Neuron-targeted liposomal coenzyme Q10 attenuates neuronal ferroptosis after subarachnoid hemorrhage by activating the ferroptosis suppressor protein 1/coenzyme Q10 system.

Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. SAH disrupts the blood‒brain barrier, leading to the release of iron ions from blood within the subarachnoid space, subsequently inducing neuronal ferroptosis. A recently discovered protein, known as ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10 by introducing the neuron-targeting peptide Tet1 onto the surface of liposomal CoQ10. Our objective was to determine whether this formulation could activate the FSP1 system and subsequently inhibit neuronal ferroptosis. Our findings revealed that neuron-targeted liposomal CoQ10 effectively localized to neurons at the lesion site after SAH. Furthermore, it facilitated the upregulation of FSP1, reduced the accumulation of malondialdehyde and reactive oxygen species, inhibited neuronal ferroptosis, and exerted neuroprotective effects both in vitro and in vivo. Our study provides evidence that supplementation with CoQ10 can effectively activate the FSP1 system. Additionally, we developed a neuron-targeted liposomal CoQ10 formulation that can be selectively delivered to neurons at the site of SAH. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH. STATEMENT OF SIGNIFICANCE: Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. Ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10. We find that it effectively localized to neurons at the lesion site after SAH and activated the FSP1/CoQ10 system. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH and other central nervous system diseases characterized by disruption of the blood-brain barrier.

Biocompatibility of Mn0.4Zn0.6Fe2O4 Magnetic Nanoparticles and Their Thermotherapy on VX2-Carcinoma-Induced Liver Tumors.

Malignant tumors are the most serious threat to human health. Much research has focused on revealing the characteristics of this disease and developing methods of treatment. Because tumor cells are more sensitive to heat than normal cells, thermotherapy for the treatment of tumors has attracted much attention. In this paper, we presented functional Mn-Zn ferrite nanoparticles with the molecular composition of Mn0.4Zn0.6Fe2O4 as the magnetic response material for the thermotherapy. The suggested Mn-Zn ferrite nanoparticles were with a self-regulation temperature of 43 degrees C which was ideal for tumor thermotherapy. The biocompatibility and anti-tumor effect of this material were well investigated. It was found that the Mn0.4Zn0.6Fe2O4 nanoparticles have no hemolysis activity, no genotoxic effects and cytotoxicity. Its Median Lethal Dose (LD50) arrived at 6.026 g/kg and it did not induce any abnormal clinical signs in laboratory animals. Moreover, the suggested nanoparticles can increase the inhibitory ratio of weight and volume of tumors, cause tumor tissues necrosis and show the therapeutic effect on the xenograft live cancers in vivo. Based on these results, we could envision the valuable application of the Mn0.4Zn0.6Fe2O4 nanoparticles for the practical thermotherapy.

Preparation and biodistribution of 188Re-labeled folate conjugated human serum albumin magnetic cisplatin nanoparticles (188Re-folate-CDDP/HSA MNPs) in vivo.

BACKGROUND: The purpose of this study was to develop intraperitoneal hyperthermic therapy based on magnetic fluid hyperthermia, nanoparticle-wrapped cisplatin chemotherapy, and magnetic particles of albumin. In addition, to combine the multiple-killing effects of hyperthermal targeting therapy, chemotherapy, and radiotherapy, the albumin-nanoparticle surfaces were linked with radionuclide (188)Re-labeled folic acid ligand ((188)Re-folate-CDDP/HSA). METHODS: Human serum albumin was labeled with (188)Re using the pre-tin method. Reaction time and optimal conditions of labeling were investigated. The particles were intravenously injected into mice, which were sacrificed at different time points. Radioactivity per gram of tissue of percent injected dose (% ID/g) was measured in vital organs. The biodistribution of (188)Re-folate-CDDP/HAS magnetic nanoparticles was assessed. RESULTS: Optimal conditions for (188)Re-labeled folate-conjugated albumin combined with cisplatin magnetic nanoparticles were: 0.1 mL of sodium gluconate solution (0.3 mol/L), 0.1 mL of concentrated hydrochloric acid with dissolved stannous chloride (10 mg/mL), 0.04 mL of acetic acid buffer solution (pH 5, 0.2 mol/L), 30 mg of folate-conjugated albumin combined with cisplatin magnetic nanoparticles, and (188)ReO(4) eluent (0.1 mL). The rate of (188)Re-folate-CDDP-HSA magnetic nanoparticle formation exceeded 90%, and radiochemical purity exceeded 95%. The overall labeling rate was 83% in calf serum at 37°C. The major uptake tissues were the liver, kidney, intestine, and tumor after the (188)Re-folate-CDDP/HSA magnetic nanoparticles were injected into nude mice. Uptake of (188)Re-folate-CDDP/HSA magnetic nanoparticles increased gradually after injection, peaked at 8 hours with a value of 8.83 ± 1.71, and slowly decreased over 24 hours in vivo. CONCLUSION: These results indicate that (188)Re-folate-CDDP/HSA magnetic nanoparticles can be used in radionuclide-targeted cancer therapy. Surface-modified albumin nanoparticles with folic acid ligand-labeled radionuclide ((188)Re) were successfully prepared, laying the foundation for a triple-killing effect of thermotherapy, chemotherapy, and radiation therapy.

Using thermal energy produced by irradiation of Mn-Zn ferrite magnetic nanoparticles (MZF-NPs) for heat-inducible gene expression.

One of the main advantages of gene therapy over traditional therapy is the potential to target the expression of therapeutic genes in desired cells or tissues. To achieve targeted gene expression, we developed a novel heat-inducible gene expression system in which thermal energy generated by Mn-Zn ferrite magnetic nanoparticles (MZF-NPs) under an alternating magnetic field (AMF) was used to activate gene expression. MZF-NPs, obtained by co-precipitation method, were firstly surface modified with cation poly(ethylenimine) (PEI). Then thermodynamic test of various doses of MZF-NPs was preformed in vivo and in vitro. PEI-MZF-NPs showed good DNA binding ability and high transfection efficiency. In AMF, they could rise to a steady temperature. To analyze the heat-induced gene expression under an AMF, we combined P1730OR vector transfection with hyperthermia produced by irradiation of MZF-NPs. By using LacZ gene as a reporter gene and Hsp70 as a promoter, it was demonstrated that expression of a heterogeneous gene could be elevated to 10 to 500-fold over background by moderate hyperthermia (added 12.24 or 25.81 mg MZF-NPs to growth medium) in tissue cultured cells. When injected with 2.6 or 4.6 mg MZF-NPs, the temperature of tumor-bearing nude mice could rise to 39.5 or 42.8 degrees C, respectively, and the beta-gal concentration could increase up to 3.8 or 8.1 mU/mg proteins accordingly 1 day after hyperthermia treatment. Our results therefore supported hyperthermia produced by irradiation of MZF-NPs under an AMF as a feasible approach for targeted heat-induced gene expression. This novel system made use of the relative low Curie point of MZF-NPs to control the in vivo hyperthermia temperature and therefore acquired safe and effective heat-inducible transgene expression.