Anticancer Activity of Novel Difluorinated Curcumin Analog and Its Inclusion Complex with 2-Hydroxypropyl-β-Cyclodextrin against Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify novel drugs with improved delivery to improve treatment outcomes. Curcumin is one such compound that can inhibit multiple signaling pathways and CSCs. However, curcumin's clinical applicability for treating PDAC is limited because of its poor solubility in water and metabolic instability. Hence, we developed a difluorinated curcumin (CDF) analog that accumulates selectively in the pancreas and inhibits PDAC growth in vitro and in vivo. In the present work, we developed its 2-hydroxy-propyl-beta-cyclodextrin (HCD) inclusion complex to increase its water solubility and hydrolytic stability. The CDFHCD inclusion complex was characterized by spectroscopic, thermal, and microscopic techniques. The inclusion complex exhibited increased aqueous solubility, hydrolytic stability, and antiproliferative activity compared to parent CDF. Moreover, CDF and CDFHCD inhibited colony and spheroid formation, and induced cell cycle and apoptosis in PDAC cell lines. Hence, CDFHCD self-assembly is an efficient approach to increase water solubility and anticancer therapeutic efficacy, which now warrants advancement towards a clinical proof of concept in PDAC patients.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is the leading cause of cancer-related deaths in the US. The development of novel drugs with improved delivery is crucial due to factors such as genetic mutations, drug resistance, multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma. Curcumin shows promise in inhibiting PDAC, but its clinical applicability is limited by poor solubility and metabolic instability. A difluorinated curcumin analog (CDF) has been developed, which selectively accumulates in the pancreas and inhibits PDAC growth. Its inclusion complex with 2-hydroxy-propyl-beta-cyclodextrin (HCD) increases water solubility and hydrolytic stability, leading to improved therapeutic efficacy against PDAC.