Drug-Loaded Nanogel for Efficient Orchestration of Cell Death Pathways by Intramitochondrial Disulfide Polymerization.

Chemotherapy using a nanoscaled drug delivery system is an effective cancer therapy, but its high drug concentration often causes drug resistance in cancer cells and normal cell damage. Combination therapy involving two or more different cell signaling pathways can be a powerful tool to overcome the limitations of chemotherapy. Herein, this article presents nanogel (NG)-mediated co-delivery of a chemodrug camptothecin (CPT) and mitochondria-targeting monomer (MT monomer) for efficient activation of two modes of the programmed cell death pathway (apoptosis and necroptosis) and synergistic enhancement of cancer therapy. CPT and the monomer are incorporated together into the redox-degradable polymeric NGs for release in response to the intracellular glutathione. The MT monomer is shown to undergo reactive oxygen species (ROS)-triggered disulfide polymerization inside the cancerous mitochondria in cooperation with the chemotherapeutic CPT elevating the intracellular ROS level. The CPT/monomer interconnection in cell death mechanisms for mitochondrial dysfunction and enhanced cell death is evidenced by a series of cell analyses showing ROS generation, mitochondria damage, impacts on (non)cancerous or drug-resistant cells, and cell death modes. The presented work provides beneficial insights for utilizing combination therapy to facilitate a desired cell death mechanism and developing a novel nanosystem for more efficacious cancer treatment.

Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer.

Lysosomes remain powerful organelles and important targets for cancer therapy because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancer by bypassing the classical caspase-dependent apoptotic pathway. However, most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth both in cancer and drug-resistant cancer xenograft models.

Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells.

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvß3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvß3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.

Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells.

Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long-term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria-targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl-monoquaternary ammonium-triphenyl phosphine (TPP) and alkyl-diquaternary ammonium-TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl-diquaternary ammonium-TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.

Self-Assembly of Mitochondria-Targeted Photosensitizer to Increase Photostability and Photodynamic Therapeutic Efficacy in Hypoxia.

The development of photosensitizers for cancer photodynamic therapy has been challenging due to their low photostability and therapeutic inefficacy in hypoxic tumor microenvironments. To overcome these issues, we have developed a mitochondria-targeted photosensitizer consisting of an indocyanine moiety with triphenylphosphonium arms, which can self-assemble into spherical micelles directed to mitochondria. Self-assembly of the photosensitizer resulted in a higher photostability by preventing free rotation of the indoline ring of the indocyanine moiety. The mitochondria targeting capability of the photosensitizer allowed it to utilize intramitochondrial oxygen. We found that the mitochondria-targeted photosensitizer localized to mitochondria and induced apoptosis of cancer cells both normoxic and hypoxic conditions through generation of ROS. The micellar self-assemblies of the photosensitizer were further confirmed to selectively localize to tumor tissues in a xenograft tumor mouse model through passive targeting and showed efficient tumor growth inhibition.

Hybrid ECG-gated versus non-gated 512-slice CT angiography of the aorta and coronary artery: image quality and effect of a motion correction algorithm.

Background Using the hybrid electrocardiogram (ECG)-gated computed tomography (CT) technique, assessment of entire aorta, coronary arteries, and aortic valve can be possible using single-bolus contrast administration within a single acquisition. Purpose To compare the image quality of hybrid ECG-gated and non-gated CT angiography of the aorta and evaluate the effect of a motion correction algorithm (MCA) on coronary artery image quality in a hybrid ECG-gated aorta CT group. Material and Methods In total, 104 patients (76 men; mean age = 65.8 years) prospectively randomized into two groups (Group 1 = hybrid ECG-gated CT; Group 2 = non-gated CT) underwent wide-detector array aorta CT. Image quality, assessed using a four-point scale, was compared between the groups. Coronary artery image quality was compared between the conventional reconstruction and motion correction reconstruction subgroups in Group 1. Results Group 1 showed significant advantages over Group 2 in aortic wall, cardiac chamber, aortic valve, coronary ostia, and main coronary arteries image quality (all P < 0.001). All Group 1 patients had diagnostic image quality of the aortic wall and left ostium. The MCA significantly improved the image quality of the three main coronary arteries ( P < 0.05). Moreover, per-vessel interpretability improved from 92.3% to 97.1% with the MCA ( P = 0.013). Conclusion Hybrid ECG-gated CT significantly improved the heart and aortic wall image quality and the MCA can further improve the image quality and interpretability of coronary arteries.

Safety and efficacy of a novel, fenestrated aortic arch stent graft with a preloaded catheter for supraaortic arch vessels: an experimental study in Swine.

Thoracic endovascular aortic repair (TEVAR) shows limitations in cases in which the aortic pathology involves the aortic arch. The study aims were to test a fenestrated aortic arch stent graft (FASG) with a preloaded catheter for the supraaortic arch vessels and to perform a preclinical study in swine to evaluate the safety and efficacy of this device. Six FASGs with 1 preloaded catheter and 5 FASGs with 2 preloaded catheters were advanced through the iliac artery in 11 swines. The presence of endoleaks and the patency and deformity of the grafts were examined with computed tomography (CT) at 4 weeks postoperatively. A postmortem examination was performed at 8 weeks. The mean procedure time for the one and two FASG groups was 30.2 (27.9-34.5) min and 43.1 (39.2-53.7) min. The mean time for the selection of the carotid artery was 4.8 (4.2-5.5) min and 6.2 (4.6-9.4) min. Major adverse event was observed in one of 11 pigs. One pig died at 4 weeks likely because of the effects of the high dose of ketamine, while the remaining 10 pigs survived 8-week. For both the one and two FASG groups, no endoleaks, no disconnection, no occlusion of the stent grafts were observed in the CT findings and the postmortem gross findings. The procedure with the FASG could be performed safely in a relatively short procedure time and involved an easy technique. The FASG is found to be safe and convenient in this preclinical study with swine.

Fluorination of graphene enhances friction due to increased corrugation.

The addition of a single sheet of carbon atoms in the form of graphene can drastically alter friction between a nanoscale probe tip and a surface. Here, for the first time we show that friction can be altered over a wide range by fluorination. Specifically, the friction force between silicon atomic force microscopy tips and monolayer fluorinated graphene can range from 5-9 times higher than for graphene. While consistent with previous reports, the combined interpretation from our experiments and molecular dynamics simulations allows us to propose a novel mechanism: that the dramatic friction enhancement results from increased corrugation of the interfacial potential due to the strong local charge concentrated at fluorine sites, consistent with the Prandtl-Tomlinson model. The monotonic increase of friction with fluorination in experiments also demonstrates that friction force measurements provide a sensitive local probe of the degree of fluorination. Additionally, we found a transition from ordered to disordered atomic stick-slip upon fluorination, suggesting that fluorination proceeds in a spatially random manner.

Robust sound-guided image manipulation.

Recent successes suggest that an image can be manipulated by a text prompt, e.g., a landscape scene on a sunny day is manipulated into the same scene on a rainy day driven by a text input "raining". These approaches often utilize a StyleCLIP-based image generator, which leverages multi-modal (text and image) embedding space. However, we observe that such text inputs are often bottlenecked in providing and synthesizing rich semantic cues, e.g., differentiating heavy rain from rain with thunderstorms. To address this issue, we advocate leveraging an additional modality, sound, which has notable advantages in image manipulation as it can convey more diverse semantic cues (vivid emotions or dynamic expressions of the natural world) than texts. In this paper, we propose a novel approach that first extends the image-text joint embedding space with sound and applies a direct latent optimization method to manipulate a given image based on audio input, e.g., the sound of rain. Our extensive experiments show that our sound-guided image manipulation approach produces semantically and visually more plausible manipulation results than the state-of-the-art text and sound-guided image manipulation methods, which are further confirmed by our human evaluations. Our downstream task evaluations also show that our learned image-text-sound joint embedding space effectively encodes sound inputs. Examples are provided in our project page: https://kuai-lab.github.io/robust-demo/.

