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<b>Background:</b> To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). <b>Methods:</b> Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [¹¹¹In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [¹⁷⁷Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. <b>Results:</b> VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [¹⁷⁷Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [¹⁷⁷Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [¹⁷⁷Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. <b>Conclusions:</b> VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [¹⁷⁷Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [¹⁷⁷Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation.