Light Dosimetry For Photodynamic Therapy Research Articles

Optimizing the Pharmacological and Optical Dosimetry for Photodynamic Therapy with Methylene Blue and Nanoliposomal Benzoporphyrin on Pancreatic Cancer Spheroids

Photodynamic therapy (PDT) is a cancer treatment that relies on the remote-controlled activation of photocatalytic dyes (photosensitizers) in cancer tissues. To effectively treat cancer, a variety of pharmacological and optical parameters require optimization, which are dependent on the photosensitizer type. As most photosensitizers are hydrophobic molecules, nanoliposomes are frequently used to increase the biocompatibility of these therapeutics. However, as nanoliposomes can influence the therapeutic performance of photosensitizers, the most suitable treatment parameters need to be elucidated. Here, we evaluate the efficacy of PDT on spheroid cultures of PANC-1 and MIA PaCa-2 pancreatic cancer cells. Two strategies to photosensitize the pancreatic microtumors were selected, based on either nanoliposomal benzoporphyrin derivative (BPD), or non-liposomal methylene blue (MB). Using a comprehensive image-based assay, our findings show that the PDT efficacy manifests in distinct manners for each photosensitizer. Moreover, the efficacy of each photosensitizer is differentially influenced by the photosensitizer dose, the light dose (radiant exposure or fluence in J/cm2), and the dose rate (fluence rate in mW/cm2). Taken together, our findings illustrate that the most suitable light dosimetry for PDT strongly depends on the selected photosensitization strategy. The PDT dose parameters should therefore always be carefully optimized for different models of cancer.

A New Optical Method for Online Monitoring of the Light Dose and Dose Profile in Photodynamic Therapy.

Photodynamic therapy (PDT) has gained widespread popularity in the last decades because of its distinctive advantages over the other commonly used cancer treatments. PDT dosimetry is a crucial factor in achieving a good optimization of PDT treatment planning. PDT dosimetry is a complex task since light dose as well as photosensitizer and oxygen concentrations in tissue need to be measured (ideally continuously) to be able to fully characterize the biological response. Light dose in PDT is routinely measured by the optical fibers that provide dose data at a limited number of discrete points and are not able to capture spatial dose profiles. The objective of this study is to propose and develop a new optical method for online monitoring of the dose profile data for PDT. Using the digital holography technique, first, the general sketch of an experimental setup for PDT light dosimetry is provided. The theory behind the proposed method for using the experimental setup in PDT light dosimetry is fully described, and its limits of validity are determined. In a proof of principle study, the ability of the method for online monitoring of the absorbed light dose profile in PDT is evaluated by a simple experimental setup. The experimental results confirm the usefulness of the proposed method in providing continuous online dose profiles. The absorbed light dose profiles from an infrared light source in a quartz cell containing water are measured and shown. The depth-dose curves are extracted and it is shown that how these dosimetric data can be used for assisting the physicians in determining the appropriate spatiotemporal characteristics for treating the infected tissues and solid tumors with the required light dose amounts. A conversion relation is also derived for transforming the measured light dose with the proposed method to the most frequently used dose values by PDT practitioners, in terms of light power per square area. There is no restriction in using the method with other commonly used light sources in PDT, like light-emitting diodes and filtered lamps, with different wavelengths in visible or infrared regions of the spectrum. More complex experimental setups can be used in future studies to study the role of accumulated photosensitizers in malignant tissues. The proposed method in this study can also be used for light dose monitoring in other biomedical applications, where light is used for treating special diseases, and patients must receive sufficient amounts of light dose. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Reconstruction of hemodynamics and sensitizer distributions during interstitial PDT using spectroscopy with linear light sources.

Light dosimetry for photodynamic therapy requires a knowledge of the optical absorption spectrum of the tissue being treated Here, we present a theoretical and experimental analysis of the capabilities of a system using interstitial linear light sources ranging in length from 2 to 5 cm to illuminate the tissue interstitially, and isotropic point-like detectors to measure the resulting diffusely transmitted light. The sources and detectors are translated in transparent plastic catheters under the control of a motorized positioning system designed for interstitial measurements in the prostate. The light source is a quartz-tungsten-halogen (QTH), and the spectrally resolved detection is accomplished using a CCD-based grating spectrometer. The data are analyzed using an approximation to the radiative transport equation, assuming homogeneous scattering and heterogeneous absorption spectra Absorption spectra are reconstructed independently for individual source-detector channel pairs. Sequential reconstruction can then be used to create a 3-dimensional reconstruction. The results of simulated data, measurements made in multi-component phantoms, and synthetic data reconstructed from in vivo measurements made with point sources demonstrate the feasibility of this method.