Aerosol synthesis of cargo-filled graphene nanosacks.

Water microdroplets containing graphene oxide and a second solute are shown to spontaneously segregate into sack-cargo nanostructures upon drying. Analytical modeling and molecular dynamics suggest the sacks form when slow-diffusing graphene oxide preferentially accumulates and adsorbs at the receding air-water interface, followed by capillary collapse. Cargo-filled graphene nanosacks can be nanomanufactured by a simple, continuous, scalable process and are promising for many applications where nanoscale materials should be isolated from the environment or biological tissue.

Event fusion photometric stereo network.

Photometric stereo methods typically rely on RGB cameras and are usually performed in a dark room to avoid ambient illumination. Ambient illumination poses a great challenge in photometric stereo due to the restricted dynamic range of the RGB cameras. To address this limitation, we present a novel method, namely Event Fusion Photometric Stereo Network (EFPS-Net), which estimates the surface normals of an object in an ambient light environment by utilizing a deep fusion of RGB and event cameras. The high dynamic range of event cameras provides a broader perspective of light representations that RGB cameras cannot provide. Specifically, we propose an event interpolation method to obtain ample light information, which enables precise estimation of the surface normals of an object. By using RGB-event fused observation maps, our EFPS-Net outperforms previous state-of-the-art methods that depend only on RGB frames, resulting in a 7.94% reduction in mean average error. In addition, we curate a novel photometric stereo dataset by capturing objects with RGB and event cameras under numerous ambient light environments.

Surface protein-retractive and redox-degradable mesoporous organosilica nanoparticles for enhanced cancer therapy.

Targeted delivery along with controlled drug release is considered crucial in development of a drug delivery system (DDS) for efficient cancer treatment. In this paper, we present a strategy to obtain such a DDS by utilizing disulfide-incorporated mesoporous organosilica nanoparticles (MONs), which were engineered to minimize the surface interactions with proteins for better targeting and therapeutic performance. That is, after MONs were loaded with a chemodrug doxorubicin (DOX) through the inner pores, their outer surface was treated for conjugation to the glutathione-S-transferase (GST)-fused cell-specific affibody (Afb) (GST-Afb). These particles exhibited prompt responsivity to the SS bond-dissociating glutathione (GSH), which resulted in considerable degradation of the initial particle morphology and DOX release. As the protein adsorption to the MON surface appeared largely reduced, their targeting ability with GSH-stimulated therapeutic activities was demonstrated in vitro by employing two kinds of the GST-Afb protein, which target human cancer cells with the surface membrane receptor, HER2 or EGFR. Compared with unmodified control particles, the presented results show that our system can significantly enhance cancer-therapeutic outcomes of the loaded drug, offering a promising way of designing a more efficacious DDS.

Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study.

BACKGROUND: Treatment of critical limb ischemia (CLI) by bypass operation or percutaneous vascular intervention is occasionally difficult. The safety and efficacy of multiple intramuscular adipose tissue-derived mesenchymal stem cells (ATMSC) injections in CLI patients was determined in the study. METHODS AND RESULTS: The study included 15 male CLI patients with ischemic resting pain in 1 limb with/without non-healing ulcers and necrotic foot. ATMSC were isolated from adipose tissue of thromboangiitis obliterans (TAO) patients (B-ATMSC), diabetes patients (D-ATMSC), and healthy donors (control ATMSC). In a colony-forming unit assay, the stromal vascular fraction of TAO and diabetic patients yielded lesser colonies than that of healthy donors. D-ATMSC showed lower proliferation abilitythan B-ATMSC and control ATMSC, but they showed similar angiogenic factor expression with control ATMSC and B-ATMSC. Multiple intramuscular ATMSC injections cause no complications during the follow-up period (mean follow-up time: 6 months). Clinical improvement occurred in 66.7% of patients. Five patients required minor amputation during follow-up, and all amputation sites healed completely. At 6 months, significant improvement was noted on pain rating scales and in claudication walking distance. Digital subtraction angiography before and 6 months after ATMSC implantation showed formation of numerous vascular collateral networks across affected arteries. CONCLUSIONS: Multiple intramuscular ATMSC injections might be a safe alternative to achieve therapeutic angiogenesis in patients with CLI who are refractory to other treatment modalities.

