Delivery of imiquimod to intestinal lymph nodes following oral administration

Intestinal lymph nodes are involved in the progression of colorectal cancer (CRC). Tumours suppress the activation of dendritic cells (DCs) in draining lymph nodes, diminishing anti-cancer immune response. Imiquimod (IMQ) facilitates DCs activation via toll-like receptor 7, suggesting that targeted delivery of IMQ to intestinal lymph nodes can improve the treatment of CRC. This study aims to enhance the delivery of IMQ to intestinal lymph nodes by a highly lipophilic prodrug approach. Amide prodrugs were synthesised by conjugating IMQ with saturated and unsaturated medium- to long-chain fatty acids. Their potential for intestinal lymphatic transport was assessed by their affinity to chylomicrons and solubility in long-chain triglycerides. Further selection of prodrug candidates was determined by resistance to enzymatic hydrolysis in intestinal lumen and release of IMQ in the lymphatics using fasting state simulated intestinal fluid supplemented with esterases, brush border enzyme vesicles and plasma. Key pharmacokinetic parameters and biodistribution in rats were assessed for the most promising compounds, prodrugs 5 and 8. The plasma concentration–time profile of IMQ following oral administration of the prodrugs was less erratic in comparison to the administration of unmodified IMQ. The lymph-to-plasma ratios of IMQ concentration increased 1.9- and 1.7-fold using prodrugs 5 and 8 in comparison to administration of unmodified IMQ, respectively. Importantly, the average concentration of IMQ in mesenteric lymph nodes (MLN) was 11.2- and 7.6-fold higher than in plasma following the administration of prodrugs 5 and 8, respectively. Additionally, the non-specific wide distribution of IMQ into various organs and tissues was reduced with prodrugs. This work suggests that the highly lipophilic prodrug approach can efficiently deliver IMQ to intestinal lymphatics. In addition, this study demonstrates the feasibility of an amide prodrug approach for intestinal lymphatic targeting.