical accessible NIR lamp and photosensitizer.

Chlorin e6-mediated photodynamic therapy promotes collagen production and suppresses MMPs expression via modulating AP-1 signaling in P. acnes-stimulated HaCaT cells

BackgroundPhotodynamic therapy (PDT) is a clinically approved therapeutic for cancers and non-neoplastic diseases, based on the use of a photosensitizer activated by light. The feasibility of PDT depends on several factors, such as PDT dose, photosensitizer efficacy, type of light source, and target tissue irradiated. MethodsIn this study, the second generation photosensitizer chlorin e6 (Ce6) and halogen light were used to investigate their PDT effect on the collagen production and MMPs expression of heat killed P. acnes-stimulated HaCaT cells. The mRNA levels of COL1A1, c-Jun, and c-Fos were detected by RT-PCR. The protein levels of MMPs, ERK and JNK were detected by western blot. The transactivation of AP-1 was detected by luciferase assay. ResultsCe6-based PDT markedly upregulated the mRNA level of COL1A1 and type I procollagen level; and at the same time downregulated the expression of MMPs in P. acnes-infected HaCaT cells. Moreover, Ce6-mediated PDT, in a dose dependent manner, inhibited P. acnes-induced phosphorylation of JNK and ERK, as wells as the phosphorylation of their downstream targets c-Jun and c-Fos. P. acnes-induced mRNA expression of c-Jun and c-Fos were also suppressed by Ce6-mediated PDT. The transactivation of AP-1 induced by P. acnes infection was also downregulated. ConclusionThese results indicated that Ce6-mediated PDT with halogen light enhanced collagen production, but inhibited the expression of MMPs in P. acnes-infected HaCaT cells, by regulating AP-1 signals. This investigation provided the first molecular basis for the increase in collagen production by Ce6-mediated PDT, suggesting its potential use for scar amelioration and skin rejuvenation in acne treatment.

Validation and application of a model of oxygen consumption and diffusion during photodynamic therapy in vitro.

The photophysical parameters for the photosensitizer Pd(II) meso-Tetra(4-carboxyphenyl) porphine (PdT790) acquired in a previous study were incorporated into the PDT oxygen diffusion models for cell suspensions and cell monolayers. The time-dependent phosphorescence signals generated by the diffusion models are shown to match signals previously measured by M.A.W. and M.S.P. when reasonable physical and photophysical parameters are used. Simulations were performed to investigate the effects of metabolic and photodynamic oxygen consumption rates on the PDT dose in each of the treatment geometries. It was found that in cell suspensions of <1 million cells per mL, PDT should not be inhibited by hypoxia if the photodynamic consumption rate is <1 mm s(-1). For cell monolayers the optimal photodynamic oxygen consumption rate was found to depend on the metabolic rate of oxygen consumption. If cells remained well oxygenated in the absence of PDT, then maximum PDT dose was delivered with the lowest practical photodynamic oxygen consumption rate. Simulations of PDT treatments for multicell tumor spheroids showed that large anoxic cores develop within the spheroids and, as a consequence, less PDT dose is delivered in comparison with similar treatments in cell suspensions and cell monolayers.

Targeted in vivo photodynamic therapy with epidermal growth factor receptor-specific peptide linked nanoparticles

In targeted photodynamic therapy (tPDT), photosensitizers (PS) are targeted to disease tissue to reduce the dosage of PS and in addition to reduce the photo damage to the non-target tissue. We synthesized iron oxide nanoparticles (NP) armored with tumor targeting peptide and PS for targeted PDT. Chitosan covered Fe3O4 NPs (30nm) were deposited with gold NPs to generate two distinct chemical surfaces. To the gold particles PS was attached with a lipoic acid linker. Human epidermal growth factor receptor (hEGFR)-specific peptide was also attached to the same particles via a nickel-nitrilotriacetic acid linker attached to the chitosan. Using these nanoparticles, peptide specific uptake and PDT mediated cell death of the SK-OV-3 cells (Her2+ positive cells) were demonstrated by confocal microscopy, T2 imaging and viability assays. Peptide mediated preferential distribution of these NPs into tumor tissue was also shown in a xenograft tumor model. After one intravenous injection and one PDT dose, peptide bound NPs retarded tumor growth significantly compared to dark controls or treatments with NPs without peptide. The tumor retardation by targeted NPs was achieved at a PS concentration of 3.9nmol/animal, whereas similar effect was seen with free PS at 220nmol/animal. Therapeutic potential of these peptide containing NPs would be a useful in targeted PDT and in imaging the target tissue.

The effect of fluence rate on the acute response of vessel diameter and red blood cell velocity during topical 5-aminolevulinic acid photodynamic therapy

In a previous study it is shown that for topically applied ALA-PDT, PpIX concentration correlates with vascular changes including vasoconstriction and/or vascular leakage of small vessels and arterioles in the mouse epidermis and dermis. In this study we report on vascular responses induced by ALA-PDT for different fluence rates, including both changes in vessel diameter and dynamics in RBC velocity in arterioles, imaged using intra-vital confocal microscopy in skinfold chambers in hairless mice. Our interest is in the dynamics of vascular changes in the early stages of illumination. We have determined the total PDT dose to be relatively low, 13 J cm(-2), and fluence rates of 26, 65 and 130 mW cm(-2) were investigated. Local vascular effects occurred very soon after the start of the therapeutic illumination in ALA-PDT. In this study, we did not find a significant difference between fluence rates. Arterioles were particularly sensitive to vasoconstriction during low dose PDT, often resulting in complete vasoconstriction. When we observed complete vasoconstriction, this coincided with changes in RBC velocity. Since the therapeutic effects of PDT are dependent on a fine balance between the need for oxygen during illumination and disruption of the vasculature, the results of the present study add to our understanding of acute vascular effects during ALA-PDT and aid our efforts to optimize PDT using porphyrin pre-cursors.

PDT dose dosimetry for pleural photodynamic therapy.

PDT dose is the product of the photosensitizer concentration and the light fluence in target tissue. Although existing systems are capable of measuring the light fluence in vivo, the concurrent measurement of photosensitizer in the treated tissue so far has been lacking. We have developed and tested a new method to simultaneously acquire light dosimetry and photosensitizer fluorescence data via the same isotropic detector, employing treatment light as the excitation source. A dichroic beamsplitter is used to split light from the isotropic detector into two fibers, one for light dosimetry, the other, after the 665 nm treatment light is removed by a band-stop filter, to a spectrometer for fluorescence detection. The light fluence varies significantly during treatment because of the source movement. The fluorescence signal is normalized by the light fluence measured at treatment wavelength. We have shown that the absolute photosensitizer concentration can be obtained by an optical properties correction factor and linear spectral fitting. Tissue optical properties are determined using an absorption spectroscopy probe immediately before PDT at the same sites. This novel method allows accurate real-time determination of delivered PDT dose using existing isotropic detectors, and may lead to a considerable improvement of PDT treatment quality compared to the currently employed systems. Preliminary data in patient studies is presented.

Abstract 3464: Aminolevulinic acid-mediated photodynamic therapy induces cell death in human osteosarcoma cells

Abstract Photodynamic therapy (PDT) is a localized cancer treatment that requires a photosensitizer (PS), molecular oxygen, and light to induce cell death. Aminolevulinic acid (ALA)-mediated PDT utilizes ALA as an inert precursor to the required PS. Subsequent to cellular uptake ALA is converted to a PS, protoporphyrin IX (PpIX), in the mitochondria via the heme pathway. The excitation of PpIX by light can then result in the generation of reactive oxygen species, leading to direct tumor cell death, damage to the microvasculature, and induction of local inflammatory response. Interestingly, PDT can evoke apoptotic and/or necrotic cell death pathways within the same cell population. The balance between apoptosis and necrosis depends on several parameters, including the total PDT dose, the intracellular localization of the PS, the fluence rate, and the cell type. Recent studies show that the cell death mechanism induced has a direct influence on the systemic immune response. Therefore, a better understanding of the interplay between different cell death mechanisms in response to PDT could lead to improved tumor response and could inform better therapeutic strategies. We first determined the cytotoxicity of ALA to the human osteosarcoma cell line MG-63. PDT is a relatively unexplored method of treatment for human osteosarcoma, and could represent a superior method to existing therapies. Data from our lab show that ALA is not significantly cytotoxic to MG-63 cells, and that it is efficiently converted to PpIX within 24 hours of treatment. We also demonstrate that ALA-mediated PDT significantly induces cell death in MG-63 cells, and that cell death increases with increased ALA concentration and light fluence. Our findings indicate that this cell death results from a combination of both apoptosis and necrosis, with necrosis representing the major pathway. Finally, we show that increased light fluence decreases the amount of observed apoptosis subsequent to ALA-mediated PDT. These results taken together suggest that ALA-mediated PDT can induce cell death in human osteosarcoma cells, and that most cells are dying by necrosis. Furthermore, our data suggests that by adjusting specific therapeutic parameters, we can shift the balance between separate death pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3464. doi:1538-7445.AM2012-3464