Graphene-based environmental barriers.

Many environmental technologies rely on containment by engineered barriers that inhibit the release or transport of toxicants. Graphene is a new, atomically thin, two-dimensional sheet material, whose aspect ratio, chemical resistance, flexibility, and impermeability make it a promising candidate for inclusion in a next generation of engineered barriers. Here we show that ultrathin graphene oxide (GO) films can serve as effective barriers for both liquid and vapor permeants. First, GO deposition on porous substrates is shown to block convective flow at much lower mass loadings than other carbon nanomaterials, and can achieve hydraulic conductivities of 5 × 10(-12) cm/s or lower. Second we show that ultrathin GO films of only 20-nm thickness coated on polyethylene films reduce their vapor permeability by 90% using elemental mercury as a model vapor toxicant. The barrier performance of GO in this thin-film configuration is much better than the Nielsen model limit, which describes ideal behavior of flake-like fillers uniformly imbedded in a polymer. The Hg barrier performance of GO films is found to be sensitive to residual water in the films, which is consistent with molecular dynamics (MD) simulations that show lateral diffusion of Hg atoms in graphene interlayer spaces that have been expanded by hydration.

Thermal transport across twin grain boundaries in polycrystalline graphene from nonequilibrium molecular dynamics simulations.

We have studied the thermal conductance of tilt grain boundaries in graphene using nonequilibrium molecular dynamics simulations. When a constant heat flux is allowed to flow, we observe sharp jumps in temperature at the boundaries, characteristic of interfaces between materials of differing thermal properties. On the basis of the magnitude of these jumps, we have computed the boundary conductance of twin grain boundaries as a function of their misorientation angles. We find the boundary conductance to be in the range 1.5 × 10(10) to 4.5 × 10(10) W/(m(2) K), which is significantly higher than that of any other thermoelectric interfaces reported in the literature. Using the computed values of boundary conductances, we have identified a critical grain size of 0.1 µm below which the contribution of the tilt boundaries to the conductivity becomes comparable to that of the contribution from the grains themselves. Experiments to test the predictions of our simulations are proposed.

Spatiotemporal Self-Assembly of Peptide Amphiphiles by Carbonic Anhydrase IX-Targeting Induces Cancer-Lysosomal Membrane Disruption.

To achieve spatiotemporal control, an enzyme-instructed self-assembly system is widely used, but this approach typically has a small effect on cellular fate. In this study, we show that the intralysosomal assembly by a carbonic anhydrase IX (CAIX)-targeting peptide amphiphile (Pep-AT) can control cellular fate with a low therapeutic dose by tuning the surface charge based on pH change. Pep-AT self-assembles into a fibrous aggregate with a negative surface charge in an extracellular environment near CAIX. During endocytosis, it changes into a nanofiber with a positive surface charge at the lysosome. Then, it can disrupt the lysosomal membrane and induce cellular apoptosis. This study demonstrates that a spatiotemporal assembly induced by a cancer enzyme and specific organelle can control the cellular fate of cancer.

Intramitochondrial co-assembly between ATP and nucleopeptides induces cancer cell apoptosis.

