Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5‐aminolevulinic acid (ALA) dendrimers

Abstract

E 11 5 5What ' 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, specifi city is relatively low and the intensity of the observed fl uorescence signal decreases over time due to protoporphyrin IX (PpIX) effl ux.This study evaluates in an in vivo model the use of a dendritic 5-aminolevulinic acid compound for fl uorescence diagnosis. Fluorescence ratios between tumour and urothelium as well as muscle were signifi cantly better as compared with h-ALA. Sustained synthesis of PpIX accounts for preservation of fl uorescence for > 24 h. OBJECTIVE• To overcome the relative lack of tumour selectivity of fl uorescence-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. MATERIALS AND METHODS• Rat bladders were instilled with h-ALA or ALA dendrimers and fl uorescence ratio between tumour and normal urothelium, as well as tumour and muscle and depth of fl uorescence were determined with Image J software.• Quantifi cation 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 fl uorescence for > 24 h.• There were signifi cantly better fl uorescence ratios with dendrimers, as well as higher penetration depths and absence of systemic reabsorption. CONCLUSION• 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 fl uorescence-guided cystoscopy.

Immobilization of ALA‐ZnII Coordination Polymer Pro‐photosensitizers on Magnetite Colloidal Supraparticles for Target Photodynamic Therapy of Bladder Cancer

“…Photodynamic therapy (PDT), which involves systemic or topical administration and illumination of a nontoxic and tumor‐targeting photosensitizer using low‐intensity visible light, is a comparatively noninvasive therapy, in sharp contrast to surgery, radiotherapy, and chemotherapy. Since the second‐generation photosensitizers have been developed, use of 5‐aminolaevulinic acid (ALA) that is a naturally occurring delta amino acid has been becoming the most active in the PDT clinical research over decades . Exogenous ALA could selectively accumulate in tumorous tissues and is converted to the photosensitizer PpIX and then heme with the catalysis of ferrochelatase enzyme.…”

Chemical approaches for the enhancement of 5-aminolevulinic acid-based photodynamic therapy and photodiagnosis

“…This demonstrates that the release of the ALA unit from 39 was essentially complete and the total porphyrin production is comparablean essential feature to be achieved for the design of an effective polyvalent ALA prodrug derivative. Based on these promising features, François et al 45 evaluated 39 for fluorescence diagnosis of bladder cancer, wherein a sustained release of PpIX was observed even after 24 h post-administration of the prodrug intravesically. A significantly lower dose of the prodrug was required to produce the same effect in comparison to free ALA (0.7 vs. 180 mM) and ALA hexyl ester 1f (0.7 vs. 8 mM).…”

Peptide-targeted dendrimeric prodrugs of 5-aminolevulinic acid: A novel approach towards enhanced accumulation of protoporphyrin IX for photodynamic therapy

“…micropinocytosis) [41], rather than being driven by enhanced lipophilicity or active transport mechanisms [26]. Although such systems lack a specific cell-targeting motif, they have been shown to provide both an enhanced and sustained production of PpIX compared to equivalent doses of free ALA. ALA dendrimers have been shown to be effective for both in vitro [41][42][43][44] and in vivo PDT applications [45] as well as in PDD of tumours [46].…”