纳米制剂实现氯硝柳胺（niclosamide）在胰腺癌治疗中的老药新用：用于增强生物利用度的快速溶解口服制剂

Pancreatic ductal adenocarcinoma (PDAC) is relatively uncommon yet remains one of the most lethal cancers worldwide. Its asymptomatic nature leads to delayed diagnosis, and by the time PDAC is detected, it has often progressed to an advanced, metastatic stage. Consequently, there is a critical need to identify new therapeutic strategies that can improve patient survival. Drug repurposing has emerged as a promising approach for rapidly expanding treatment options in PDAC. Our in-vitro screening suggested niclosamide (NIC) as a promising repurposed drug candidate for the treatment of PDAC. Various PDAC cell lines including gemcitabine resistant mia paca2 cells were susceptible to NIC induced apoptosis. Prior studies from various researchers also revealed role of NIC in killing cancer cells while compromising the tumor stromal barriers. However, its extremely poor water solubility often resulted in <10% oral bioavailability, which is not sufficient for anticancer activity. Poor lipid and organic solvent solubility limit the choices of nanoformulation approaches for NIC. We have explored a hydrophobic ion pairing approach with ionizable lipid for the development of self-nanoemulsifying drug delivery system (SNEDDS). Complexation between negatively charged NIC and lipophilic cation resulted in improved drug loading in SNEDDS while preventing the precipitation of drug in aqueous media. Different batches of NIC-SNEDDS were prepared using oleyl amine and ionizable lipid DLin-DMA. The particle size and zeta potential of the DLin-DMA based blank formulation were 18.35±0.99 nm and +18±0.69 mV, respectively, whereas the oleyl amine based blank formulation exhibited a particle size of 23.97±0.89 nm and a zeta potential of +32±0.77 mV. Due to very high positive charge blank formulation containing oleyl amine showed higher cytotoxicity. In contrast, the DLin-DMA blank formulation showed negligible cytotoxicity due to their ionizable nature - neutral at physiological pH and cationic at lower pH. Based on these results, DLin-DMA based nanoformulation was optimized for NIC. The optimized formulation NIC-SNEDDS exhibited a particle size of 23.67±1.2 nm and a zeta potential of +15.5±0.56 mV. NIC alone showed the IC₅₀ of 2.33±1.5 µM in MIA PaCa2. The final formulation demonstrated an IC₅₀ of 2.20±1.4 µM in MIA PaCa2 cells, confirming its promising anticancer activity. In PANC-1 cells, NIC-SNEDDS exhibited an IC₅₀ of 3.09±1.1 µM IC₅₀ compared to NIC alone (14.8 µM). Predictive pharmacokinetic modelling using Gastroplus indicated >75% oral bioavailability of the NIC oral formulation compared to suspension. Thus, a hydrophobic ion pairing approach with ionizable lipid enabled the development of a self-nanoemulsifying drug delivery system of niclosamide. Currently, we are investigating the effect of NIC on in vivo pancreatic tumor bearing mice.