title: Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5-aminolevulinic acid (ALA) dendrimers.
abstract: What's known on the subject? and What does the study add? Fluorescence cystoscopy with hexylaminolevulinate (h-ALA, Hexvix®) is known to improve tumour detection in non-muscle-invasive bladder cancer. However, specificity is relatively low and the intensity of the observed fluorescence signal decreases over time due to protoporphyrin IX (PpIX) efflux. This study evaluates in an in vivo model the use of a dendritic 5-aminolevulinic acid compound for fluorescence diagnosis. Fluorescence ratios between tumour and urothelium as well as muscle were significantly better as compared with h-ALA. Sustained synthesis of PpIX accounts for preservation of fluorescence for >24 h.
  
  
  OBJECTIVE
  • To overcome the relative lack of tumour selectivity of fluorescence-guided cystoscopy using 5-aminolevulinic acid (ALA) or its ester derivative (e.g. hexylaminolevulinate, h-ALA; Hexvix®), we evaluated the use of dendrimers bearing different ALA loads in rats bearing orthotopic bladder tumours.
  
  
  METHODS
  • Rat bladders were instilled with h-ALA or ALA dendrimers and fluorescence ratio between tumour and normal urothelium, as well as tumour and muscle and depth of fluorescence were determined with Image J software. • Quantification of ALA and/or esters systemic reabsorption was evaluated by high-performance liquid chromatography.
  
  
  RESULTS
  • Slow hydrolysis of ALA from dendrimers as observed in vitro implies a higher initial ALA load and longer resting times in vivo. Sustained synthesis of protoporphyrin IX (PpIX) explains persistence of fluorescence for >24 h. • There were significantly better fluorescence ratios with dendrimers, as well as higher penetration depths and absence of systemic reabsorption.
  
  
  CONCLUSIONS
  • The prolonged and sustained PpIX synthesis, the improved tumour selectivity with a deeper penetration and the absence of systemic reabsorption are primary indicators that ALA dendrimers could be an alternative to h-ALA in fluorescence-guided cystoscopy.
authors.affiliation: Centre Alexis Vautrin, 6 Avenue de Bourgogne, CS 30519 54519 Vandoeuvre Lès Nancy, Université De Lorraine, Vandoeuvre-les-Nancy Cedex 54506 CNRS, UMR 7039, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: François
authors.forename: Sinan
authors.initials: S
authors.lastname: Battah
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: MacRobert
authors.forename: Lina
authors.initials: L
authors.lastname: Bezdetnaya
authors.forename: François
authors.initials: F
authors.lastname: Guillemin
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: D'Hallewin
mesh_terms: D000283:Administration, Intravesical; D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D050091:Dendrimers / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D008856:Microscopy, Fluorescence / Q000379:methods*; D009374:Neoplasms, Experimental; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000378:metabolism
chemical_list: D050091:Dendrimers; D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid; C419924:5-aminolevulinic acid hexyl ester