Optimization of light dosimetry for photodynamic therapy of Barrett's esophagus: efficacy vs. incidence of stricture after treatment

Photodynamic therapy (PDT) may be used to ablate high-grade dysplasia/early stage cancer (HGD/T1) in patients with Barrett's esophagus. PDT may result in esophageal stricture. This nonrandomized, unblinded, dose de-escalation study in consecutive patients was designed to determine the lowest light dose effective for ablation of HGD/T1 while reducing the incidence of stricture. A total of 113 patients received an injection of porfimer sodium (2 mg/kg). Three days later, 630 nm light was delivered by using a 20-mm-diameter PDT balloon at doses of 115 J/cm (n=59), 105 J/cm (n=18), 95 J/cm (n=17), or 85 J/cm (n=19). Treatment efficacy was determined by obtaining biopsy specimens of the treated area 3 months later. The incidence of stricture was determined by the need for esophageal dilation to treat dysphagia. A stricture was considered severe if 6 or more dilations were required. The incidence of severe stricture was related to the light dose. At 115 J/cm, 15.3% of patients developed severe strictures compared with 5.3% to 5.6% of those treated with the lower doses. At a light dose of 115 J/cm, 17.0% of patients had residual HGD/T1. Light doses of 105 J/cm, 95 J/cm, and 85 J/cm resulted in residual HGD/T1 in 33.3%, 29.4%, and 31.6% of patients, respectively. None of the observations were statistically significant. Decreasing the light dose below 115 J/cm appeared to result in a reduced incidence rate of severe stricture but higher relative frequencies of residual HGD/T1 in Barrett's esophagus.

STUDIES OF TIN ETHYL ETIOPURPURIN PHOTODYNAMIC THERAPY OF THE CANINE PROSTATE

Previous studies have demonstrated the technical feasibility of destroying prostate tissue using photodynamic therapy for benign and malignant disease. A series of canine studies was performed to evaluate the systemic uptake and distribution of the photosensitizer tin ethyl etiopurpurin (SnET2) in the prostate and surrounding tissues, and determine the optimal combination of drug dose, light dose and time interval between drug and light administration using transurethral and transperineal interstitial light delivery. Adult male mongrel source dogs received intravenous bolus injections of 0.5 or 1.0 mg./kg. SnET2 in 4 studies. In the first study the concentration of SnET2 in the prostate and surrounding tissue was measured at various time points after dosing. In the second study a tissue dose response relationship of SnET2-PDT was studied after transperineal interstitial light application. The third and fourth studies evaluated the tissue effects of combined transurethral and transperineal interstitial light application on SnET2 sensitized prostates. Substantial amounts of SnET2 were measured in the prostate between 24 and 168 hours after infusion. Drug and light dose dependent prostatic tissue necrosis and volume reduction were documented in the dose response relationship study. The combination of transurethral and transperineal light resulted in the extensive destruction of glandular epithelium with minimal damage to surrounding structures. Average prostate volume decreased 52%. Transperineal interstitial light delivery with multiple diffusers resulted in substantial glandular destruction of the prostate. An average volume reduction of more than 60% was achieved. SnET2-PDT is a viable minimally invasive treatment modality for prostate tissue destruction.

The importance of In situ light dosimetry for photodynamic therapy of oral cavity tumors

The importance of In situ light dosimetry for photodynamic therapy of oral cavity tumors

The importance of in situ light dosimetry for photodynamic therapy of oral cavity tumors.

Photodynamic therapy (PDT) is being evaluated for treatment of localized head and neck cancer. "Light dose" is usually prescribed as incident fluence, which takes no account of reflected and scattered light. This study investigates variations in total tissue fluence for a given incident fluence in the oral cavity. Light dosimetry was performed in 19 patients treated with PDT for cancers in the oral cavity and in 5 volunteers. Illumination was with 652 nm laser light delivered via a microlens. In situ dosimetry was performed with isotropic probes held against the tissue in the illuminated area. Tissue fluences of 254% to 305% of the incident fluence were measured in the illuminated area in healthy volunteers. In the patient population tissue fluences were 133% to 545% of the incident fluence. The relationship between incident and total tissue fluence depended on the location and pigmentation of the target area and was not predictable. In situ dosimetry during cavity illumination allows for more controlled tissue illumination and should be employed as the basis for light dose prescription in PDT for head and neck cancer.

