Abstract
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.
Highlights
Insulin production by pancreatic b-cells is usually a well-regulated process
Uncontrolled overproduction of insulin can arise, in most cases as a result of insulin-producing lesions. Such lesions cause major clinical symptoms, and treatment can be challenging. These lesions manifest in endogenous adult hyperinsulinemic hypoglycemia, most often caused by an insulinoma, which is an insulin-producing neuroendocrine tumor arising from pancreatic b-cells [1]
In 0.5%–5% of cases, adult hyperinsulinemic hypoglycemia is caused by nesidioblastosis, characterized by proliferation of abnormal b-cells throughout the pancreas [2]
Summary
Insulin production by pancreatic b-cells is usually a well-regulated process. uncontrolled overproduction of insulin can arise, in most cases as a result of insulin-producing lesions. The only surgical treatment option for patients with nesidioblastosis and diffuse CHI not responding to medication is partial pancreatectomy Even after such an invasive procedure, hypoglycemic episodes often persist, requiring continued treatment with medication and, in certain cases of CHI, total pancreatectomy [2,4]. Because of these challenges, a novel, preferably minimally invasive treatment option for hyperinsulinemic hypoglycemia in adults, as well as in children, is warranted. We have developed an approach for rtPDT of insulin-producing lesions using the peptide exendin-4 coupled to the photosensitizer IRDye700DX (LI-COR Biosciences) We hypothesize that this novel method will allow specific cell killing of GLP-1R–positive cells
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