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Doxorubicin-Loaded MnO₂@Zeolitic Imidazolate Framework-8 Nanoparticles as a Chemophotothermal System for Lung Cancer Therapy.

ABSTRACT: Doxorubicin-loaded MnO₂@zeolitic imidazolate framework-8 (DOX/MnO₂@ZIF-8) nanoparticles, a smart multifunctional therapeutic platform, were prepared for the treatment of lung cancer. The morphology, structure, and redox and photothermal properties of MnO₂@ZIF-8 were characterized by the corresponding methods. The anticancer drug DOX released from the DOX/MnO₂@ZIF-8 nanoparticles was measured. The cell viability of Lewis lung cancer (LLC) cells treated with MnO₂@ZIF-8 or DOX/MnO₂@ZIF-8 nanoparticles was determined using the cell counting kit-8 (CCK-8) method. The cellular uptake of DOX/MnO₂@ZIF-8 nanoparticles into LLC cells was observed using a confocal laser scanning microscope. TUNEL staining was performed to evaluate the in vivo therapeutic efficacy of DOX/MnO₂@ZIF-8 nanoparticles. The results showed that the as-prepared MnO₂@ZIF-8 nanoparticles had an average particle size of 155.59 ± 13.61 nm and the DOX loading efficiency was 12 wt %. MnO₂@ZIF-8 could react with H₂O₂ to generate O₂ and showed a great photothermal conversion effect both in vitro and in vivo. Up to 82% of total DOX could be released from DOX/MnO₂@ZIF-8 nanoparticles at pH = 5.0. The CCK-8 assay showed that MnO₂@ZIF-8 had low cytotoxicity to LLC cells, while DOX/MnO₂@ZIF-8 can significantly reduce the cell viability. DOX/MnO₂@ZIF-8 can be accumulated in LLC cells over time. Compared with PBS and DOX/MnO₂@ZIF-8 groups, the mice in the DOX/MnO₂@ZIF-8 + NIR group had the most apoptotic cells and significantly reduced tumor volume. In conclusion, these findings suggest that the as-prepared MnO₂@ZIF-8 nanoparticles with synergetic therapeutic effects by photothermal therapy and improved tumor microenvironment and as a pH-responsive nanocarrier for delivering the nonspecific anticancer drug DOX might be applied in the treatment of lung cancer.

SUBMITTER: Tan C

PROVIDER: S-EPMC8158835 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles have emerged as a promising platform for drug delivery and controlled release. Considering most ZIF-8 nanoparticle drug carriers are designed to be administered intravenously, and thus would directly contact vascular smooth muscle cells (VSMCs) in many circumstances, the potential interactions of ZIF-8 nanoparticles with VSMCs require investigation. Here, the effects of low doses of ZIF-8 nanoparticles on VSMC morphology, actin organization, and contractility are investigated. Two nanoscale imaging tools, atomic force microscopy, and direct stochastic optical reconstruction microscopy, show that even at the concentrations (12.5 and 25 µg/ml) that were deemed "safe" by conventional biochemical cell assays (MTT and LDH assays), ZIF-8 nanoparticles can still cause changes in cell morphology and actin cytoskeleton organization at the cell apical and basal surfaces. These cytoskeletal structural changes impair the contractility function of VSMCs in response to Angiotensin II, a classic vasoconstrictor. Based on intracellular zinc and actin polymerization assays, we conclude that the increased intracellular Zn2+ concentration due to the uptake and dissociation of ZIF-8 nanoparticles could cause the actin cytoskeleton dis-organization, as the elevated Zn2+ directly disrupts the actin assembly process, leading to altered actin organization such as branches and networks. Since the VSMC phenotype change and loss of contractility are fundamental to the development of atherosclerosis and related cardiovascular diseases, it is worth noting that these low doses of ZIF-8 nanoparticles administered intravenously could still be a safety concern in terms of cardiovascular risks. Moving forward, it is imperative to re-consider the "safe" nanoparticle dosages determined by biochemical cell assays alone, and take into account the impact of these nanoparticles on the biophysical characteristics of VSMCs, including changes in the actin cytoskeleton and cell morphology.

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Doxorubicin-Loaded MnO₂@Zeolitic Imidazolate Framework-8 Nanoparticles as a Chemophotothermal System for Lung Cancer Therapy.

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Doxorubicin-Loaded MnO2@Zeolitic Imidazolate Framework-8 Nanoparticles as a Chemophotothermal System for Lung Cancer Therapy.

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Doxorubicin-Loaded MnO₂@Zeolitic Imidazolate Framework-8 Nanoparticles as a Chemophotothermal System for Lung Cancer Therapy.