Radiance modelling using the P3 approximation

Light dosimetry is an essential component of effective photodynamic therapy (PDT) of tumours. Present PDT light dosimetry techniques rely on fluence-based models and measurements. However, in a previous paper by Barajas et al, radiance-based light dosimetry was explored as an alternative approach. Although successful in demonstrating the use of Monte Carlo (MC) simulations of radiance in tissue optical characterization, the MC proved time consuming and impractical for clinical applications. It was proposed that an analytical solution to the transport equation for radiance would be desirable as this would facilitate and increase the speed of tissue characterization. It has been found that the P3 approximation is one such potential solution. Radiance and fluence expressions based on the P3 approximation were used to optically characterize an Intralipid-based tissue phantom of varying concentration of scatterer (Intralipid) and absorber (methylene blue) using a plane wave illuminated, semi-infinite medium geometry. The results obtained compare favourably with the Grosjean approximation of fluence (a modified diffusion theory) using the same optical parameters . The results illustrate that radiance-based light dosimetry is a viable alternative approach to tissue characterization and dosimetry. It is potentially useful for clinical applications because of the limited number of invasive measurements needed and the speed at which the tissue can be characterized.

Skin Necrosis due to Photodynamic Action of Benzoporphyrin Depends on Circulating Rather than Tissue Drug Levels: Implications for Control of Photodynamic Therapy

In an ideal world, photodynamic therapy (PDT) of abnormal tissue would reliably spare the surrounding normal tissue. Normal tissue responses set the limits for light and drug dosimetry. The threshold fluence for necrosis (TFN) was measured in normal skin following intravenous infusion with a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA) Verteporin as a function of drug dose (0.25-2.0 mg/kg), wavelength of irradiation (458 and 690 nm) and time interval (0-5 h) between drug administration and irradiation. The BPD-MA levels were measured in plasma and skin tissue to elucidate the relationship between TFN, drug kinetics and biodistribution. The PDT response of normal skin was highly reproducible. The TFN for 458 and 690 nm wavelengths was nearly identical and the estimated quantum efficiency for skin response was equal at these two wavelengths. Skin phototoxicity, quantified in terms of 1/TFN, closely correlated with the plasma pharmacokinetics rather than the tissue pharmacokinetics and was quadratically dependent on the plasma drug concentration regardless of the administered drug dose or time interval between drug and light exposure. This study strongly suggests that noninvasive measurements of the circulating drug level at the time of light treatment will be important for setting optimal light dosimetry for PDT with liposomal BPD-MA, a vascular photosensitizer.

First experience with FoscanR mediated photodynamic therapy for head and neck tumours

Introduction. The authors aimed to determine the efficacy and the importance of in situ light dosimetry in photodynamic therapy (PDT) with the second generation photosensitizer Foscan® as a new treatment modality for head and neck tumours. Material and methods. From April to August 1997 11 patients with 13 tumours were treated with PDT in the Netherlands Cancer Institute. The incident light dose was 20 J/cm2 (healthy mucosa shielded) at 4 days after 0.15 mg/kg Foscan® (i.v.). Light dosimetry was performed. Results. There were eight complete responses, one recurrence, five partial responses (tumours larger than 4 cm and in a heavily pigmented tumour), after follow-up of 6–18 months. In all cases the total tissue light dose (including scattered and reflected light) was higher than the incident light dose (110–450%). Conclusion. Foscan®-mediated PDT offers effective alternative to standard treatment modalities in head and neck cancer. In situ light dosimetry is necessary for standardisation of this treatment.

Pharmacokinetics of Tetra (m-hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

Pharmacokinetics of Tetra (m-hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

Pharmacokinetics of Tetra (m‐hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

