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.
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 alpha-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 a 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.
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giuntini
authors.forename: Ludovic
authors.initials: L
authors.lastname: Bourré
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: MacRobert
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.forename: Ian M
authors.initials: IM
authors.lastname: Eggleston
mesh_terms: D000622:Aminolevulinic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011524:Protoporphyrins / Q000096:biosynthesis*; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D017319:Photosensitizing Agents; D011355:Prodrugs; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX