Mitocytosis-inducing nanoparticles alleviate gemcitabine resistance via dual disruption of pyrimidine synthesis and redox homeostasis in pancreatic ductal adenocarcinoma
Time：2025/8/19 17:20:48 Views：112
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumor types, and metabolic reprogramming is a central driver of its progression. By altering biosynthetic processes and energy metabolism pathways, metabolic reprogramming not only enhances tumor cell proliferation, but also promotes the development of a dense matrix and an immunosuppressive microenvironment. It is these pathological features that significantly limit the efficacy of various anti-tumor therapies. gemcitabine remains the first-line chemotherapeutic agent for PDAC, and metabolic reprogramming of PDAC cells plays multiple regulatory roles in gemcitabine resistance. Among them, dihydroorotate dehydrogenase (DHODH) contributes to gemcitabine resistance by participating in the de novo pyrimidine synthesis pathway. Therefore, improving drug resistance is crucial for achieving safe and effective anti-tumor therapy. The results were published online in Biomaterials (IF = 12.9) under the title of Mitocytosis-inducing nanoparticles alleviate gemcitabine resistance via dual disruption of pyrimidine synthesis and redox homeostasis in pancreatic ductal adenocarcinoma.
Metabolic reprogramming of pancreatic tumor cells plays multiple regulatory roles in gemcitabine resistance. On the one hand, PDAC cells are desensitized to gemcitabine through intrinsic resistance mechanisms. As a hydrophilic molecule, the intracellular uptake of gemcitabine is mainly mediated by human equilibrative nucleoside transporter 1 (hENT1). After gemcitabine absorbed, it is mostly inactivated by rapid deamination induced by cytidine deaminase, and only a small proportion is phosphorylated intracellular to exert its effect. The activity of these enzymes largely determines the efficacy of gemcitabine. On the other hand, adaptive changes in the pyrimidine metabolic pathway in PDAC cells further diminished the efficacy of gemcitabine. A Study has shown that the inhibition of dihydrofolate synthase (DHODH), a key enzyme in pyrimidine biosynthesis, partially reverses the resistance of tumor cells to gemcitabine. Due to the resistance of PDAC to gemcitabine, monotherapy has had limited success in improving survival in patients with advanced disease. Current clinical guidelines recommend the standard AG chemotherapy regimen (nab-paclitaxel and gemcitabine), which can extend patient survival moderately while reducing adverse effects. However, this combination regimen may destroy the outer stroma of PDAC lesions and accelerate tumor metastasis. Therefore, the development of more targeted combination strategies remains the focus of current research. Combining gemcitabine with metabolic modulators is a promising strategy for PDAC treatment. Currently, metabolic modulators used in tumor therapies are mainly small molecules, but their delivery efficiency is limited, especially because the dense stroma of PDAC further hinders drug penetration into the tumor core. By virtue of their unique size characteristics and multifunctionality, nanodrug delivery systems (NDDSs) are able to overcome the barrier of dense matrix of PDAC and achieve tumor-targeted delivery and lesion-responsive drug release, thus improving the pharmacokinetic properties of small molecule drugs. NDDSs also show great potential in multi-drug combination therapy by flexibly regulating the loading of multi-component drugs, providing a new idea for efficient drug delivery and precision target therapy in PDAC. However, although many studies have explored the application of various NDDSs in pancreatic tumor therapy, their clinical application has not yet made substantial progress due to the complexity of the preparation process and the biosafety of the materials. Polyphenols, which are widely found in natural plants, have good biosafety and can coordinate metal ions to form NDDSs. This coordination is pH-dependent and can achieve discoordination in response to the acidic conditions in tumor tissues, making them ideal carriers for delivering therapeutic drugs and achieving tumor-responsive release.
In this study, we developed GE11 peptide-functionalized polyphenol-iron nanoparticles to target PDAC cells with high epidermal growth factor receptor (EGFR) expression. These nanoparticles enabled the co-delivery of a long carbon chain-modified gemcitabine prodrug and the DHODH inhibitor leflunomide. The long carbon chain modification allowed the drug to enter the cell by passive diffusion, thus improving intracellular drug accumulation [18,19]. Leflunomide was selected to inhibit DHODH, which not only interferes with pyrimidine metabolism and alleviate gemcitabine resistance but also disrupts cellular redox homeostasis by inhibiting the conversion of ubiquinone to ubiquinol [20]. Leflunomide has also been shown to have a regulatory effect on the immune cell and has been used in clinical studies of various solid tumors and hematological tumors [21]. Additionally, the nanoparticles could induce mitocytosis, enabling deep tumor penetration and drug delivery [22]. This approach is expected to achieve effective penetration into the core lesion, regulate cell metabolism, disrupt redox homeostasis, alleviate gemcitabine resistance, and exhibit a good tumor cell cytotoxicity. Furthermore, it could activate anti-tumor immune responses, thereby exerting superior anti-tumor effects.
Link to the original article:
https://www.sciencedirect.com/science/article/pii/S0142961225005496?dgcid=coauthor
