Cancer is one of the leading causes of morbidity and mortality in the world, but more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy and hypothesize that the FT efficacy can be significantly improved via accelerating the Fenton reaction by simultaneously increasing the local concentrations of all reactants (Fe 2+ , Fe 3+ , and H 2 O 2 ) in cancer cells. Thus, Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded Fe 3 O 4 /Gd 2 O 3 hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2) (FeGd-HN@Pt@LF/RGD2), were exploited in this study for FT of orthotopic brain tumors. FeGd-HN@Pt@LF/RGD2 nanoparticles were able to cross the blood−brain barrier because of its small size (6.6 nm) and LF-receptor-mediated transcytosis. FeGd-HN@Pt@LF/RGD2 can be internalized into cancer cells by integrin α v β 3 -mediated endocytosis and then release Fe 2+ , Fe 3+ , and CDDP upon endosomal uptake and degradation. Fe 2+ and Fe 3+ can directly participate in the Fenton reaction, whereas the CDDP can indirectly produce H 2 O 2 to further accelerate the Fenton reaction. The acceleration of Fenton reaction generates reactive oxygen species to induce cancer cell death. FeGd-HN@Pt@LF/RGD2 successfully delivered reactants involved in the Fenton reaction to the tumor site and led to significant inhibition of tumor growth. Finally, the intrinsic magnetic resonance imaging (MRI) capability of the nanoparticles was used to assess and monitor tumor response to FT (self-MRI monitoring).
The recently emerged exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) (<5 nm) are promising T-weighted contrast agents for magnetic resonance imaging (MRI) due to their good biocompatibility compared with Gd-chelates. However, the best particle size of ES-MIONs for T imaging is still unknown because the synthesis of ES-MIONs with precise size control to clarify the relationship between the r (or r/r) and the particle size remains a challenge. In this study, we synthesized ES-MIONs with seven different sizes below 5 nm and found that 3.6 nm is the best particle size for ES-MIONs to be utilized as T-weighted MR contrast agent. To enhance tumor targetability of theranostic nanoparticles and reduce the nonspecific uptake of nanoparticles by normal healthy cells, we constructed a drug delivery system based on the 3.6 nm ES-MIONs for T-weighted tumor imaging and chemotherapy. The laser scanning confocal microscopy (LSCM) and flow cytometry analysis results demonstrate that our strategy of precise targeting via exposure or hiding of the targeting ligand RGD on demand is feasible. The MR imaging and chemotherapy results on the cancer cells and tumor-bearing mice reinforce that our DOX@ES-MION3@RGD@mPEG3 nanoparticles are promising for high-resolution T-weighted MR imaging and precise chemotherapy of tumors.
Background-Three-fourths of cardiac arrest survivors die before hospital discharge or suffer significant neurological injury. Except for therapeutic hypothermia and revascularization, no novel therapies have been developed that improve survival or cardiac and neurological function after resuscitation. Nitrite (NO 2 Ϫ ) increases cellular resilience to focal ischemia/reperfusion injury in multiple organs. We hypothesized that nitrite therapy may improve outcomes after the unique global ischemia/reperfusion insult of cardiopulmonary arrest. Methods and Results-We developed a mouse model of cardiac arrest characterized by 12 minutes of normothermic asystole and a high cardiopulmonary resuscitation rate. In this model, global ischemia and cardiopulmonary resuscitation were associated with blood and organ nitrite depletion, reversible myocardial dysfunction, impaired alveolar gas exchange, neurological injury, and an Ϸ50% mortality. A single low dose of intravenous nitrite (50 nmolϭ1.85 mol/kgϭ0.13 mg/kg) compared with blinded saline placebo given at cardiopulmonary resuscitation initiation with epinephrine improved cardiac function, survival, and neurological outcomes. From a mechanistic standpoint, nitrite treatment restored intracardiac nitrite and increased S-nitrosothiol levels, decreased pathological cardiac mitochondrial oxygen consumption resulting from reactive oxygen species formation, and prevented oxidative enzymatic injury via reversible specific inhibition of respiratory chain complex I. Conclusion-Nitrite therapy after resuscitation from 12 minutes of asystole rapidly and reversibly modulated mitochondrial reactive oxygen species generation during early reperfusion, limiting acute cardiac dysfunction, death, and neurological impairment in survivors. (Circulation. 2009;120:897-905.)
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