Quantitative PDT dose reponses in vivo

Quantitative PDT dose reponses in vivo

In vivo monitoring of Foscan-mediated photodynamic therapy in clinical head and neck procedures using optical spectroscopy

Photodynamic therapy with m-THPC (Foscan) is as established treatment for superficial squamous cell carcinoma and is also being considered for treatment of larger head and neck tumors. Recently, clinical implementation of Foscan-mediated PDT in the head and neck has not been optimal; a subset of patients has experienced incomplete response. It is well-understood that sufficient quantities of light, drug and oxygen must be present in the targeted tissue in order to deliver sufficient damage. This requirement is complicated by variations in the tissue optical properties and in the photosensitizer uptake rates; however, most clinical protocols do not measure the affect of these factors on the PDT dose delivered to individual patients. This study represents a first step toward incorporating optical techniques developed to monitor PDT treatments in pre-clinical models into the clinical treatment of head and neck cancer. This clinical study incorporates reflectance and fluorescence spectroscopic measurements are into the PDT-treatment protocol. Spectral analysis allows the extraction of Foscan concentrations and the quantitative determination of tissue physiological parameters that are important to the PDT-delivered dose (e.g. blood volume and hemoglobin saturation). The study identifies the practical and technical challenges of translating these techniques into the clinical setting. Moreover, the data presented here contribute to understanding the link between these optical measurements and the PDT-dose delivered to individual patients during treatment.

A heterogeneous algorithm for PDT dose optimization for prostate.

The object of this study is to develop optimization procedures that account for both the optical heterogeneity as well as photosensitizer (PS) drug distribution of the patient prostate and thereby enable delivery of uniform photodynamic dose to that gland. We use the heterogeneous optical properties measured for a patient prostate to calculate a light fluence kernel (table). PS distribution is then multiplied with the light fluence kernel to form the PDT dose kernel. The Cimmino feasibility algorithm, which is fast, linear, and always converges reliably, is applied as a search tool to choose the weights of the light sources to optimize PDT dose. Maximum and minimum PDT dose limits chosen for sample points in the prostate constrain the solution for the source strengths of the cylindrical diffuser fibers (CDF). We tested the Cimmino optimization procedures using the light fluence kernel generated for heterogeneous optical properties, and compared the optimized treatment plans with those obtained using homogeneous optical properties. To study how different photosensitizer distributions in the prostate affect optimization, comparisons of light fluence rate and PDT dose distributions were made with three distributions of photosensitizer: uniform, linear spatial distribution, and the measured PS distribution. The study shows that optimization of individual light source positions and intensities are feasible for the heterogeneous prostate during PDT.

Integrated light dosimetry system for prostate photodynamic therapy.

A light dosimetry system is developed for prostate PDT, which integrates four main components: a light fluence rate calculation engine, an optimization tool for treatment planning, a light delivery system, and an in vivo light fluence rate measurement system. Three-dimensional light fluence rate distribution in a prostate is calculated using a kernel algorithm, which takes into account of heterogeneous optical properties. A Cimmino optimization algorithm is used to optimize the parameters of the cylindrical diffusing fibers (CDFs) to generate uniform PDT dose (or light fluence rate under uniform drug distribution) to cover the heterogeneous prostate. The light delivery system is composed of a 12-channel beamsplitter and the intensities of each channel (i.e., source) are controlled individually by programmable motorized attenuators. Our tests show that the light fluence rate calculation is fast and the accuracy is close to that of a finite-element method model, and the approach that uses the treatment CDFs to determine optical properties, improves the accuracy of light fluence rate prediction. The light delivery system allows real time control of the light source intensities for both PDT dosimetry and PDT light delivery. Integrating the fast light fluence rate calculation, optimization, instant source intensity adjustment, and in vivo light fluence rate measurement, the dosimetry system is suitable for prostate PDT.