Photodynamic Therapy Of Skin Cancer Research Articles

Optical coherence tomography-guided photodynamic therapy for skin cancer: Case study

Photodynamic therapy (PDT) has been identified as a successful therapy for skin cancer. This case study investigates the role of optical coherence tomography (OCT) in lesion (squamous cell carcinoma) mapping, assisting the surgeon to correctly deliver PDT and monitor the outcome. Optical coherence tomographic images were acquired pre-treatment to assess tumour extent and margins to enable guidance of the PDT. Tomographic images taken post-PDT up to 6 months revealed complete response to the treatment and no recurrence. OCT-guided PDT is one of the promising approaches to efficiently discriminate between tumor involved and noninvolved margins. It reduces the untoward healthy tissue necrosis and provides an encouraging monitoring of the healing process.

Photodynamic Therapy in the Dermatological Field and Enhanced Cutaneous Absorption of Photosensitizer

The combination of light and chemicals to treat skin diseases is widely practiced in the fleld of dermatology, and has led to the concept of photodynamic therapy in recent years. In PDT for skin cancer, 5-aminolevulinic acid is applied topically to the afiected area to be absorbed percutaneously through passive difiusion, and typically requires 4{6h before performing PDT. In this study, we attempted to reduce the absorption period in PDT by ionizing ALA using direct current pulsed iontophoresis and Bowen's disease. In all subjects, protoporphyrin IX production was conflrmed after iontophoresis, and its production levels were comparable to the conventional occlusive dressing technique. Skin biopsies from the treated lesion showed the disappearance of tumour cells. 1. INTRODUCTION In recent years, the application of optical technology to clinical medicine has been thriving. Many apparati applying optical technology have been developed and are widely used in clinical settings; e.g., lasers have produced revolutionary results in surgery, most cases of chemical tests on specimens have been conducted using optical techniques, and automated assays have been developed, resulting in tremendous advances in patient diagnostics and medical examinations. Furthermore, a non- invasive treatment method has been recently developed, in which certain drugs given to the body are activated by light to exert their efiects, and the therapeutic efiects of this modality have drawn close attention. The modality is referred to as photodynamic therapy, and is based on the combined use of photosensitizers and photoradiation. That method administers a photosensitizer with a-nity for the tumor cells, followed by light irradiation which results in the selective disruption of only the tumor cells in the body. Since photodynamic therapy (PDT) is less invasive than surgical therapy, it can be used in patients with serious complications and also in elderly patients, and it is being increasingly applied in many clinical flelds, especially dermatology (1). In the fleld of dermatology, it is widely recognized that PDT, in which an excitation light is applied to externally applied 5-aminolevulinic acid (5-ALA), a porphyrin precursor, is efiective for the treatment of superflcial malignant tumors of the skin. However, since the percutaneous absorption of photosensitizers is extremely low, treatment using these substances requires a long time, making it di-cult to establish this method as a standard treatment modality and to apply it on an outpatient basis. In this study, PDT was optimized by introducing the photosensitizer into the skin within a short time by iontophoresis, which involves the application of a microelectric current to the skin to increase the percutaneous absorption of ionic drugs. The results of this study conflrm that iontophoresis indeed enhances the percutaneous absorption of the photosensitizer within a short time, which dramatically reduces the time required for treatment. The flndings of this study are reported herein. Since 5-ALA has an extremely low percutaneous absorbency, there are several methods to improve its absorption such as liposomal 5-ALA, and iontophoresis may dramatically enhance its absorption (2{4).

Photodynamic therapy: Dermatology and ophthalmology as main fields of current applications in clinic

Photodynamic therapy (PDT) of skin tumors or pre-cancerous lesions and of age-related macular degeneration combines the administration of porphyrins or porphyrin precursors and illumination with red light at the diseased sites. Photosensitizers absorbing light beyond 630 nm where tissues have the highest transmittance produce singlet oxygen, a highly reactive activated oxygen species and a major cytotoxin. The PDT of age-related macular degeneration is performed with red laser light after i.v. injection of verteporfin (Visudyne) a hydrophobic porphyrin carried by serum lipoproteins whose endocytosis leads to accumulation of the porphyrin in endothelial cells of choroidal neo-vessels. In the PDT of skin cancers, local synthesis of the photosensitizer occurs after topical application of the natural protoporphyrin IX precursor delta-aminolevulinic acid (or its ester forms) on the lesions. In all the cases, the photosensitizers should be rapidly excreted to avoid a long lasting skin photosensitivity.

