A positive temperature coefficient is the term which has been used to indicate that an increase in solubility occurs as the temperature is raised, whereas a negative coefficient indicates a decrease in solubility with rise in temperature.

Effect of Temperature

Many reviews on PDT have been published. This field is now so large, and embraces so many subspecialities, from laser technology and optical penetration through diffusing media to a number of medical fields including dermatology, gastroenterology, ophthalmology, blood sterilization and treatment of microbial-viral diseases, that it is impossible to cover all aspects in a single review. Here, we will concentrate on a few basic aspects, all important for the route of development leading PDT to its present state: early work on hematoporphyrin and hematoporphyrin derivative, second and third generation photosensitizers, 5-aminolevulinic acid and its derivatives, oxygen and singlet oxygen, PDT effects on cell organelles, mutagenic potential, the basis for tumour selectivity, cell cooperativity, photochemical internalization, light penetration into tissue and the significance of oxygen depletion, photobleaching of photosensitizers, optimal light sources, effects on the immune system, and, finally, future trends.

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Milestones in the development of photodynamic therapy and fluorescence diagnosis

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: sensitizers, clinical studies and future directives.

Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) are techniques that combine the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug (possessing no dark toxicity) to cause destruction of selected cells. Despite its still widespread clinical use, Photofrin(®) has several drawbacks that limit its general clinical use. Consequently, there has been extensive research into the design of improved alternative photosensitizers aimed at overcoming these drawbacks. While there are many review articles on the subject of PDT and PACT, these have focused on the photosensitizers that have been used clinically, with little emphasis placed on how the chemical aspects of the molecule can affect their efficacy as PDT agents. Indeed, many of the PDT/PACT agents used clinically may not even be the most appropriate within a given class. As such, this review aims to provide a better understanding of the factors that have been investigated, while aiming at improving the efficacy of a molecule intended to be used as a photosensitizer. Recent publications, spanning the last 5 years, concerning the design, synthesis and clinical usage of photosensitizers for application in PDT and PACT are reviewed, including 5-aminolevulinic acid, porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and porphycenes. It has been shown that there are many important considerations when designing a potential PDT/PACT agent, including the influence of added groups on the lipophilicity of the molecule, the positioning and nature of these added groups within the molecule, the presence of a central metal ion and the number of charges that the molecule possesses. The extensive ongoing research within the field has led to the identification of a number of potential lead molecules for application in PDT/PACT. The development of the second-generation photosensitizers, possessing shorter periods of photosensitization, longer activation wavelengths and greater selectivity for diseased tissue provides hope for attaining the ideal photosensitizer that may help PDT and PACT move from laboratory investigation to clinical practice.

Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments

Summary
Background 5-aminolaevulinic acid (ALA) is used as a protoporphyrin IX-precursor for the photodynamic therapy of superficial skin cancer and cutaneous metastases of internal malignancies. However, the permeability of hydrophilic ALA across the skin is very low.

Objectives and methods  The objective of this study was to optimize and enhance the in vitro skin permeation of ALA by two resurfacing techniques: erbium:yttrium-aluminium-garnet (Erb:YAG) laser and microdermabrasion. Light microscopic changes in pig skin caused by these techniques were also compared. The electrically assisted methods, iontophoresis and electroporation, were also used to facilitate ALA permeation across laser- or microdermabrasion-treated skin.

Results  Among the modalities tested in this study the Erb:YAG laser showed the greatest enhancement of ALA permeation. The laser fluence was found to play an important role in controlling the drug flux, producing enhancement ratios from 4-fold to 246-fold relative to the control. The skin permeation of ALA across microdermabrasion-treated skin was approximately 5–15-fold higher than that across intact skin. Both the ablated effect of the stratum corneum (SC) and ALA flux were proportional to the treatment duration of microdermabrasion. The application of iontophoresis or electroporation alone also increased the ALA permeation by approximately 15-fold and 2-fold, respectively. The incorporation of iontophoresis or electroporation with the resurfacing techniques caused a profound synergistic effect on ALA permeation.

Conclusions  This basic study has encouraged the further investigation of ALA permeation by laser or microdermabrasion.

Enhancement of topical 5-aminolaevulinic acid delivery by erbium:YAG laser and microdermabrasion: a comparison with iontophoresis and electroporation

5-Aminolevulinic acid (ALA) is being assessed for photodynamic therapy of cancer and other diseases worldwide. However, its stability properties in solution are not well understood yet. The breakdown of ALA in pH-buffered solutions was examined in this work. Solutions of ALA in PBS buffered to physiological pH were found to be unstable, leading to a breakdown product that absorbs photons around 278 nm. The ability of the solution to stimulate porphyrin production in cells is gradually lost upon breakdown, though the kinetics for this are different from those for formation of the UV absorbing product. It is likely, therefore, that several chemical pathways contribute to the breakdown of dissolved ALA at physiological pH. Temperature studies of the formation kinetics of the UV absorbing product also indicate that a complex formation process is involved.

The stability of 5-aminolevulinic acid in solution.

The formation of protoporphyrin IX (PpIX) in human skin during topical application of 5-aminolevulinic acid (ALA) was found to be strongly temperature dependent, with an activation energy of about 17 kcal/mol. This temperature dependence is mainly related to porphyrin production and not to ALA penetration into the skin. The penetration of ALA into mouse and human skin was almost temperature independent. The activation energy of PpIX production in mouse skin was practically identical with that in human skin. The activation energy of ALA uptake by cells in vitro was about 10 kcal/mol and that for PpIX production was about 13 kcal/mol. The latter activation energy was within the error limits similar to that for the activity of the enzyme porphobilinogen deaminase, suggesting that this enzyme might represent a rate-limiting step for PpIX production in living tissue.

Øystein Bech Gadmar

Papers

The stability of 5-aminolevulinic acid in solution.

The Temperature Dependence of Protoporphyrin IX Production in Cells and Tissues