Current Advances in 5-Aminolevulinic Acid Mediated Photodynamic Therapy

Abstract

Kennedy and Pottier discovered that photodynamic therapy (PDT) could be carried out using a procedure consisting of topical application of the porphyrin-precursor, 5-aminolevulinic acid (ALA) to the skin, followed after some time by illumination with various light parameters in the 1980s. Since then, ALA-PDT has expanded enormously and now covers most aspects of dermatological disease. The purpose of this review is to discuss a range of ingenious strategies that investigators have devised for improving the overall outcome (higher efficiency and lower side effects) of ALA-PDT. The big advance of using ALA esters instead of the free acid to improve skin penetration was conceived in the 1990s. A variety of more recent innovative approaches can be divided into three broad groups: (a) those relying on improving delivery or penetration of ALA into the skin; (b) those relying on ways to increase the synthesis of protoporphyrin IX inside the skin; (c) those relying on modification of the illumination parameters. In the first group, we have improved delivery of ALA with penetration-enhancing chemicals, iontophoresis, intracutaneous injection, or fractionated laser. There is also a large group of nanotechnology-related approaches with ALA being delivered using liposomes/ethosomes, ALA dendrimers, niosomes, mesoporous silica nanoparticles, conjugated gold nanoparticles, polymer nanoparticles, fullerene nanoparticles, and carbon nanotubes. In the second group, we can find the use of cellular differentiating agents, the use of iron chelators, and the effect of increasing the temperature. In the third group, we find methods designed to reduce pain as well as improve efficiency including fractionated light, daylight PDT, and wearable light sources for ambulatory PDT. This active area of research is expected to continue to provide a range of intriguing possibilities.

Keywords: 5-Aminolevulinic acid; Heme biosynthesis; Nanotechnology; Photodynamic therapy; Protoporphyrin IX; Skin penetration.

Fig. 1

Heme biosynthetic cycle in eukaryotic cells. Exogenously administered ALA bypasses the feedback control mechanism whereby heme inhibits ALA synthase which is designed to prevent excess accumulation of PPIX in normal cells. Consequently, excess free PPIX accumulates in the cells since ferrochelatase is now rate limiting. ALA-S 5-aminolevulinic acid synthase, ALA-D 5-aminolevulinic acid dehydratase, PBG-D porphobilinogen deaminase, UCS uroporphyrinogen co-synthase, UGD uroporphyrinogen decarboxylase, CPO coproporphyrinogen oxidase, PPO protoporphyrinogen oxidase, FCH ferrochelatase

Fig. 2

Methods of increasing ALA penetration into the skin. Fractional laser, iontophoresis, penetration enhancers, and intracutaneous injection are all methods/techniques to either improve the permeability of the skin or increase the penetration ability of ALA. Fractional laser irradiates the skin to remove skin layers in microscopic holes so ALA can reach deeper structures underneath. Iontophoresis is a technique to push compounds into the body through the skin by applying a local electric current and creating a repulsion force. Penetration enhancers work in combination with ALA (usually as an emulsion of other substances) to increase the ability of ALA to move transdermally across the lipophilic stratum corneum. Intracutaneous injection is the simple approach to inject ALA into the skin

Fig. 3

Methods of biochemically enhancing PPIX accumulation by modulating enzymes in heme biosynthesis cycle. Iron chelators can enhance PPIX accumulation by depriving the enzyme ferrochelatase of the ferrous iron it needs to form heme. Differentiation agents (vitamin D, retinoids, methotrexate, calcium, or androgens) can increase expression of coproporphyrinogen oxidase producing more PPIX

Fig. 4

Methods of improving ALA-PDT by manipulating the light delivery parameters. Fractionated light delivery applies 20 % of the calculated red light dose after 4 h of ALA, incubation followed after 2 h by the remaining 80 % of the light dose. Daylight PDT involves exposing the patient to daylight for several hours as soon as the ALA has been applied. Wearable light sources allow a very low irradiance of red light to be applied for a longer time to reduce pain and make the treatment more patient friendly. iPDT uses an initial low dose of blue light exposure followed by red light to reduce the pain of treatment