INVESTIGADORES
CASAS Adriana Gabriela
artículos
Título:
The use of dipeptide derivatives of 5-aminolaevulinic acid promotes their entry to tumour cells and improves tumour selectivity of photodynamic therapy
Autor/es:
DI VENOSA G; VALLECORSA P.; GIUNTINI F.; MAMONE L; BATLLE A; VANZULLI S; JUARRANZ A; MACROBERT A; EGGLESTON I.; CASAS, A.
Revista:
MOLECULAR CANCER THERAPEUTICS
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Lugar: Philadelphia; Año: 2015 vol. 14 p. 440 - 451
ISSN:
1535-7163
Resumen:
The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in Photodynamic Therapy (PDT). However the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA (AcLeuALAMe) and phenylalanyl-ALA (AcPheALAMe), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumour model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50 to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from AcPheALAMe appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase (APEH). In vivo studies revealed that topical application of the peptide prodrug AcPheALAMe gave greater selectivity than with ALA itself, and induced tumour photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of employing particularly AcPheALAMe both for topical treatment of basal cell carcinomas, and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic.