Applications and Biological Activity of Nanoparticles of Manganese and Manganese Oxides in In Vitro and In Vivo Models
Abstract
:1. Introduction
2. Medical Applications of Manganese and Manganese Oxide Nanoparticles
2.1. Biological Imaging
2.2. Modulating Tumour Microenvironment, Drug Delivery/Chemotherapy, Photo- and Radiotherapy
2.3. Theranostic Nanoplatforms
Mn/Mn Oxide Nanoform | Modification | Application | Comments | Research Model | Reference |
---|---|---|---|---|---|
Mn3O4 | - | MRI contrasting agent | - | Balb/c nude mice with nasopharyngeal carcinoma (NPC)2 xenografted tumour | Xiao et al. 2013 [23] |
MnO | PVP | MRI contrasting agent | - | Human lung carcinoma cell line (SPCA-1 cells) KM mice | Hu et al. 2013 [24] |
Mn3O4 | PEG, Cy7.5 | Dual modality contrasting agent (MRI + fluorescence) | - | BALB/c mice | Zhan et al. 2017 [25] |
Fe3O4/MnO nanocrystals | - | MRI contrasting agent | T1 and T2 mode | BALB/c nude mice | Im et al. 2013 [26] |
Mn | Doped on silica NPs | Cancer treatment + drug delivery | induce ferroptosis via GSH depletion; might be loaded with drugs, e.g., sorafenib | Human hepatocellular carcinoma cell line (HepG2) | Tang et al. 2019 [27] |
MnO2 | Ce6, PEG-cRGD | Photosensitizer delivery for PTT and PDT | - | Human prostate adenocarcinoma cell line (PC3) | Zeng et al. 2019 [29] |
MnO2 | BSA, IR780, doxorubicin | Combined photo- and chemotherapy for cancer treatment | MnO2 degradation leading to red-ox imbalance as additional anti-cancer mechanism | Human breast adenocarcinoma (MCF-7), Balb/c nude mice inoculated with MCF-7 tumor | Yuan et al. 2019 [30] |
MnO2 | OA | Radiosensitizer delivery | Mn-induced O2 release as additional anti-cancer mechanism | Human non-small cell lung cancer cell line (H1299), human head and neck squamous cell carcinoma cell line (SCC7), athymic female nude mice inoculated with H1299 cells | Liu et al. 2020 [31] |
MnO2 | BSA, ICG | Combined photothermal and photodynamic for cancer treatment | Mn-induced O2 release as additional anti-cancer mechanism | Nude mice inoculated with murine melanoma (B16F10) cells | Wen et al. 2020 [32] |
MnO | PEG, Cy5.5 | MRI contrasting agent + drug delivery for targeted therapy | Good retention and selectiveness | Sprague–Dawley rats with surgically developed myocardial ischemia | Zheng et al. 2018 [33] |
MnO2 | BPD | Drug delivery for targeted therapy + MRI contrasting agent | Mn-induced O2 release as additional anti-cancer mechanism | HepG2 orthotopic mice | Wang et al. 2020 [37] |
MnO2 | captopril–stabilized Au nanoclusters, DSP | Sensitizer (PDT) and drug delivery for targeted therapy +MRI contrasting agent | Mn ion-related depletion of GSH as mechanism supporting the effects of PDT | Mice inoculated with mouse cervical carcinoma (U14) cells | Bi et al. 2018 [38] |
MnO | Loaded into LCN with BA | Chemodynamic therapy + fluorescent imaging | Mn ions catalyse Fenton-like reaction, triggering apoptosis | Balb/c mice with 4T1 (breast cancer) xenografted tumour | Urandur et al. 2020 [39] |
MnO2 | GOx | Starvation/hyperthermia therapy+ MRI and PA contrasting agent | Mn-dependent reaction releases O2 necessary for GOx activity | Human melanoma (A375 cells), nude mice inoculated with A375 cells | He et al. 2020 [40] |
3. Analysis of the Biological Impact of Nano-Sized Manganese Compounds
3.1. In Vitro Studies
3.1.1. Studies Suggesting Cytotoxicity and Investigating Cytotoxicity Mechanisms
3.1.2. Studies Showing No Cytotoxicity of the Nanoparticles of Mn Oxides
3.2. Studies on In Vivo Toxicity
