Antitumor Activity of Alexidine Dihydrochloride Nanocarriers in Renal Cell Carcinoma.

Renal cell carcinomas (RCC) have recently been shown to exhibit a high abundance of phosphatidylglycerols, which are products of the protein-tyrosine phosphatase mitochondrial 1 enzyme (PTPMT1) and precursors of cardiolipins. Effective treatments for RCC are still in need. This study evaluates the therapeutic effect of PTPMT1 inhibition using the poorly water-soluble inhibitor alexidine dihydrochloride, which has not previously been proposed for RCC treatment. Considering that this inhibitor is poorly water-soluble and has inconsistent antitumor activity in its pure form due to solubility limits, we incorporated it in nanocarriers composed of phosphatidylcholine and cholesterol. These solvent-free nanocarriers had an average size of 66 nm, a drug loading capacity of 21%, an encapsulation efficiency of 99%, a positive surface charge, and excellent storage stability. We assessed their safety and efficacy in two human RCC cell lines, 786O and A498, alongside the human non-neoplastic kidney cell line HEK293 as a control. Results revealed a marked antitumor activity of the nanocarriers and selectivity toward highly metabolically active RCC cells. Thus, after only 24 h of treatment, a significant decrease in the viability of 786O cells was recorded, while A498 and control cells exhibited only minimal reductions in viability. Advanced mass spectrometry imaging (DESI-MSI) revealed that untreated 786O cells had significantly higher levels of phosphatidylglycerols, cardiolipins, and 4-hydroxynonenal glutathione compared to A498 and HEK293. Treatment with nanocarriers markedly impacted the levels of these metabolites in RCC cells. In conclusion, RCC tumors with upregulated phosphatidylglycerol metabolism may be particularly sensitive to PTPMT1 inhibition by nanocarriers.