Systemic Component of Protoporphyrin IX Production in Nude Mouse Skin upon Topical Application of Aminolevulinic Acid Depends on the Application Conditions¶

Topical application of 5-aminolevulinic acid (ALA) for protoporphyrin IX (PpIX)–based photodynamic therapy of skin cancer is generally considered not to induce systemic side effects because PpIX is supposed to be formed locally. However, earlier studies with topically applied ALA have revealed that in mice PpIX is not only produced in the application area but also in other organs including skin outside the application area, whereas esterified ALA does not. From these results, it was concluded that it is not redistribution of circulating PpIX that causes the fluorescence distant from the ALA application site, but rather, local PpIX production induced by circulating ALA. In the present study we investigate the effects of the ALA concentration in the cream, the application time, the presence of a penetration enhancer, the presence of the stratum corneum and esterification of ALA on the PpIX production in nude mouse skin outside the area where ALA is applied. For this purpose, ALA and ALA hexyl ester (ALAHE) were applied to one flank, and the PpIX fluorescence was measured in the contralateral flank. During a 24 h application of ALA, PpIX was produced in the contralateral flank. No PpIX could be detected in the contralateral flank after ALA application times ranging from 1 to 60 min. Tape-stripping the skin prior to short-term ALA application, but not the addition of a penetration enhancer, resulted in PpIX production in the contralateral flank. When ALAHE was applied, no PpIX fluorescence was measured in the contralateral flank under any application condition. The results suggest that the systemic component of PpIX production outside the ALA application area plays a minor or no role in relevant clinical situations, when the duration of ALA (ester) application is relatively short and a penetration enhancer is possibly added.

Revitalized Strategies Against Multi-Resistant Bacteria: Antimicrobial Photodynamic Therapy and Bacteriophage Therapy

The formation and spread of infections by multi-resistant bacteria is favoured by the absence of hygienic measures to prevent the spread in hospital settings as well as the frequent use of antibiotics. Overall, approximately 20% of Staphylococcus aureus isolates in Europe are reported as methicillin resistant and cause serious nosocomial infections. Therefore, the worldwide rise in antibiotic resistance in clinical practise has led to the search for alternative methods of selectively destroying pathogens without harming the host tissue. One “new” approach to treat microbial infections uses light in combination with a photosensitizer to induce a phototoxic reaction by reactive oxygen species similar as in photodynamic therapy of skin cancer. In particular, different classes of molecules including porphyrins, phthalocyanines, phenothiazine and fullerenes have demonstrated antimicrobial efficacy against a broad spectrum of multi-resistant bacteria upon irradiation with visible light. Another “new” approach is called bacteriophage therapy, which involves using phages or their products as bioactive agents for the prophylaxis and/or treatment of bacterial infectious diseases. Phages were used topically, orally or systemically and have demonstrated efficacy against Gram (-) bacteria, whereas purified phageencoded agents are also effective against Gram (+) bacteria. Keywords: Antibacterial, phototoxicity, photosensitizer, phages, bacteriophage-conjugated photosensitizer

Light Dosimetry at Tissue Surfaces for Oblique Incident Circular Fields.

Oblique incident light fields are sometimes unavoidable for photodynamic therapy of skin cancers, e.g., for large fields on uneven surface. We have performed Monte-Carlo simulation for circular fields (R = 0.25, 0.35, 0.5, 1, 2, 3, and 8 cm) for reduced scattering coefficient μs' = 10 cm-1 and attenuation coefficient μa = 0.1 - 1.0 cm-1. We used anisotropy g = 0.9 and the index of refraction n = 1.4 for all Monte-Carlo simulations. Compared to a broad beam of normal incidence, the peak fluence rate along the central-axis for a slanted beam is increased for otherwise the same geometrical conditions and optical properties. The effective attenuation coefficient is slightly decreased for a slanted beam compared to a normal incident beam. The beam profile for a slanted beam at a fixed depth is no longer symmetrical but is higher towards the lateral side of beam incidence. Since the broad beam with finite radius R can be considered as a convolution of a pencil beam, solution for a slanted pencil beam can be used to determine the light fluence distribution for circular beams with oblique beam incidence. An analytical solution can be obtained for the pencil beam obliquely incident on a semi-infinite medium. The solution can be approximated using the diffusion or P3 theory with one point source or two point sources located at appropriate depths with appropriate weights along the beam pathlength inside the phantom, with corresponding image sources to fulfill the extended boundary condition. The analytical solution agrees well with Monte-Carlo Simulation at depths z > 2cosθ t /μ' t , θt is the incident angle after refraction at the interface. Measurements using an isotropic detector were made in a liquid phantom composed of intralipid and ink to verify the Monte-Carlo simulation results.

