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.
João M J M Ravasco, Jhenifer Oliveira, João Conniot et al.· ACS nano medicine· 0 citations
Osteoarthritis (OA) is driven in part by chondrocyte senescence, mitochondrial dysfunction and chronic inflammation, yet disease-modifying therapies that directly target these ageing mechanisms are lacking. Here, we identify the grape-seed-derived polyphenol procyanidin C1 (PCC1) as a senotherapeutic candidate that preserves chondrocyte mitochondrial homoeostasis and attenuates senescence via activation of the Nrf2/HO-1 axis. In tert-butyl hydroperoxide-induced senescent chondrocytes, PCC1 reduced senescence-associated β-galactosidase activity, dampened secretion of senescence-associated secretory phenotype factors, restored mitochondrial membrane potential and dynamics, limited extracellular matrix degradation and suppressed NF-κB activation. Network pharmacology and transcriptomic analyses converged on Nrf2 as a potential molecular target of PCC1, which we validated using cellular thermal shift and drug affinity responsive target stability assays. Genetic silencing of Nrf2 abrogated PCC1-mediated protection in vitro, confirming that Nrf2 is required for the anti-senescent and mitochondrial effects of PCC1. In a surgically induced anterior cruciate ligament transection model of OA, PCC1 administration reduced cartilage erosion, preserved matrix organisation and subchondral bone structure, and mitigated synovial inflammation in Nrf2-sufficient mice, whereas Nrf2 deficiency abolished these benefits. Together, these findings establish a mechanistic link between PCC1, Nrf2/HO-1 activation and chondrocyte mitochondrial homoeostasis in osteoarthritis, and support Nrf2-directed senotherapies as a regenerative strategy to slow OA progression.
Yu-Biao Zhang, Mao Chen, Wenxiang Cai et al.· Cell Death & Disease· 0 citations