Summary of In vitro and in vivo studies testing the effects of pure and surface-modified ZnO NPsa.
| Surface mod. | Size (in nm) | Main finding | VT | VV | Model systems | Dose/concentration | Cellular/tumoral effects | CCS | Mechanism | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|
| Pure | 21C, 131HD | ZnO NPs selectively induce apoptosis in CCs via ROS, mediated by p53, bax/bcl-2 and caspase pathways | ● | HepG2, A549, BEAS-2B, rat astrocytes & hepatocytes | 5–15 μg mL−1 | Dose-dependent ↓ cell viability | ● | ↑ p53 and bax and ↓ bcl2 | 89 | |
| Pure | 5C, 6C | Newly synthesized ZnO QDs with promising optical properties show cytotoxic effects in CC lines | ● | K562, K562/A02, HepG2 | 1.25–100 μg mL−1 | Dose-dependent ↓ cell viability | 146 | |||
| Pure | 35C | ZnO NPs restore oxidative balance, hepatocyte integrity and tumor markers to normal levels in HCC | ● | ● | VT: HepG2, PC3, A549; VV: HCC | VT: 0–1000 μmol L; VV: 10 μg kg−1 per week | Dose-dependent ↓ cell viability | Restoration of oxidant and antioxidant activity (MDA, GSH, GPx, GSR, SOD, CAT), hepatocyte integrity (ALT, AST, LDH) and tumor biomarkers (AFP, AFU) to normal levels in CCs | 147 | |
| Pure | 95HD | ZnO NPs exert toxicity in normal and CCs through ROS generation, whereas CeO2 and TiO2 NPs do not | ● | A549, NCI-H460, SK-MES-1, HeLa, Jurkat, AT II | 2–6 μg cm−2 | ↓ cell viability | Complete particle dissolution and ↑ ROS | 57 | ||
| Pure | 100HD | ZnO and Ag NPs evoke stress-induced autophagy in pulmonary and hepatic cells while TiO2 NPs do not | ● | A549, HepG2 | 1–500 μg mL−1 | Dose-dependent ↓ cell viability | Autophagy induction (↑ LC3B, atg4b, p62 and ↓ atg12, atg5) in a time-dependent manner, and apoptotic cell death via caspase-3 | 148 | ||
| Pure | 40C | Apoptosis and oxidative stress as relevant mechanisms of antitumor activity and genotoxicity of ZnO-NPs | ● | ESC | 50, 300 and 500 mg kg−1 per body weight | Oxidative stress (↑ MDA and ↓ CAT, GST) and DNA damage. Apoptosis (↑ Bax and p53, ↓ Bcl2). NAC restores oxidative balance in the liver and kidney without ↓ the antitumor efficacy of NPs | 184 | |||
| Pure | 20HD, 70HD | Genotoxic anticancer effects of ZnO NPs via ROS, leading to non-apoptotic cell death in an orthotopic mouse model of human small-cell lung cancer | ● | ● | VT: H82, H187, BEAS-2B, MCF-7, OUS-11, LS174T, N417; VV: N417 | VT: 0–20 μg mL−1; VV: 0.04–0.25 mg kg−1 | Dose-dependent ↓ cell viability. ↓ tumor density | ● | ↑ ROS and DNA leakage from nuclei. Phos. of CHK2 in N417 and LS174T cells. ↑ cleaved PARP in LS174T cells. Q-VD-OPh (inhibitor of caspase-3, 1, 8, 9, slightly ↑ viability by inhibiting apoptosis, but did not block ZnO toxicity) | 185 |
| Fe-doped (0–10%) | 20.2C–8.3C (0–10%) | Fe doping reduces ZnO toxicity in animals due to decreased NP dissolution rates and associated toxicological responses | ● | ● | VT: RAW264.7, BEAS-2B; VV: rat & mouse lung, zebrafish embryo | VT: 12.5 μg mL−1; VV: 0–50–150 μg mL−1 | ↓ toxicity with ↑ Fe doping | ↑ Fe doping leads to ↓ inhibitory effect of Zn2+ in zebrafish embryo hatching, ↓ PMN cell counts in the BAL fluid and IL-6 mRNA and ↑ heme oxygenase 1 in mouse lung, and ↓ BAL PMN cell counts, LDH, and albumin in rat lung | 163 | |
| Fe-doped (0–10%) | 11C, 5.5C (0, 10%) | 2% Fe-doped ZnO NPs are found to be optimal to cause selective CC death and reduce metastasis formation | ● | ● | VT: mMSC, Beas-2B, HeLa, KLN205; VV: KLN 205 | VT: 0–35 μg mL−1; VV: 125 μg per animal | ↓ cell viability. ↓ toxicity with ↑ Fe doping. ↓ tumor growth and metastasis (2, 10%) | ● | ↑ ROS, membrane and mitochondrial damage and autophagy. ↓ toxicological response with ↑ Fe doping due to resulting ↓ in cellular levels of Zn2+. VV: pure NPs led to weight loss and premature death of mice | 77 |
| La-doped (0–5%) | 33C, 29C (0, 5%) | Doping ZnO NPs with La increases NP photocatalytic activity and cytotoxicity | ● | MDA-MB-231, KCL22, HeLa | 6–500 μg mL−1 | Dose-dependent ↓ viability. ↑ toxicity with La doping | 164 | |||
| Sm-, Eu-, Gd-doped | >100C | Sm-doped ZnO NPs displays the most significant antitumor activity compared to other lanthanide-doped ZnO NPs | ● | ● | EAC | VT: 0–0.05 mol; VV: 150–350 mg kg−1 | Dose-dependent ↓ cell viability for Sm3+ : ZnO NPs | Compared to pure NPs, Sm-doping ↓ tumor size, ↓ PI3K, Akt and mTOR, ↓ CXCR4 and P450, ↓ Bcl2 : Bax ratio, ↓ liver function enzymes (AST, ALT) and induce G2 cell cycle arrest | 165 | |
| PEG or starch coated | 40–1200HD | Toxicity towards osteoblast CCs is dependent on NP size, aspect ratio and coating. PEG-capped NPs exhibit higher toxicity than starch-capped NPs | ● | MG-63 | 1 μM to 7 mM | Dose-dependent ↓ cell viability. ↓ toxicity with ↑ NP size | 167 |
a
Ccore size, HDhydrodynamic size, VT in vitro, VV in vivo, CCS cancer-cell specific.