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Improved Peptide Prodrugs of 5-ALA for PDT: Rationalization of Cellular Accumulation and Protoporphyrin IX Production by Direct Determination of Cellular Prodrug Uptake and Prodrug Metabolization

Giuntini, F; Bourre, L; MacRobert, AJ; Wilson, M; Eggleston, IM; (2009) Improved Peptide Prodrugs of 5-ALA for PDT: Rationalization of Cellular Accumulation and Protoporphyrin IX Production by Direct Determination of Cellular Prodrug Uptake and Prodrug Metabolization. J MED CHEM , 52 (13) 4026 - 4037. 10.1021/jm900224r.

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Abstract

Twenty-seven dipeptide derivatives of general structure Ac-Xaa-ALA-OR were synthesized as potential prodrugs for 5-aminolaevulinic acid-based photodynamic therapy (ALA-PDT). Xaa is an (x-amino acid, chosen to provide a prodrug with appropriately tailored lipophilicity and water solubility. Although no simple correlation is observed between downstream production of protoporphyrin IX (PpIX) in PAM212 keratinocytes and HPLC-derived descriptors of compound lipophilicity, quantification of prodrug uptake reveals that most of the dipeptides are actually more efficiently accumulated than ALA in PAM212 and also A549 and Caco-2 cell lines. Subsequent ALA release is the limiting factor, which emphasizes the importance of decoupling prodrug uptake and intracellular metabolization when assessing the efficacy of ALA derivatives for PDT. In agreement with PpIX fluorescence studies, at,I concentration of 0.1 MM, L-Phe derivatives 4m and 4o, and L-Leu, L-Met, and L-Glu derivatives 4f, 4k, and 4u, exhibit significantly enhanced photoxicity in PAM212 cells compared to ALA.

Type:Article
Title:Improved Peptide Prodrugs of 5-ALA for PDT: Rationalization of Cellular Accumulation and Protoporphyrin IX Production by Direct Determination of Cellular Prodrug Uptake and Prodrug Metabolization
DOI:10.1021/jm900224r
Keywords:DELTA-AMINOLEVULINIC-ACID, GRADIENT RP HPLC, PHOTODYNAMIC THERAPY, 5-AMINOLEVULINIC ACID, ENDOGENOUS PROTOPORPHYRIN, ALA DERIVATIVES, DRUG-DELIVERY, IN-VITRO, ESTERS, SKIN
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute > Microbial Diseases
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Surgery and Interventional Science (Division of) > Research Department of General Surgery

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