Copper-based Nanoplatform Shows Promise Against Metastatic Tumor Growth

The researchers designed multifunctional copper-based nano-PROTACs, named CHNDs, that harvester targeted macromolecule degradation pinch copper-mediated compartment death. The macromolecule target is hexokinase 2, aliases HK-2, a cardinal enzyme that catalyzes nan first committed measurement of glycolysis and supports nan precocious metabolic request of quickly increasing tumors. By degrading HK-2 alternatively than simply inhibiting it, nan level intends to trim glycolytic compensation much effectively.

The squad first constructed PEI-based HK-2 degraders, termed PHDs. These degraders nexus a 3-bromopyruvate warhead that engages HK-2 pinch a thalidomide derivative that recruits nan cereblon E3 ligase. This creation brings HK-2 adjacent to nan ubiquitin-proteasome system, enabling targeted degradation. In 4T1 bosom crab cells and CT26 colon crab cells, PHDs reduced HK-2 look to astir 43.7% and 42.1%, respectively, impairing glycolytic activity.

To merge this degradation strategy pinch cuproptosis, nan researchers built CHNDs from copper-based metal-organic model nanoparticles dressed up pinch PEGylated PHDs. The particles stay comparatively unchangeable nether physiological conditions but disassemble much readily successful tumor-like acidic and glutathione-rich environments. This allows nan strategy to merchandise copper ions and PEG-PHDs successful a controlled manner. PEG-PHDs suppress glycolysis done HK-2 degradation, while copper ions trigger mitochondrial stress, DLAT aggregation, iron-sulfur macromolecule disruption, and cuproptotic compartment death.

In compartment experiments, CHNDs showed stronger anticancer activity than either nan HK-2 degrader aliases nan copper nanoplatform alone. The curen reduced glycolytic flux, lactate production, and ATP levels, while expanding reactive oxygen species, depolarizing mitochondria, and promoting DLAT aggregation. Transcriptomic study further showed wide disruption of proteasome activity, ubiquitin-mediated proteolysis, endoplasmic reticulum macromolecule processing, oxidative accent responses, mitochondrial respiratory concatenation assembly, and oxidative phosphorylation. Together, these results bespeak that CHNDs enactment done coordinated disruption of macromolecule homeostasis, redox balance, and crab power metabolism.

The strategy besides showed antitumor effects successful rodent models. In an orthotopic 4T1 bosom crab model, CHNDs achieved a tumor inhibition complaint of 55.3%. In a CT26 colon tumor model, nan inhibition complaint reached 76.6%, and median endurance accrued from 21 to 29 days, pinch a subset of animals surviving to time 100. Tumor insubstantial analyses confirmed HK-2 down-regulation, enhanced DLAT aggregation, and accrued tumor compartment death. In a spontaneous lung metastasis exemplary utilizing 4T1 bosom tumors, CHNDs besides reduced lung bioluminescence signals and metastatic nodules, suggesting imaginable antimetastatic activity.

The study offers a mechanistic model for strengthening cuproptosis therapy by shutting down glycolytic compensation. Rather than treating copper toxicity and tumor metabolism arsenic abstracted targets, CHNDs bring them together successful 1 nanoplatform. Still, nan activity remains preclinical. Long-term metallic ion accumulation, immunological consequences, pharmacokinetics, tumor heterogeneity, and information successful larger animal models will request observant information earlier this strategy tin move toward objective translation. Even astatine this stage, nan study provides a valuable illustration of really targeted macromolecule degradation and metal-induced compartment decease tin beryllium integrated for precision metabolic crab therapy.

Source:

Journal reference:

Li, S., et al. (2026). Multifunctional Engineered Metal–Organic Frameworks arsenic Targeted Protein Degraders for Augmenting Cancer Therapy via Hexokinase 2 Degradation and Provoking Cuproptosis. Research. DOI: 10.34133/research.1217. https://spj.science.org/doi/10.34133/research.1217