The pharmacokinetics of the photosensitizer 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC) was investigated in the plasma of 20 patients by absorption and fluorescence spectroscopy. The temporal behavior was characterized by a rapid decrease in concentration during the first minutes after intravenous injection of 0.15 mg/kg mTHPC. A minimum concentration in the plasma was reached after about 45 min. The drug concentration then increased again, attaining a maximum after about 10 h, after which it decreased again with a halflife of about 30 h. Irradiation tests in the oral cavity at different time intervals after the injection revealed that the tissue reaction was only partially correlated with the mTHPC plasma level. The tissue response was stronger at later drug-light intervals (1-4 days) than during the first hours after injection even though the mTHPC plasma concentration was higher at the shorter times. Relative mTHPC concentrations were also measured in the mucosae of the oral cavity, the esophagus and the bronchi of 27 patients by light-induced fluorescence spectroscopy using an optical fiber-based spectrometer. These measurements were performed prior to photodynamic therapy (PDT), 4 days after injection of the photosensitizer. Highly significant linear correlations were found between the relative mTHPC concentrations in the mucosae of these three organs. Likewise, the plasma levels of mTHPC measured just before PDT were significantly correlated with the mTHPC concentrations in the three types of mucosae mentioned above. These results indicate that mTHPC plasma levels measured just before PDT can be used for PDT light dosimetry.

Pharmacokinetics of Tetra(m-hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

Pharmacokinetics of Tetra(m-hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

Skin Necrosis due to Photodynamic Action of Benzoporphyrin Depends on Circulating Rather than Tissue Drug Levels: Implications for Control of Photodynamic Therapy

In an ideal world, photodynamic therapy (PDT) of abnormal tissue would reliably spare the surrounding normal tissue. Normal tissue responses set the limits for light and drug dosimetry. The threshold fluence for necrosis (TFN) was measured in normal skin following intravenous infusion with a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA) Verteporfin as a function of drug dose (0.25-2.0 mg/kg), wavelength of irradiation (458 and 690 nm) and time interval (0–5h) between drug administration and irradiation. The BPD-MA levels were measured in plasma and skin tissue to elucidate the relationship between TFN, drug kinetics and biodistribution. The PDT response of normal skin was highly reproducible. The TFN for 458 and 690 nm wavelengths was nearly identical and the estimated quantum efficiency for skin response was equal at these two wavelengths. Skin phototoxicity, quantified in terms of 1/ TFN, closely correlated with the plasma pharmacokinetics rather than the tissue pharmacokinetics and was quadratically dependent on the plasma drug concentration regardless of the administered drug dose or time interval between drug and light exposure. This study strongly suggests that noninvasive measurements of the circulating drug level at the time of light treatment will be important for setting optimal light dosimetry for PDT with liposomal BPD-MA, a vascular photosensitizer.

Temporal and illumination-induced variations in the in vivo light transmission spectra of four photosensitizers in EMT6/Ed murine tumours.

Temporal and illumination-induced variations in the in vivo light transmission spectrum of the photosensitizer will influence light dosimetry for photodynamic therapy (PDT). The present authors have studied the in vivo spectra of four photosensitizers in the EMT6/Ed murine tumour model in Balb/c mice. The following photosensitizers were used: bis(dimethylthexylsiloxy)silicon 2,3-naphthalocyanine (SiNc 8), benzoporphyrin-derivative monoacid ring A (BPD Verteporfin), Photofrin and ethanolamined hypocrellin B (HBEA-R2). Spectra were measured non-invasively in the EMT6/Ed murine tumour model in the spectral range 600-840 nm, using a diode laser, a dye laser and a Ti:sapphire laser. Red-shift and broadening of the SiNc 8 absorption band was observed at 790 nm, and a slight red-shift was observed in the BPD, HBEA-R2 and Photofrin in vivo absorption spectrum. Exposure to 300 J of light at the peak absorption wavelength caused complete photobleaching of BPD at 690 nm, and a reduced absorption by SiNc 8 at 780 nm, Photofrin at 626 nm, and HBEA-R2 at 656 nm.

Monte Carlo modelling of angular radiance in tissue phantoms and human prostate: PDT light dosimetry

Photodynamic therapy (PDT) is a promising technique for destroying tumours. Photosensitizing drugs presently available are not sufficiently tumour specific; hence, light dosimetry is required in order to control light exposure and thereby restrict cell kill to the target tissue to avoid damage to healthy tissue. Current light dosimetry methods rely on tissue optical characterization by fluence measurements at several points. Fluence-based tissue characterization is impractical for tumours in organs such as prostate where access by optical probes is limited and the tumours are highly optically inhomogeneous. This paper explores the potential of radiance-based light dosimetry as an alternative. Correlation is found between Monte Carlo simulation of radiance in a tissue phantom and radiance measurements made using a new radiance probe. Radiance is sensitive to variations in the tissue optical parameters, absorption coefficient , scattering coefficient , and anisotropy factor g, and therefore is potentially useful for tissue characterization. Radiance measurements have several advantages over fluence measurements. Radiance measurements provide more information from a single location, better spatial resolution of the tissue optical parameters, and higher sensitivity in discriminating between different media. However, the Monte Carlo method is too slow to be of practical value for tissue characterization by correlation of measured and simulated radiance. An analytical solution to the transport equation for radiance would be desirable as this would facilitate and increase the speed of tissue characterization.

