Macrophage-hitchhiked, effervescence-induced nanoemulsions for enhanced oral chemotherapy and immunotherapy: Impact on absorption route.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer. Paclitaxel (PTX), typically administered intravenously (IV) as chemotherapy, shows promise for triggering immunogenic cell death (ICD) and may serve as a potential immunotherapy. This study introduces an oral PTX delivery method using an enteric-coated gelatin capsule containing capric acid oil and an effervescent agent, optionally with decylamine-conjugated β-glucans (DA-βGlus). Upon dissolving in the small intestine, the capsule undergoes an effervescence reaction that produces emulsified oil droplets (ODs) by bile salts, forming either Bared/ODs/PTX or DA-βGlus/ODs/PTX, with the latter featuring surface-attached DA-βGlus. The study evaluates the oral absorption, pharmacokinetics, and therapeutic efficacy of these formulations, comparing them to IV administration. IV PTX causes rapid spikes in plasma concentration, quick metabolism, and elimination, which can be unsafe. In contrast, the oral delivery system maintains consistent drug levels in the bloodstream for longer periods, improving overall effectiveness. Bared/ODs/PTX follows conventional fat absorption pathways, limiting tumor targeting. On the other hand, DA-βGlus/ODs/PTX uses DA-βGlus to enhance specificity for tumors through endogenous macrophage-mediated transport, effectively acting as "cellular tumor-seeking vehicles". This method reduces tumor stroma fibrosis, delivers PTX precisely, induces apoptosis, triggers PTX-induced ICD, and enhances cytotoxic T cell responses, augmenting targeted anti-PDAC strategies.