Pervasive Genomic Damage in Experimental Intracerebral Hemorrhage: Therapeutic Potential of a Mechanistic-Based Carbon Nanoparticle.

Therapy for intracerebral hemorrhage (ICH) remains elusive, in part dependent on the severity of the hemorrhage itself as well as multiple deleterious effects of blood and its breakdown products such as hemin and free iron. While oxidative injury and genomic damage have been seen following ICH, the details of this injury and implications remain unclear. Here, we discovered that, while free iron produced mostly reactive oxygen species (ROS)-related single-strand DNA breaks, hemin unexpectedly induced rapid and persistent nuclear and mitochondrial double-strand breaks (DSBs) in neuronal and endothelial cell genomes and in mouse brains following experimental ICH comparable to that seen with γ radiation and DNA-complexing chemotherapies. Potentially as a result of persistent DSBs and the DNA damage response, hemin also resulted in senescence phenotype in cultured neurons and endothelial cells. Subsequent resistance to ferroptosis reported in other senescent cell types was also observed here in neurons. While antioxidant therapy prevented senescence, cells became sensitized to ferroptosis. To address both senescence and resistance to ferroptosis, we synthesized a modified, catalytic, and rapidly internalized carbon nanomaterial, poly(ethylene glycol)-conjugated hydrophilic carbon clusters (PEG-HCC) by covalently bonding the iron chelator, deferoxamine (DEF). This multifunctional nanoparticle, DEF-HCC-PEG, protected cells from both senescence and ferroptosis and restored nuclear and mitochondrial genome integrity in vitro and in vivo. We thus describe a potential molecular mechanism of hemin/iron-induced toxicity in ICH that involves a rapid induction of DSBs, senescence, and the consequent resistance to ferroptosis and provide a mechanistic-based combinatorial therapeutic strategy.

Critical Comparison of the Superoxide Dismutase-like Activity of Carbon Antioxidant Nanozymes by Direct Superoxide Consumption Kinetic Measurements.

The superoxide dismutase-like activity of poly(ethylene glycolated) hydrophilic carbon clusters (PEG-HCCs), anthracite and bituminous graphene quantum dots (PEG-aGQDs and PEG-bGQDs, respectively), and two fullerene carbon nanozymes, tris malonyl-C60 fullerene (C3) and polyhydroxylated-C60 fullerene (C60-OHn), were compared using direct optical stopped-flow kinetic measurements, together with three native superoxide dismutases (SODs), CuZnSOD, MnSOD, and FeSOD, at both pH 12.7 and 8.5. Computer modeling including both SOD catalytic steps and superoxide self-dismutation enabled the best choice of catalyst concentration with minimal contribution to the observed kinetic change from the substrate self-dismutation. Biexponential fitting to the kinetic data ranks the rate constant (M-1 s-1) in the order of PEG-HCCs > CuZnSOD ≈ MnSOD ≈ PEG-aGQDs ≈ PEG-bGQDs > FeSOD ≫ C3 > C60-OHn at pH 12.7 and MnSOD > CuZnSOD ≈ PEG-HCCs > FeSOD > PEG-aGQDs ≈ PEG-bGQDs ≫ C3 ≈ C60-OHn at pH 8.5. Nonlinear regression of the kinetic model above yielded the same ranking as the biexponential fit, but provided better mechanistic insight. The data obtained by freeze-quench EPR direct assay at pH 12.7 also yield the same ranking as stopped-flow data. This is a necessary assessment of a panel of proclaimed carbon nano SOD mimetics using the same two direct methods, revealing a dramatic, 3-4 orders of magnitude difference in SOD activity between PEG-HCCs/PEG-GQDs from soluble fullerenes.

Enhancing Prostate-Cancer-Specific MRI by Genetic Amplified Nanoparticle Tumor Homing.

Precise localization and visualization of early-stage prostate cancer (PCa) is critical to improve the success of focal ablation and reduce cancer mortality. However, it remains challenging under the current imaging techniques due to the heterogeneous nature of PCa and the suboptimal sensitivity of the techniques themselves. Herein, a novel genetic amplified nanoparticle tumor-homing strategy to enhance the MRI accuracy of ultrasmall PCa lesions is reported. This strategy could specifically drive TfR expressions in PCa under PCa-specific DD3 promoter, and thus remarkably increase Tf-USPIONs concentrations in a highly accurate manner while minimizing their non-specific off-target effects on normal tissues. Consequently, this strategy can pinpoint an ultrasmall PCa lesion, which is otherwise blurred in the current MRI, and thereby addresses the unmet key need in MRI imaging for focal therapy. With this proof-of-concept experiment, the synergistic gene-nano strategy holds great promise to boost the MRI effects of a wide variety of commonly used nanoscale and molecular probes that are otherwise limited. In addition, such a strategy may also be translated and applied to MR-specific imaging of other types of cancers by using their respective tumor-specific promoters.

Designing next generation of photon upconversion: Recent advances in organic triplet-triplet annihilation upconversion nanoparticles.

Organic triplet-triplet annihilation upconversion (TTA-UC) nanoparticles have emerged as exciting therapeutic agents and imaging probes in recent years due to their unique chemical and optical properties such as outstanding biocompatibility and low power excitation density. In this review, we focus on the latest breakthroughs in such new version of upconversion nanoparticle, including their design, preparation, and applications. First, we will discuss the key principles and design concept of these organic-based photon upconversion in regard to the methods of selection of the related triplet TTA dye pairs (photosensitizer and emitter). Then, we will discuss the recent approaches s to construct TTA-UCNPs including silica TTA-UCNPs, lipid-coated TTA-UCNPs, polymer encapsulated TTA-UCNPs, nano-droplet TTA-UCNPs and metal-organic frameworks (MOFs) constructed TTA-UCNPs. In addition, the applications of TTA-UCNPs will be discussed. Finally, we will discuss the challenges posed by current TTA-UCNP development.

Phase I clinical trial of lenalidomide in combination with bevacizumab in patients with advanced cancer.

PURPOSE: Lenalidomide and bevacizumab have antitumor activity in various tumor types. We conducted a phase I study of this combination in patients with advanced cancer. PATIENTS AND METHODS: A "3 + 3" study design was used. Lenalidomide 10 or 20 mg (orally, days 1-21) and bevacizumab 5, 7.5, or 10 mg/kg, (intravenously, every 2 weeks) were given at four escalating dose levels, followed by an expansion phase at the highest maximum tolerated dose (MTD) (1 cycle = 4 weeks). Dose-limiting toxicity (DLT), MTD, adverse events, and clinical outcomes were assessed. RESULTS: Thirty-one patients were enrolled (median age, 60 years; men, 52 %). The most common tumor types were colorectal carcinoma (n = 11) and melanoma (n = 5). Overall, 105 cycles (median, 2) were administered. No DLTs were observed. The maximum tested dose (level 4) was used in the expansion phase. The most common toxicities were fatigue (n = 7, 23 %) and skin rash (n = 4, 13 %). One patient developed a transient ischemic attack (3.2 %); prophylactic anticoagulation became mandatory in the subsequent 17 treated patients. Of 31 patients, 27 were evaluable for response. Stable disease (SD) was noted in 10 (37 %) patients, including five patients with SD for ≥6 months (tumor types: clear cell sarcoma, germ cell tumor, colorectal carcinoma, and melanoma). The median progression-free survival and overall survival were 2.8 and 5.5 months, respectively. CONCLUSIONS: The combination of lenalidomide with bevacizumab in patients with advanced solid tumors was safe. Prolonged stable disease was noted in selected tumor types, warranting further clinical evaluation.