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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In Vitro Studies | |||||||
Mn Nanoform (Size; Shape by TEM; Surface Modification) | Cell System | Concentration Tested; Stability | Exposure Time | Cellular Internalization | Toxicity Endpoints | Results | References |
Elemental Mn (40 nm; irregularly shaped cubes) | PC-12/rat pheochromocytoma | 1–100 μg Mn/mL stability not measured | 24 h | Effective internalization (the CytoViva 150 URI system) | Cellular morphology, cytotoxicity (MTT), ROS level; depletion of DA, DOPAC, and HVA | Moderate cytotoxicity; induction of concentration-dependent DA, DOPAC, and HVA depletion; >10-fold increase in ROS | Hussain et al. 2006 [49] |
Elemental Mn (40 nm; e irregularly shaped spheres) | PC-12/rat pheochromocytoma | 10 μg Mn/mL Average diameter in water: 5030 nm; in culture medium: 2390 nm. | 24 h | Not measured | Expression of genes associated with dopaminergic system and redox status | Significant dopaminergic neurotoxicity; no effect on redox status related genes, suppression of Th and Park2, up-regulation of Snca (genes involved in DA metabolism and PD pathogenesis) | Wang et al. 2009 [50] |
Elemental Mn (20 nm; irregular shape) | N27/rat dopaminergic neural cell line | 25–400 μg Mn/mL Stability not measured | 3, 6, 9 h | Effective internalization after 6 h of incubation (TEM) | Cytotoxicity (Sytox green), mitochondrial superoxide production, H2O2 induction, autophagy | Cell viability decrease, oxidative stress induction, proapoptotic protein kinase Cδ (PKCδ) cleavage, autophagy induction | Afeseh Ngwa et al. 2011 [51] |
MnO2 (40 nm; round shape) | SH-SY5Y/human neuroblastoma | 10, 30, 60 μg MnO2/mL Average diameter 299.60 nm in water | 24, 48 h | Not measured | Cell morphology, cytotoxicity (MTT, NRU), MMP, ROS level, oxidative stress (LPO, GSH, SOD, CAT level), PS translocation, chromosome condensation, caspase-3 state, genotoxicity | Cell viability decrease, ROS induction, oxidative stress markers increase, apoptosis (caspase-3 activation, PS translocation, fragmentation of chromosomes) | Alarifi et al. 2017 [52] |
Mn3O4 (25 nm; spheres) | PC-12/rat pheochromocytoma | 5–20 μg Mn3O4/mL Average diameter 123 nm in water and 115 nm in culture medium | 24 h | Not measured | Cytotoxicity (CCK-8, LDH release), intracellular ROS level, oxidative stress (SOD, MDA, and GSH), apoptosis, cytosolic Ca2+ concentration, MMP, apoptosis-related proteins level, DA and DA-related proteins level | Cell viability decrease, ROS induction, oxidative stress markers increase, up-regulation of Bax and suppression of Bcl-2 expression, caspase-3 and caspase-9 cleavage, cytosolic Ca2+ concentration increase, DA level decrease, decreased expression of DOPA decarboxylase | Chen et al. 2020 [53] |
Mn3O4 (30 nm; spheres) | CCL-149/rat lung epithelium | 5, 10, 20 μg Mn3O4/mL Average diameter 100 nm | 24 h | Effective internalization (TEM, ICP-MS) | ROS level, GSH level, caspase-3 activity, apoptosis, LDH release | ROS induction, apoptosis, red-ox status disturbances, | Frick et al. 2011 [54] |
MnO2 (20–120 nm; nanoflakes) | MCF-7/human breast cancer; HT1080/human fibrosarcoma | 5–200 μg MnO2/mL Average diameter 350 nm in culture medium | 24 h | Effective internalization (ICP-MS) | Cytotoxicity (MTT, NRU, LDH release), ROS level, oxidative stress markers (GSH, TBARS, SOD, CAT), apoptosis, MMP, cell cycle | Cell viability decrease and oxidative stress induction (more significant for HT1080), apoptosis, cell cycle disturbances, up-regulation of pro-apoptotic genes, and down-regulation of anti-apoptotic genes | Alhadlaq et al. 2018 [55] |
MnO2, Mn2O3, and Mn3O4 (50 nm; spherical shape) | Caco-2/human colorectal adenocarcinoma | 25 μM NP/mL Average diameter MnO2—232.1 nm Mn2O3—435.7 nm, Mn3O4—273 nm in water Stability not measured | 24 h | Effective internalization (TEM) | Cytotoxicity (Alamar blue) | Cell viability decrease; incubation wit NPs protected from H2O2 cytotoxicity (effect decreased with growing concentrations of NPs), ROS-scavenging activity highest for MnO2 | Jiang et al. (2020) [56] |
MnO2, Mn3O4 (different structures) | bTC3/Murine insulinoma | 3.126–200 μg NP/mL Stability not measured | 48 h | Effective internalization after 3.5 h (TEM) | Cytotoxicity (bioluminescence, MTS) | Low cytotoxicity (significant for high concentrations of hausmannite Mn3O4); incubation wit NPs protected from H2O2 cytotoxicity (effect decreased from 50 μg NP/mL with growing concentrations of NPs) | Tootoonchi et al. 2017 [57] |
Mn3O4 (9 nm) | Cytotoxicity: HEK 293/Human embryonic kidney cells apoptosis: NP69/Human nasopharyngeal epithelial cells CNE-2/human nasopharyngeal carcinoma cells | 10, 100, 150 Mn3O4 Stability not measured | 24, 48 h | Effective internalization (TEM) | Cytotoxicity (MTT), apoptosis | Cell viability unaltered, no apoptosis | Xiao et al. 2013 [23] |
Mn3O4 (10 nm; spherical shape; coated with PEG and Cy7.5) | PC-3 (human prostate adenocarcinoma), A549 (human lung carcinoma), HepG2 (human hepatocellular carcinoma) | 200–1000 μg NP/mL Stability not measured | 24 h | Effective internalization (confocal microscopy) | Cytotoxicity (CCK-8) | Cell viability unaltered | Zhan et al. 2017 [25] |
MnO (60 nm; coated with PEG and Cy5.5) | NRVM (neonatal rat ventricular myocytes), CF (cardiac fibroblasts), and H9c2 (rat myoblast) | 0–100 μM NP Stability not measured | 48 h | Not measured | Cytotoxicity (MTT) | Cell viability unaltered | Zheng et al. 2018 [33] |
MnO (20 nm; coated with PEG) | SPCA-1 (human lung carcinoma) | 0–100 μg NP/mL Average diameter 30 nm in PBS | 24 h | Not measured | Cytotoxicity (MTT) | Cell viability unaltered | Hu et al. 2013 [24] |
MnO2 (3 nm thick; nanosheets; conjugated with Au nanoclusters and DSP) | L929 (fibroblast cells) | 0–200 μg NP/mL Stability not measured | 24 h | Effective internalization (confocal microscopy) | Cytotoxicity (MTT) | Cell viability unaltered | Bi et al. 2019 [38] |
MnO (7.3 nm;loaded into LCN wit BA) | Cytotoxicity: HEK 293 (human embryonic kidney cells) Internalization: MDA-MB-231, 4T1 (human breast cancer cells) | 5, 10 μg Mn/mL | 48 h | Effective internalization after 12 h (confocal microscopy, flow cytometry) | Cytotoxicity (MTT) | Cell viability unaltered | Urandur et al. 2020 [39] |
MnO2 (2 nm thick; nanosheets; loaded with GOx) | A375 (human melanoma) | 0–1 nM NP/mL Stability not measured | 24 h | Not measured | Cytotoxicity (MTT, CAM + PI staining) | Cell viability unaltered | He et al. 2020 [40] |
In Vivo Studies | |||||||
Mn Nanoform (Size; Shape) | Animals | Dose Tested/Route | Exposure Time | Bio-Accumulation | Toxicity Endpoints | Results | References |
MnO2 (23 nm) | Male Wistar rats | Daily doses of 2.63 and 5.26 mg Mn/kg; intratracheal instillation | 3, 6, and 9 weeks | Increased Mn level in blood and brain | Open field behaviour changes, electrophysiology, body and organ weights | Behavioural changes: increased immobility, decreased rearing, electrophysiological brain activity pattern altered, no weight gain from the 6th week on | Oszlánczi et al. [58] |
