Skin Laser Treatments Enhancing Transdermal Delivery of ALA

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ABSTRACT

Drug delivery across skin has been limited due to barrier properties of the skin, especially those of the stratum corneum (SC). Use of the laser radiation has been suggested for the controlled removal of the SC. The purpose of this study was to study in vitro the influence of infrared radiation from the erbium:yttrium–aluminum–garnet (Er:YAG) laser (λ = 2940 nm), and visible from the 2nd harmonic of a neodymium:yttrium–aluminum–garnet (Nd:YAG) laser (λ = 532 nm) on transdermal delivery of 5-aminolevulinic acid (ALA). Pinna skin of the inner side of rabbit ear was used for skin permeation. The light sources were an Er:YAG laser (Key III Plus KaVo) and a Q-switched Nd:YAG laser (Lotis TII SL-2132). Permeation study, morphological and structural skin examination by histology and differential scanning calorimetry (DSC) were carried out. Permeation profiles and histological observations obtained after irradiation with infrared and visible laser radiation differed due to different biophysical effects on irradiated skin. Wavelength of 2940 nm required lower energy contribution to produce the same level of permeation than visible radiation at 532 nm. Structural analysis by DSC shows a selective impact on the lipidic structure. Laser pretreatment enhanced the delivery of ALA trough the skin by SC ablation.

Section snippets

INTRODUCTION

Photodynamic therapy (PDT) involves a combination of a photosensitizer, light, and oxygen to cause destruction of selected cells, mainly through generation of highly cytotoxic singlet oxygen.1 Common photosensitizers, such as porphyrins, cannot be administered by topical application to neoplastic skin lesions, because their high molecular weights preclude successful penetration of the stratum corneum (SC). When administered intravenously, these agents accumulate in normal skin and lead to

Chemicals

ALA (5-aminolevulinic acid, hydrochloride salt) was obtained from Sigma–Aldrich, Madrid, Spain. Trypsin (trypsin from bovine pancreas 13,000 U/mg) was obtained from Sigma–Aldrich. All other chemicals were of analytical reagent grade.

Skin Samples

Pinna skin of the inner side of rabbit ear (New Zealand rabbits of 2.9–3.1 kg from Granja Conicular San Bernardo, Navarra, Spain) was used for skin permeation studies. The animals were sacrificed and the ears were removed. Pinna skin was peeled away from the

RESULTS

In order to assess the effect of the radiation from both Er:YAG laser and second harmonic of Nd:YAG laser on the integrity of the skin structure, pinna skin of the inner side of rabbit ear was irradiated, with laser fluences in the range of 1–1.6 J/cm2 at 2940 nm and 6.6–7 J/cm2 at 532 nm. Higher repetition rates were needed at 532 nm (15 Hz) than at 2940 nm (1–2 Hz) in order to achieve an increase in the drug permeability.

The cumulative amount of ALA (mg/cm2) in the receptor compartment as a function

DISCUSSION

The increased porphyrin accumulation in tumors as compared to normal skin associated with topical ALA occurs because ALA, being a water-soluble molecule, penetrates normal SC poorly. Neoplastic skin lesions are thought to possess a compromised SC barrier that allows enhanced ALA penetration. Maximum tumor-to-normal tissue ratios are observed 3–6 h after topical administration and can be as high as 18:1.18 However, prolonged application times cause widespread skin fluorescence and ALA and PpIX

CONCLUSIONS

In this study we show that the laser treatment was capable of delivering sufficient ALA through the skin by SC ablation. Er:YAG and second harmonic of Nd:YAG laser radiations can modulate skin histology and transdermal drug delivery, although the particular characteristics of the laser radiation–skin interaction depend on the their own parameters of actuation, mainly wavelength and pulse duration. SC laser removal requires the appropriate selection of fluences and repetition rates in order to

ACKNOWLEDGEMENTS

The work described in the present study was supported by Intramural Project 200880I215 of the Spanish CSIC. In addition the authors wish to thank Dr. Roberto Sastre and Dr. Olga García for their assistance in Differential Scanning Calorimetry.

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