Photodynamic therapy of skin cancer: controlled drug delivery of 5-ALA and its esters

Photodynamic therapy (PDT) is a tool for the treatment of certain cancerous and pre-cancerous conditions in dermatology. 5-Aminolevulinic acid (5-ALA) and simple derivatives thereof are the principal compounds used for this purpose. For optimal efficacy, the drug must be released at an appropriate rate from the formulation and penetrate the skin, ideally to reach the target tissue at a sufficiently high concentration. Because ALA is a polar, zwitterionic compound, its formulation in conventional topical vehicles, and its inherently poor skin permeability, poses important challenges for the pharmaceutical scientist. The synthesis of more lipophilic (e.g. ester) prodrugs of ALA resolves, in part, these issues but then demands that questions, related to biotransformation back to the parent 5-ALA and to stability, be addressed. The objective of this review, therefore, is to evaluate the state-of-the-art and identify those areas in which additional research is necessary.

Pain caused by photodynamic therapy of skin cancer.

Pain resulting from photodynamic therapy (PDT) of skin cancer was investigated. The study included 69 lesions (60 patients) with different types of skin tumours or precursors. Protoporphyrin IX, which is produced by the topical application of delta-aminolevulinic acid, was used as a photosensitizing agent. Twenty-three of the lesions (19 patients) were examined with a fluorescence imaging system which demarcates the tumour area from the healthy skin and visualizes the contrast between the fluorescence from healthy skin and that from the tumour. EMLA is used on all patients as part of our routine PDT protocol but despite this the major side-effect of PDT is pain during treatment. There is a large variation in pain intensity experienced by the patients, as measured by a visual analogue scale (VAS). Patients with actinic keratoses experienced more pain than those with Bowen's disease or basal cell carcinoma. The mean VAS score was higher when treating lesions located on the head than when treating lesions on the torso or the extremities. Also, treatment of large skin areas resulted in more pain than treatment of small areas, and men experienced more pain than women. The pain experienced by the patients did not correlate with treatment dose, Fitzpatrick skin type, age or fluorescence intensity.

Systemic component of protoporphyrin IX production in nude mouse skin upon topical application of aminolevulinic acid depends on the application conditions.

Topical application of 5-aminolevulinic acid (ALA) for protoporphyrin IX (PpIX)-based photodynamic therapy of skin cancer is generally considered not to induce systemic side effects because PpIX is supposed to be formed locally. However, earlier studies with topically applied ALA have revealed that in mice PpIX is not only produced in the application area but also in other organs including skin outside the application area, whereas esterified ALA does not. From these results, it was concluded that it is not redistribution of circulating PpIX that causes the fluorescence distant from the ALA application site, but rather, local PpIX production induced by circulating ALA. In the present study we investigate the effects of the ALA concentration in the cream, the application time, the presence of a penetration enhancer, the presence of the stratum corneum and esterification of ALA on the PpIX production in nude mouse skin outside the area where ALA is applied. For this purpose, ALA and ALA hexyl ester (ALAHE) were applied to one flank, and the PpIX fluorescence was measured in the contralateral flank. During a 24 h application of ALA, PpIX was produced in the contralateral flank. No PpIX could be detected in the contralateral flank after ALA application times ranging from 1 to 60 min. Tape-stripping the skin prior to short-term ALA application, but not the addition of a penetration enhancer, resulted in PpIX production in the contralateral flank. When ALAHE was applied, no PpIX fluorescence was measured in the contralateral flank under any application condition. The results suggest that the systemic component of PpIX production outside the ALA application area plays a minor or no role in relevant clinical situations, when the duration of ALA (ester) application is relatively short and a penetration enhancer is possibly added.

Stratum corneum lipids liposomes for the topical delivery of 5-aminolevulinic acid in photodynamic therapy of skin cancer: preparation and in vitro permeation study.

BackgroundPhotodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is a skin cancer therapy that still has limitations due to the low penetration of this drug into the skin. We have proposed in this work a delivery system for 5-ALA based on liposomes having lipid composition similar to the mammalian stratum corneum (SCLLs) in order to optimize its skin delivery in Photodynamic Therapy (PDT) of skin cancers.MethodsSCLLs were obtained by reverse phase evaporation technique and size distribution of the vesicles was determinated by photon correlation spectroscopy. In vitro permeation profile was characterized using hairless mouse skin mounted in modified Franz diffusion cell.ResultsSize exclusion chromatography on gel filtration confirmed vesicle formation. SCLLs obtained by presented a degree of encapsulation of 5-ALA around 5.7%. A distribution of vesicle size centering at around 500 nm and 400 nm respectively for SCLLs and SCLLs containing 5-ALA was found. In vitro 5-ALA permeation study showed that SCLLs preparations presented higher skin retention significantly (p < 0.05) on the epidermis without SC + dermis, with a decreasing of skin permeation compared to aqueous solution.ConclusionsThe in vitro delivery performance provided by SCLLs lead to consider this systems adequate for the 5-ALA-PDT of skin cancer, since SCLLs have delivered 5-ALA to the target skin layers (viable epidermis + dermis) to be treated by topical PDT of skin cancer.

A vehicle for photodynamic therapy of skin cancer: influence of dimethylsulphoxide on 5-aminolevulinic acid in vitro cutaneous permeation and in vivo protoporphyrin IX accumulation determined by confocal microscopy

Topical application of 5-aminolevulinic acid (5-ALA) followed by light irradiation is a new concept of photodynamic therapy (PDT) of skin cancers. 5-ALA is a prodrug that can be converted by the heme biosynthetic pathway into protoporphyrin IX, an effective photosensitizer. In the present work we propose the enhancement of 5-ALA-induced protoporphyrin IX accumulation by dimethylsulphoxide (DMSO) and ethylenediamine–tetraacetic acid disodium salt (EDTA). The presence of 20% DMSO (w/w) in oil-in-water emulsions increased the in vitro permeation of 5-ALA through hairless mouse skin. In vivo studies demonstrated a significant increase in the amount of protoporphyrin IX extracted from healthy hairless mouse skin after 3 h treatment with an oil-in-water emulsion containing 10% 5-ALA (w/w), 3% EDTA (w/w) and 20% DMSO (w/w). By confocal scanning laser microscopy imaging, an observed increase in red fluorescence, at 476 nm excitation and emission detected longer than 590 nm, in skin that had received this treatment, was attributed to protoporphyrin IX accumulation. Although no effect of EDTA on short-term protoporphyrin IX accumulation in skin was detected, this chelator could protect 5-ALA from decomposition during prolonged topical administration. The results obtained indicate that association of 5-ALA, EDTA and 20% DMSO may enhance the delivery of 5-ALA to the skin in the topical PDT.

Photodynamic therapy of skin cancers: sensitizers, clinical studies and future directives.

Photodynamic therapy (PDT) is a new modality of skin cancer treatment. It involves the administration of photosensitizing drugs which, when localized in tumor tissue can produce its destruction by absorbing an adequate dose of light of an appropriate wavelength. A large number of photosensitizing agents have been tested in PDT experiments. Topical application of 5-aminolevulinic acid (5-ALA) followed by light irradiation is the most commonly used method. 5-ALA is a prodrug converted in situ via the heme cycle into protoporphyrin IX, an effective photosensitizer agent. Treatment of nonmelanoma skin cancers by PDT has met with varying degrees of success. In the case of 5-ALA, this therapy's main limitation is the poor penetration of 5-ALA into skin, due to hydrophilic and charge characteristics. However, the efficacy of 5-ALA-PDT may be improved by (a) development of adequate drug delivery systems; (b) use of enhancers of PpIX production and accumulation in target tissue, and (c) modifications of the 5-ALA molecule. Optimal timing, light sources, doses, and number of applications are also important factors for topical 5-ALA therapy and must be well defined. The aim of this review is to highlight recent progress in 5-ALA-PDT of skin cancer, and to present ways holding promise for its improvement.

Photodynamic therapy of skin cancers

Photodynamic therapy of skin cancers

30 In vivo fluourescence spectroscopy monitoring of BPD virteporfin concentration changes in skin tissue in ring photodynamic therapy of skin cancer

30 In vivo fluourescence spectroscopy monitoring of BPD virteporfin concentration changes in skin tissue in ring photodynamic therapy of skin cancer

Photodynamic therapy of skin cancer in C3H mice by ruby laser with phthalocyanine

Photodynamic therapy of skin cancer in C3H mice by ruby laser with phthalocyanine