Changes in in vivo optical properties and light distributions in normal canine prostate during photodynamic therapy.

The optical absorption and transport scattering coefficients of normal prostate tissue have been measured in vivo in dogs. The measurements were made at 630 nm before and during treatment by Photofin photodynamic therapy using interstitial optical fiber fluence-rate detectors. Corresponding measurements were made ex vivo, at 1 week after treatment, in the contralateral lobe. The optical properties were derived by applying a diffusion theory model to the fluence rates measured at two different source-detector fiber distances. While the in vivo pretreatment and in vivo contralateral post-treatment absorption and scattering values are self-consistent and in agreement with published data, significant changes were observed in the light fluence rates, and hence in the derived optical properties, during light irradiation. The possible causes of such changes are considered, and the implications for light dosimetry in photodynamic therapy are discussed.

Light dosimetry for photodynamic therapy in the esophagus.

Photodynamic therapy (PDT) is an efficient technique to treat superficial early cancers in the pharynx, esophagus, and tracheo-bronchial tree. However, the lack of selectivity of some of the clinically used photosensitizers can result in significant damage to the healthy tissue during the treatment. In the esophagus, this may lead to medical complications such as stenosis and fistula. Insufficient selectivity may be compensated to some extent by accurate light dosimetry. Here, we present an approach to safer and more efficient PDT by improved light dosimetry in the esophagus. This includes the utilization of a suitable light distributor, the estimation of the radiant energy density in the tissue, and the knowledge of the esophagus morphology. The light distributor presently used in the clinic is described and several techniques to study light propagation in the esophageal wall have been investigated and are discussed. Thickness of different histological layers of the esophageal wall have been measured ex vivo and are presented. Under these conditions and based on a simple model of the light distribution in the tissue, some basic and clinically useful notions of light dosimetry can be drawn. These notions, associated with measured value of tissue optical properties at the wavelengths of interest with the presently used photosensitizers, are discussed regarding the particular morphology of the esophageal wall. In particular, the importance of the illumination wavelength from the safety point of view is shown. The proposed approach allows for improved safety and efficacy of PDT in the esophagus, particularly in the clinical tests of new photosensitizers.

Optimizing light dosimetry in photodynamic therapy of the bronchi by fluorescence spectroscopy

Under identical conditions (drug and light dose, timing), the results of photodynamic therapy (PDT) of carcinomas of the bronchi with tetra(meta-hydroxyphenyl)chlorin (mTHPC) show large variations between patients. Before patients underwent PDT treatment, the mTHPC level was measured in the lesion, the normal surrounding tissue and the oral cavity, with an apparatus based on fluorescence spectroscopy. The fluctuations in degree of tissue reaction and tumour destruction between patients could be explained by individual variations in the mTHPC level in the mucosa of the bronchi. The patients who showed the highest mTHPC fluorescence signal also had the strongest response to PDT. In addition, a correlation between the mTHPC level in the oral cavity and bronchial mucosa was found. It is concluded that PDT can be improved by measuring the mTHPC level in the bronchi or the oral cavity before treatment by fluorescence spectroscopy, and then by adjusting the light dose to be applied to the observed mTHPC level.

Optimizing light dosimetry in photodynamic therapy of early stage carcinomas of the esophagus using fluorescence spectroscopy.

Under standardized conditions (drug and light dose, timing), the result of the photodynamic therapy (PDT) of carcinomas of the esophagus with tetra(meta-hydroxyphenyl)chlorin (mTHPC) shows large variations between patients. Before patients underwent PDT treatment, the mTHPC level was measured in the lesion, the normal surrounding tissue, and the oral cavity, with an apparatus based on fluorescence spectroscopy. The fluctuations in degree of tumor destruction between patients can be explained by individual variations in the mTHPC level in the mucosa of the esophagus. The patients showing the highest mTHPC fluorescence signal had also the highest response to PDT. Also, a correlation between the mTHPC level in the oral cavity and esophagus mucosa has been found. PDT can be improved by measuring the mTHPC level in the esophagus or the oral cavity before treatment by fluorescence spectroscopy, and then by adjusting the light dose to be applied to the observed mTHPC level.