International Journal of Nanomedicine (Jul 2022)
Functionalized Mesoporous Silica Nanoparticles for Drug-Delivery to Multidrug-Resistant Cancer Cells
Abstract
Nóra Igaz,1 Péter Bélteky,2 Dávid Kovács,1,3 Csaba Papp,4 Andrea Rónavári,2 Diána Szabó,5 Attila Gácser,4 Zoltán Kónya,2,6 Mónika Kiricsi1 1Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary; 2Department of Applied and Environmental Chemistry, University of Szeged, Szeged, Hungary; 3Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d’Azur, Inserm, CNRS, Valbonne, France; 4HCEMM-USZ Fungal Pathogens Research Group, Department of Microbiology, University of Szeged, Szeged, Hungary; 5Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Szeged, Hungary; 6Eötvös Loránd Research Network, Reaction Kinetics and Surface Chemistry Research Group, Szeged, HungaryCorrespondence: Mónika Kiricsi, Department of Biochemistry and Molecular Biology, University of Szeged, Közép fasor 52, Szeged, H-6726, Hungary, Tel +36 (62) 544-887, Email [email protected] Zoltán Kónya, Department of Applied and Environmental Chemistry, University of Szeged, Rerrich square 1, Szeged, H-6720, Hungary, Tel +36 (62) 544620, Email [email protected]: Multidrug resistance is a common reason behind the failure of chemotherapy. Even if the therapy is effective, serious adverse effects might develop due to the low specificity and selectivity of antineoplastic agents. Mesoporous silica nanoparticles (MSNs) are promising materials for tumor-targeting and drug-delivery due to their small size, relatively inert nature, and extremely large specific surfaces that can be functionalized by therapeutic and targeting entities. We aimed to create a fluorescently labeled MSN-based drug-delivery system and investigate their internalization and drug-releasing capability in drug-sensitive MCF-7 and P-glycoprotein-overexpressing multidrug-resistant MCF-7 KCR cancer cells.Methods and Results: To track the uptake and subcellular distribution of MSNs, particles with covalently coupled red fluorescent Rhodamine B (RhoB) were produced (RhoB@MSNs). Both MCF-7 and MCF-7 KCR cells accumulated a significant amount of RhoB@MSNs. The intracellular RhoB@MSN concentrations did not differ between sensitive and multidrug-resistant cells and were kept at the same level even after cessation of RhoB@MSN exposure. Although most RhoB@MSNs resided in the cytoplasm, significantly more RhoB@MSNs co-localized with lysosomes in multidrug-resistant cells compared to sensitive counterparts. To examine the drug-delivery capability of these particles, RhoB@Rho123@MSNs were established, where RhoB-functionalized nanoparticles carried green fluorescent Rhodamine 123 (Rho123) - a P-glycoprotein substrate – as cargo within mesopores. Significantly higher Rho123 fluorescence intensity was detected in RhoB@Rho123@MSN-treated multidrug-resistant cells than in free Rho123-exposed counterparts. The exceptional drug-delivery potential of MSNs was further verified using Mitomycin C (MMC)-loaded RhoB@MSNs (RhoB@MMC@MSNs). Exposures to RhoB@MMC@MSNs significantly decreased the viability not only of drug-sensitive but of multidrug-resistant cells and the elimination of MDR cells was significantly more robust than upon free MMC treatments.Conclusion: The efficient delivery of Rho123 and MMC to multidrug-resistant cells via MSNs, the amplified and presumably prolonged intracellular drug concentration, and the consequently enhanced cytotoxic effects envision the enormous potential of MSNs to defeat multidrug-resistant cancer.Graphical Abstract: Keywords: mesoporous silica nanoparticles, drug-delivery, fluorescently labeled MSNs, functionalized MSNs, multidrug resistance
