Uncovering the Fate and Risks of Intravenously Injected Prussian Blue Nanoparticles in mice by an Integrated Methodology of Toxicology, Pharmacokinetics, Proteomics, and Metabolomics.

BACKGROUND: Prussian blue (PB) nanoparticles (NPs) have been intensively investigated for medical applications, but an in-depth toxicological investigation of PB NPs has not been implemented. In the present study, a comprehensive investigation of the fate and risks of PB NPs after intravenous administration was carried out by using a mouse model and an integrated methodology of pharmacokinetics, toxicology, proteomics, and metabolomics. RESULTS: General toxicological studies demonstrated that intravenous administration of PB NPs at 5 or 10 mg/kg could not induce obvious toxicity in mice, while mice treated with a relatively high dose of PB NPs at 20 mg/kg exhibited loss of appetite and weight decrease in the first two days postinjection. Pharmacokinetic studies revealed that intravenously administered PB NPs (20 mg/kg) underwent fast clearance from blood, highly accumulated in the liver and lungs of mice, and finally cleared from tissues. By further integrated proteomics and metabolomics analysis, we found that protein expression and metabolite levels changed significantly in the liver and lungs of mice due to the high accumulation of PB NPs, leading to slight inflammatory responses and intracellular oxidative stress. CONCLUSIONS: Collectively, our integrated experimental data imply that the high accumulation of PB NPs may cause potential risks to the liver and lungs of mice, which will provide detailed references and guidance for further clinical application of PB NPs in the future.

A tumor-penetrable drug nanococktail made from human histones for interventional nucleus-targeted chemophotothermal therapy of drug-resistant tumors.

Nanoparticle-based chemophotothermal therapy (CPT) is a promising treatment for multidrug resistant tumors. In this study, a drug nanococktail of DIR825@histone was developed by employing doxorubicin (DOX), NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser. After localized intervention, DIR825@histone penetrated tumor tissues by transcytosis, efficiently entered tumor cells and targeted the cell nuclei. DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release. Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting. Moreover, an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury. Therefore, DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.

Engineering temperature-sensitive plateletsomes as a tailored chemotherapy platform in combination with HIFU ablation for cancer treatment.

Chemotherapy is widely used in combination with high-intensity focused ultrasound (HIFU) ablation for cancer therapy; however, the spatial and temporal integration of chemotherapy and HIFU ablation remains a challenge. Here, temperature-sensitive plateletsomes (TSPs) composed of platelet (PLT) membrane, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine were developed to adequately integrate chemotherapy with HIFU tumor ablation in vivo. Methods: The thermosensitive permeability of TSPs was evaluated under both water bath heating and HIFU hyperthermia. The targeting performance, pharmacokinetic behavior and therapeutic potential of TSPs in combination with HIFU ablation were evaluated using HeLa cells and a HeLa cell tumor-bearing nude mouse model in comparison with temperature-sensitive liposomes (TSLs). Results: TSPs showed high drug loading efficiency and temperature-sensitive permeability. When applied in vivo, TSPs showed a circulation lifetime comparable to that of TSLs and exhibited PLT-specific cancer cell affinity and a vascular damage response. Upon HIFU hyperthermia, TSPs displayed ultrafast drug release and enhanced tumor uptake, providing high drug availability in the tumor site to cooperate with HIFU ablation. After HIFU ablation, TSPs rapidly targeted the postoperative tumor site by adhesion to the damaged tumor vasculature, leading to targeted and localized postoperative chemotherapy. Conclusion: Due to effective integration at both intraoperative and postoperative stages, TSPs could be a promising chemotherapy nanoplatform in combination with HIFU ablation for cancer therapy.