In Vivo Multimodal Self-Immolative Prodrug Nanomicelle-Hydrogel Modulate Key Intratumoral and Metastatic Genomic Signaling Pathways in Pancreatic Cancer.

To address the critical challenge of high-lethality pancreatic ductal adenocarcinoma and poor response to conventional chemotherapies, this study introduces a self-immolative micelle encapsulating paclitaxel (PTX) or gemcitabine (GEM), two frontline chemotherapeutic agents. These chemotherapeutic agents present a 2.3-fold reduction for GEM and a 61.7-fold reduction for PTX in IC50 values when conjugated to the micelle system, compared to their free drug counterparts. Through longitudinal bioluminescence imaging, we observed a significant reduction in peritoneal tumor implants versus metastatic tumor deposits growth and a decrease in metastatic spread in the GEM- and GEM+PTX-micelle (micelle@GEM and micelle@GEM+PTX)-treated groups compared with the free drug formulations. Gene expression analysis of treated tumors revealed interesting oncogenic pathways, including PI3K-Akt and MAPK signaling, suggesting a targeted action at the molecular level. Our results identified the dual roles of PSMA1 and UBE2C as poor prognostic markers of pancreatic cancer progression and as candidate genes of interest, with key roles in the ubiquitination and proteasome degradation pathways in the pathophysiology of the disease. These data suggest that encapsulation of PTX and GEM in these micelles embedded within a hydrogel could alter the pharmacokinetics and pharmacodynamics of these agents, thereby modulating their interactions with cellular targets. Such targeted approaches could transform the treatment of pancreatic cancer by providing tailored therapies based on the unique genomic landscape of an individual's tumor, thus optimizing the clinical outcomes.