In vivo evaluation of biodistribution and toxicity of pH-responsive strontium nanoparticles for gene delivery

Purpose: Low efficacy of parenteral administration of naked therapeutic genes is associated with the presence of biological barriers including circulatory monocytes that clear and eliminate foreign materials via reticuloendothelial system. Chemically synthesized inorganic strontium nanoparticles (SNPs) present a way to improve the delivery of genetic content to the targeted tissues of mammary carcinoma while protecting the load from premature degradation. Methods: Biodistribution profiles in the brain, liver, spleen, kidneys, lung, and mammary tumor of BALB/c mice were investigated at 1, 2 and 4 h following intravenous administration of fluorescent siRNA-loaded SNPs. Following SNPs-mediated in vivo delivery of p53 gene and MAPK siRNA, the effects of exogenous p53 expression and silencing of endogenous MAPK were analyzed via tumor size measurement over 14 days. Results: SNPs mainly accumulate in the liver and kidney with notable deposition in the brain, lung, spleen, and tumor tissues. However, higher salt concentrations hindered the optimal localization of SNPs in tumor tissues. Despite lower residual accumulation in tumor tissues, mice treated with SNPs carrying either p53 gene or MAPK siRNA demonstrated slower tumor growth than those treated with the naked gene or siRNA. Unlike p53 gene, higher siRNA concentration resulted in lower regression activity of the carcinoma tissues, which might be due to unexpected off-target effects. Conclusion: The effective role of SNPs in overcoming biological barriers in vivo and supporting gene trafficking for substantial nucleic acid activities at the targeted tissues provides an opportunity for future novel therapeutic strategies for breast cancer.