Receptor-Targeted Photodynamic Therapy of Glucagon-Like Peptide 1 Receptor-Positive Lesions.
Treatment of hyperinsulinemic hypoglycemia is challenging. Surgical treatment of insulinomas and focal lesions in congenital hyperinsulinism is invasive and carries major risks of morbidity. Medication to treat nesidioblastosis and diffuse congenital hyperinsulinism has varying efficacy and causes significant side effects. Here, we describe a novel method for therapy of hyperinsulinemic hyperglycemia, highly selectively killing β-cells by receptor-targeted photodynamic therapy (rtPDT) with exendin-4-IRDye700DX, targeting the glucagon-like peptide 1 receptor (GLP-1R). Methods: A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. The efficacy and specificity of rtPDT with exendin-4-IRDye700DX were examined in vitro in cells with different levels of GLP-1R expression. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. Induction of cellular damage and the effect on tumor growth were analyzed to determine treatment efficacy. Results: Exendin-4-IRDye700DX has a high affinity for the GLP-1R, with a half-maximal inhibitory concentration of 6.3 nM. rtPDT caused significant specific phototoxicity in GLP-1R-positive cells (2.3% ± 0.8% and 2.7% ± 0.3% remaining cell viability in CHL-GLP-1R and INS-1 cells, respectively). The tracer accumulates dose-dependently in GLP-1R-positive tumors. In vivo, rtPDT induces cellular damage in tumors, shown by strong expression of cleaved caspase-3, and leads to a prolonged median survival of the mice (36.5 vs. 22.5 d, respectively; P < 0.05). Conclusion: These data show in vitro as well as in vivo evidence of the potency of rtPDT using exendin-4-IRDye700DX. This approach might in the future provide a new, minimally invasive, highly specific treatment method for hyperinsulinemic hypoglycemia.
['Boss|Marti|M|', 'Bos|Desiree|D|', 'Frielink|Cathelijne|C|', 'Sandker|Gerwin|G|', 'Bronkhorst|Patricia|P|', 'van Lith|Sanne A M|SAM|', 'Brom|Maarten|M|', 'Buitinga|Mijke|M|', 'Gotthardt|Martin|M|']
D000818:Animals D045744:Cell Line, Tumor D044903:Congenital Hyperinsulinism D006224:Cricetinae D003412:Cricetulus D000077270:Exenatide D005260:Female D000067757:Glucagon-Like Peptide-1 Receptor D006801:Humans D007211:Indoles D051379:Mice D008807:Mice, Inbred BALB C D046768:Nesidioblastosis D017646:Organosilicon Compounds D010778:Photochemotherapy D051381:Rats
photodynamic therapy hyperinsulinemic hypoglycemia glucagon-like peptide 1 receptor exendin