In-silico modeling of degrading nanomaterials as a novel approach for tumor therapy
Stefaan J Soenen, Bella B Manshian, S Pokhrel, K Tamm, L Sikk and L Madler
KU Leuven, Belgium
: J Pharm Drug Deliv Res
Abstract
Here, our aim was to develop ZnO NMs with finely tuned degradation kinetics to maximize cancer-cell specific cell death. ZnO NMs were doped with different levels of Fe ions. Based on the intrinsic physicochemical properties of the NMs, quantitative nanostructure-activity relationship models were generated to define the dissolution rate and cell death of the different NMs and to generate an optimal formulation for toxicby- design NMs that could selectively kill cancer cells while noncancerous cells remained unaffected. Cytotoxicity of these NMs was tested in HeLa and KLN 205 (cancerous), MSC and BEAS-2B (non-cancerous) cell lines. Data revealed that low Fe-doping caused higher overall toxicity that was diminished as the Fedoping increased. In-silico analysis revealed that 2% Fe-doped NMs were the most selective towards cancer cells, mainly through higher levels of oxidative stress and mitochondrial damage. These findings were confirmed in co-culture models where cancer cells were cultured with non-cancerous cells and exposed to the NMs. Thus, 2% Fe-doping, 25 μg/ml concentration, 8 hr. duration selectively killed cancer cells while the non-cancerous cells did not display significant toxicity. This was further evaluated in a syngeneic mouse model (DBA/2 mice with subcutaneous KLN 205 cells). Upon administration of pure, or 2 or 10% Fe-doped ZnO, the level of Zn2+ ions present in the tumor were inversely correlated to the Fe-doping level. The pure ZnO NMs were found to be toxic to the mice, while 10% Fe-doped NMs did not cause any toxicity nor a major therapeutic benefit. However, 2% Fe-doped NMs resulted in a clear reduction in tumor growth, without any negative effect on animal well-being. In conclusion, we have demonstrated that through controlled dissolution and in-silico modelling, NMs can be generated that cause selective cancer cell toxicity. This principle is likely generic and is easily applicable to other NM formulations.
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