Statin-dye conjugates for selective targeting of mutant cancer cells.

Over 90% of pancreatic ductal adenocarcinoma (PDAC) patients involve mutations ( ), for which current treatment options are limited. Statins, commonly used to lower cholesterol, have demonstrated certain selective toxicity towards -transformed cells, prompting the question of whether statins could achieve selective uptake specifically in cells. To investigate this, we synthesized statin-dye conjugates by attaching a fluorescent dye (Cy5.5) to two statins: simvastatin and pravastatin, aiming to assess whether selective uptake indeed occurs. Our findings revealed that these conjugates exhibited markedly enhanced uptake in cells compared to wild-type ( ) cells. Given the magnitude of the selective uptake, we realized that the uptake of these conjugates itself is of considerable intrinsic interests. We evaluated the uptake of these conjugates in both and cells and examined their potential to selectively target pancreatic cancer cells (PCCs) using an engineered PDAC tumor model co-cultured with PCCs and cancer-associated fibroblasts (CAFs). Our findings indicate that cancer cells exhibited higher uptake of statin-Cy5.5 conjugates enhanced macropinocytosis compared to cancer cells and CAFs. We also found enhanced uptake of the statin-Cy5.5 conjugate in MCF10A cells with deficiency, a condition known to elevate macropinocytosis, compared to control MCF10A cells with wild-type . Notably, in the PCC and CAF co-culture model, the pravastatin-Cy5.5 conjugate selectively killed PCCs without affecting the CAFs. These findings highlight the potential of stain-drug conjugates as targeted delivery vehicles for cancer therapy.