title: Tunable phosphatase-sensitive stable prodrugs of 5-aminolevulinic acid for tumor fluorescence photodetection.
abstract: 5-Aminolevulinic acid (5-ALA) has been at the forefront of small molecule based fluorescence-guided tumor resection and photodynamic therapy. 5-ALA and two of its esters received marketing authorization but suffer from several major limitations, namely low stability and poor pharmacokinetic profile. Here, we present a new class of 5-ALA derivatives aiming at the stabilization of 5-ALA by incorporating a phosphatase sensitive group, with or without self-cleavable linker. Compared to 5-ALA hexyl ester (5-ALA-Hex), these compounds display an excellent stability under acidic, basic and physiological conditions. The activation and conversion into the 5-ALA is controlled and can be structure-tailored. The prodrugs display reduced acute toxicity compared to 5-ALA-Hex with superior dose response profiles of protoporphyrin IX synthesis and fluorescence intensity in human glioblastoma cells in vitro. Clinically relevant fluorescence kinetics in vivo shown in U87MG glioblastoma spheroid tumor model in chick embryos provide a solid basis for their further development and translation to clinical fluorescence guided tumor resection and photodynamic therapy.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland. Electronic address: andrej.babic@unige.ch.
authors.forename: Andrej
authors.initials: A
authors.lastname: Babič
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland.
authors.forename: Viktorija
authors.initials: V
authors.lastname: Herceg
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland.
authors.forename: Imène
authors.initials: I
authors.lastname: Ateb
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Allémann
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland.
authors.forename: Norbert
authors.initials: N
authors.lastname: Lange
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000473:pathology; D005453:Fluorescence; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D010778:Photochemotherapy; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D011524:Protoporphyrins / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism
chemical_list: D011355:Prodrugs; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D000469:Alkaline Phosphatase
keywords: 5-Aminolevulinic acid; Alkaline phosphatase; Photodynamic therapy; Prodrugs; Tumor photodetection