title: The use of dipeptide derivatives of 5-aminolaevulinic acid promotes their entry to tumor cells and improves tumor selectivity of photodynamic therapy.
abstract: 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 methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), 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 tumor 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 Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor 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 using particularly Ac-Phe-ALA-Me 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.
authors.affiliation: Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Di Venosa
authors.affiliation: Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Vallecorsa
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giuntini
authors.affiliation: Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Leandro
authors.initials: L
authors.lastname: Mamone
authors.affiliation: Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Alcira
authors.initials: A
authors.lastname: Batlle
authors.affiliation: Instituto de Estudios Oncologicos, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vanzuli
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Juarranz
authors.affiliation: Division of Surgery and Interventional Sciences and UCL Institute of Biomedical Engineering, University College London, London, United Kingdom. a.macrobert@ucl.ac.uk.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: MacRobert
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Eggleston
authors.affiliation: Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Adriana
authors.initials: A
authors.lastname: Casas
mesh_terms: D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D008297:Male; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010778:Photochemotherapy; D011166:Porphyrins / Q000096:biosynthesis; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004151:Dipeptides; D011166:Porphyrins; D000622:Aminolevulinic Acid; D018631:ras Proteins