MnO2 (30–60 nm) | Male Wistar rats | Daily doses of 50 and 100 μg MnO2/kg; intraperitoneal injection | 15 days | Not measured | Behaviour changes, Sucrose preference, Catecholamine concentration, ROS and LPO level, histopathological analysis of tissues | Depressive-like behaviours (increased immobility, anhedonia), oxidative stress induction and catecholamine level decrease in hippocampus tissue, necrotic, and apoptotic cells in brain tissue | Sadeghi et al. 2018 [62] |
MnO2 (42.63 nm) | Male and female Wistar rats | Daily dose of 30, 300, 1000 mg MnO2/kg; oral gavage | 28 days | Increased Mn level in blood, liver, heart, kidneys, spleen | DNA damage (comet assay, micronucleus test, chromosomal aberration assay), blood biochemistry changes, fractionation of brain for ATPases, histopathological analysis of tissues | DNA damage, increased MN frequency and chromosome aberration for doses of 300 and 1000 mg/kg, discrepancies in brain tissue enzyme activity and blood biochemical parameters, tissue damage for the highest dose | Singh et al. 2013 [63] |
Mn3O4 (~18 nm; spherical shape) | Female rats | 2.5 and 1.25 mg Mn3O4/kg; 3 times a week, 18 doses in total; intraperitoneal injection | 6 weeks | Increased Mn level in brain and kidneys | Behaviour changes, urine analysis, blood biochemistry and hematology changes, histopathological analysis of tissues | Discrepancies in some blood and urine parameters | Katsnelson et al. 2015 [64] |
Mn3O4 (10 nm; spherical shape; coated with PEG and Cy7.5) | Male BALB/c mice | 20 mg/kg Mn3O4; intravenously | 14 days | NPs present in liver and kidneys; rapid biodegradation and clearance | Blood biochemistry, histopathological analysis of tissues | No tissue damage, no discrepancies in biochemical markers for liver and kidney functions | Zhan et al. 2018 [65] |
MnO2 (2 nm thick nanosheets; coated with soy phospholipid) | Female Kunming mice | 5, 10, 20 mg MnO2/kg; intravenously | 30 days | Not measured | Body weight changes, histopathological analysis of tissues | No body weight discrepancies, no tissue damage | Liu et al. 2018 [66] |
MnO (60 nm; coated with PEG and Cy5.5) | C57BL/6J mice | 7 mg Mn/kg (4 and 24 h) 35 mg Mn/kg (28 h) | 4 h, 24 h, 28 days | NPs present after 4, but not after 24 h; rapid clearance | Behaviour changes, histopathological analysis of tissues | No behaviour changes, no tissue damage | Zheng et al. 2018 [33] |
MnO (7.3 nm; loaded into LCN wit BA) | BALB/b mice | 40 mg/kg Mn; intravenously | 21 days | Cleared from blood after 8 h (MnO + BA NPs) or >48 h(LCN + MnO + BA) | Histopathological analysis of tissues | No tissue damage | Urandur et al. 2020 [39] |
MnO2 (2 nm thick; nanosheets; loaded with GOx) | Nude mice | 5 mg/kg; intratumorally | 30 days | Not measured | Body weight changes, histopathological analysis of tissues | No body weight discrepancies, no tissue damage | He et al. 2020 [40] |
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Sobańska, Z.; Roszak, J.; Kowalczyk, K.; Stępnik, M. Applications and Biological Activity of Nanoparticles of Manganese and Manganese Oxides in In Vitro and In Vivo Models. Nanomaterials 2021, 11, 1084. https://doi.org/10.3390/nano11051084
Sobańska Z, Roszak J, Kowalczyk K, Stępnik M. Applications and Biological Activity of Nanoparticles of Manganese and Manganese Oxides in In Vitro and In Vivo Models. Nanomaterials. 2021; 11(5):1084. https://doi.org/10.3390/nano11051084
Chicago/Turabian StyleSobańska, Zuzanna, Joanna Roszak, Kornelia Kowalczyk, and Maciej Stępnik. 2021. "Applications and Biological Activity of Nanoparticles of Manganese and Manganese Oxides in In Vitro and In Vivo Models" Nanomaterials 11, no. 5: 1084. https://doi.org/10.3390/nano11051084