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Mechanistic Insight into MnO₂ Quantum Dot Nanotheranostics Using a 3D-Printed Tumor Model

par Abrishami, Amir;Shavandi, Armin ; [et al.]
Référence (2025-09-09: Torino), 34th Annual Conference of the European Society for Biomaterials, ESB Torino
Publication Publié, 2025-09-09

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Résumé :

Introduction: Manganese dioxide (MnO₂) quantum dots (QDs) as emerging theranostic nanomaterials are promising for redox-triggered cancer therapy and imaging because of their ability to produce reactive oxygen species (ROS), deplete glutathione (GSH), and emit intrinsic fluorescence (FL). However, their therapeutic performance is highly dependent on surface ligand chemistry, which influences catalytic accessibility, size, stability, and intratumoral delivery. Small-molecule ligands like cysteine (Cys) offer high reactivity and diffusivity, while protein-based coatings such as casein (Cas) provide biocompatibility and prolonged circulation but may hinder penetration. Yet, conventional in vitro or in vivo tumor models inadequately capture these behaviors in spatially organized tissues. To address this, we developed an innovative volumetrically printed 3D tumor model with physiological properties to systematically investigate the ligand-dependent performance of MnO₂ QDs in a controlled and perfusable microenvironment. Materials and Methods: Cys–MnO₂ and Cas–MnO₂ QDs were synthesized via aqueous redox precipitation and characterized for morphology, size distribution, surface chemistry, and FL emission intensity. Enzyme-mimetic activities, including peroxidase (POD) by TMB assay, catalase (CAT) by oxygen meter, and chemodynamic (CD) by MB degradation, were assessed comprehensively. HT-29 colorectal cancer cells were used for 2D assessment of cytotoxicity (MTT, Live/Dead), uptake, and ROS/oxygen generation (FL microscopy) of QDs. For 3D modeling, a customized GelMA–PEGDA–LAP bioresin (5% w/v GelMA, 10% v/v PEGDA, 0.3 mg/mL LAP), optimized in a prior group study, was volumetrically printed as a vascular construct, and tumor cell spheroids (~1 mm, 4×10⁶ cells/mL) were developed within the central cavity. For the performance validation of the 3D model, QDs with different surface ligands were injected through surrounding channels, and spatiotemporal diffusion and cytotoxicity were assessed over 48 h using FL microscopy and live/dead staining. Results: Successful synthesis of both MnO₂ QD formulations was confirmed by comprehensive physicochemical characterization. TEM showed the core sizes of ~1–3 nm, while DLS revealed hydrodynamic diameters of 3.34 ± 0.75 nm for Cys–MnO₂ and 20.79 ± 1.64 nm for Cas–MnO₂. Cas–MnO₂ exhibited ~48% higher FL intensity than Cys–MnO₂ at equal concentrations, attributed to improved colloidal stability. Cys–MnO₂ demonstrated ~22% higher POD-like activity than Cas–MnO₂ (Michaelis constant reduced from 8.040 mM to 6.260 mM) and was the only formulation with kinetic measurable CAT-like activity. For CDT assays, Cys–MnO₂ reached effective ROS generation at ~33% lower sensitivity compared to Cas–MnO₂. In 2D assays, both QDs significantly reduced cell viability, increased intracellular ROS, and enhanced oxygen release, with no significant difference between formulations. FL scanning in 3D showed that Cas–MnO₂ stayed localized to the periphery, whereas Cys–MnO₂ entered the tumor core more quickly and deeply. In comparison to the control group, live/dead staining revealed significant cytotoxicity with Cys-MnO₂ and less tumor suppression with Cas-MnO₂ after 48 hours. Discussion: Surface ligand chemistry critically modulates the functional performance of MnO₂ QDs. Our findings align with prior reports that ultrasmall nanostructures with minimal surface shielding, like cysteine-capped MnO₂ QDs, exhibit enhanced redox activity and deeper tumor penetration due to increased accessibility to intracellular reductants. In contrast, casein-coated QDs benefit from improved stability but show delayed activation, likely due to the diffusional barrier imposed by the protein corona. Notably, the 3D tumor model better recapitulated these differences, supporting recent evidence that physiomimetic architectures are essential for uncovering spatial limitations in nanotherapeutic delivery. Conclusion: This work presents a versatile 3D-printed tumor model as a physiologically relevant tool for the simultaneous assessment of the delivery and performance of MnO₂-based QDs, emphasizing the significance of ligand selection in this process. The platform highlights the crucial role of ligand chemistry in nanotherapeutic design by allowing controlled comparison of nanoparticle diffusion, redox activity, and cytotoxicity within a biomimetic 3D matrix. Although encouraging for mechanistic assessment, more research involving additional tumor microenvironmental characteristics will be required to completely confirm its predictive capability.