title: Alkoxyamines: toward a new family of theranostic agents against cancer.
abstract: Theranostics combines therapeutic and diagnostic or drug deposition monitoring abilities of suitable molecules. Here we describe the first steps of building an alkoxyamine-based theranostic agent against cancer. The labile alkoxyamine ALK-1 (t(1/2) = 50 min at 37 °C) cleaves spontaneously to generate (1) a highly reactive free alkyl radical used as therapeutic agents to induce cell damages leading to cell death and (2) a stable nitroxide used as contrast agent for Overhauser-enhanced magnetic resonance imaging (OMRI). The ALK-1 toxicity was studied extensively in vitro on the glioblastoma cell line U87-MG. Cell viability appeared to be dependent on ALK-1 concentration and on the time of the observation following alkoxyamine treatment. For instance, the LC50 at 72 h was 250 μM. Data showed that cell toxicity was specifically due to the in situ released alkyl radical. This radical induced oxidative stress, mitochondrial changes, and ultimately the U87 cell apoptosis. The nitroxide production, during the alkoxyamine homolysis, was monitored by OMRI, showing a progressive MRI signal enhancement to 6-fold concomitant to the ALK-1 homolysis. In conclusion, we have demonstrated for the first time that the alkoxyamines are promising molecules to build theranostic tools against solid tumors.
authors.affiliation: CRMSB, CNRS-UMR-5536, Université Victor Segalen Bordeaux 2 , 146 rue Léo Saignat, Case 93, 33076 Bordeaux Cedex, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Moncelet
authors.forename: Pierre
authors.initials: P
authors.lastname: Voisin
authors.forename: Neha
authors.initials: N
authors.lastname: Koonjoo
authors.forename: Véronique
authors.initials: V
authors.lastname: Bouchaud
authors.forename: Philippe
authors.initials: P
authors.lastname: Massot
authors.forename: Elodie
authors.initials: E
authors.lastname: Parzy
authors.forename: Gérard
authors.initials: G
authors.lastname: Audran
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Franconi
authors.forename: Eric
authors.initials: E
authors.lastname: Thiaudière
authors.forename: Sylvain R A
authors.initials: SR
authors.lastname: Marque
authors.forename: Paul
authors.initials: P
authors.lastname: Brémond
authors.forename: Philippe
authors.initials: P
authors.lastname: Mellet
mesh_terms: D000438:Alcohols / Q000737:chemistry* / Q000494:pharmacology*; D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000438:Alcohols; D000588:Amines; D000970:Antineoplastic Agents; C059688:alkoxyl radical