Otimização da liberação cutânea do ácido 5-aminolevulínico para terapia fotodinâmica do câncer de pele: avaliação in vitro e in vivo da influência de promotores de absorção cutânea

Author(s)

Maria Bernadete Riemma Pierre

• Document type: Doctoral Thesis
• Press: São Paulo. , gráficos, ilustrações, tabelas.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2004-03-26

Examining board members

Maria Vitoria Lopes Badra Bentley; Maria Jose Vieira Fonseca; Erika Rosa Maria Kedor; Renata Fonseca Vianna Lopez; Vladi Olga Consigliere de Matta

• Advisor: Maria Vitoria Lopes Badra Bentley
• Field of knowledge: Health Sciences - Pharmacy
• Indexed in: Banco de Dados Bibliográficos da USP-DEDALUS
• Location: Universidade de São Paulo. Biblioteca do Conjunto das Químicas; CQ/T615.19015; P615o M17852-F

Abstract

In photodynamic therapy (PDT), 5-aminolevulinic acici (5-ALA) applied topically is converted, via the heme cycle, into protoporphyrin IX (PpIX), a photosensitizing agent, which upon excitation with light can induce tumor destruction. Due to its hydrophilic characteristics, 5-ALA has limited penetration into the skin. This study has proposed the 5-ALA-PDT optimization by mistures containing ceramide + 5-ALA (or its ester derivatives ALA n-hexyl and ALA n- octyl ester) or by using skin penetration enhancer, oleic acid (OA). The ceramide was not a good adjuvant for the proposed system, because there was a reduction as in the drugs permeation as in drugs retention through the skin, compared to the controls. For an appropriate skin cancer treatment, a higher skin retention is required, since the PDT efficiency depends on the PpIX concentration in the target tissue. The 5-ALA (1% w/w) in vitro skin permeation study was carried out in the presence of oleic acid (OA) in different concentrations (2.5%, 5.0% and 10.0% w/w) using porcine ear skin. The in vitro 5-ALA flux through the skin as well as its retention in the [epidermis+ dermis] after 12 hs were increased (~ 2.4 and 2 times) respectively, using 10.0% w/w OA compared to the control 5-ALA (1 % w/w) in PG solution. In vivo studies of 5-ALA-induced PpIX accumulation were carried out with 1.0% 5-ALA formulations at different concentrations of OA, using healthy mice skin. The amount of PpIX determined after 4h by chemical extraction from the tissue, was significantly increased with the formulations containing OA 5.0 % w/w (1.8 times) and 10.0% w/w (2.16 times) compared to the control. 5-ALA formulations containing 5.0% or 10.0% w/w OA were evaluated for the PpIX acumulation by non-invasive technique, using an optical fibre probe for the spectrofluorometric measurement, 4 hours after aplication. In this case, 5.0% and 10.0% w/w OA concentrations could increase the PpIX induced by 5-ALA, 3.5 and 5.6 times respectively, compared to the control. Then, the formulation 1.0% 5-ALA + 10.0% OA was submited to the PpIX kinetic study, showing increased fluorescence at the time interval 30 min to 8 hs after application, compared to the control. We can conclude that 10% w/w OA probably has facilitated the 5-ALA skin permeation, leading to a higher 5-ALA conversion to PpIX and then, a higher photosensitizer accumulation in a short time after formulation application, compared to the control. The in vitro and in vivo results showed the potentiality of formulations containing OA for optimizing the 5-ALA cutaneous delivery and in vivo PpIX accumulation in the skin. (AU)