Mitochondria are essential intracellular organelles involved in many cellular processes, especially adenosine triphosphate (ATP) production. Since cancer cells require high ATP levels for proliferation, ATP elimination can be a unique target for cancer growth inhibition. We describe a newly developed mitochondria-targeting nucleopeptide (MNP) that sequesters ATP by self-assembling with ATP inside mitochondria. MNP interacts strongly with ATP through electrostatic and hydrogen bonding interactions. MNP exhibits higher binding affinity for ATP (-637.5 kJ mol-1) than for adenosine diphosphate (ADP) (-578.2 kJ mol-1). To improve anticancer efficacy, the small-sized MNP/ADP complex formed large assemblies with ATP inside cancer cell mitochondria. ATP sequestration and formation of large assemblies of the MNP/ADP-ATP complex inside mitochondria caused physical stress by large structures and metabolic disorders in cancer cells, leading to apoptosis. This work illustrates a facile approach to developing cancer therapeutics that relies on molecular assemblies.

Intramitochondrial Disulfide Polymerization Controls Cancer Cell Fate.

Recent advances in supramolecular chemistry research have led to the development of artificial chemical systems that can form self-assembled structures that imitate proteins involved in the regulation of cellular function. However, intracellular polymerization systems that operate inside living cells have been seldom reported. In this study, we developed an intramitochondrial polymerization-induced self-assembly system for regulating the cellular fate of cancer cells. It showed that polymeric disulfide formation inside cells occurred due to the high reactive oxygen species (ROS) concentration of cancer mitochondria. This polymerization barely occurs elsewhere in the cell owing to the reductive intracellular environment. The polymerization of the thiol-containing monomers further increases the ROS level inside the mitochondria, thereby autocatalyzing the polymerization process and creating fibrous polymeric structures. This process induces dysfunction of the mitochondria, which in turn activates cell necroptosis. Thus, this in situ polymerization system shows great potential for cancer treatment, including that of drug-resistant cancers.

Drug resistance-free cytotoxic nanodrugs in composites for cancer therapy.

Drug resistance is a major cause of treatment failure for small-molecule cancer chemotherapies, despite the advances in combination therapies, drug delivery systems, epigenetic drugs, and proteolysis-targeting chimeras. Herein, we report the use of a drug resistance-free cytotoxic nanodrug as an alternative to small-molecule drugs. The present nanodrugs comprise 2 nm core gold nanoparticles (AuNPs) covered completely with multivalent hydrocarbon chains to a final diameter of ∼10 nm as single drug molecules. This hydrophobic drug-platform was delivered in composite form (∼35 nm) with block-copolymer like other small-molecular drugs. Upon uptake by cells, the nanodrugs enhanced the intracellular levels of reactive oxygen species and induced apoptosis, presumably reflecting multivalent interactions between aliphatic chains and intracellular biomolecules. No resistance to our novel nanodrug was observed following multiple treatment passages and the potential for use in cancer therapy was verified in a breast cancer patient-derived xenograft mouse model. These findings provide insight into the use of nano-scaled compounds as agents that evade drug resistance to cancer therapy.

Clinical outcomes of endovascular treatment for ruptured thoracic aortic disease.

BACKGROUND/AIMS: Untreated rupture of the thoracic aorta is associated with a high mortality rate. We aimed to review the clinical results of endovascular treatment for ruptured thoracic aortic disease. METHODS: We retrospectively reviewed data on 37 patients (mean age, 67.0 ± 15.18 years) treated for ruptured thoracic aortic disease from January 2005 to May 2016. The median follow-up duration was 308 days (interquartile range, 61 to 1,036.5). The primary end-point of the study was the composite of death, secondary intervention, endoleak, and major stroke/paraplegia after endovascular treatment. RESULTS: The etiologies of ruptured thoracic aortic disease were aortic dissection (n = 11, 29.7%), intramural hematoma (n = 7, 18.9%), thoracic aortic aneurysm (n = 14, 37.8%), and traumatic aortic transection (n = 5, 13.5%). Three patients died within 24 hours of thoracic endovascular aortic repair, and one showed type I endoleak. The technical success rate was 89.2% (33/37). The in-hospital mortality rate was 13.5% (5/37); no deaths occurred during follow-up. The composite outcome rate during follow-up was 37.8% (14/37), comprising death (n = 5, 13.5%), secondary intervention (n = 5, 13.5%), endoleak (n = 5, 13.5%), and major stroke/paraplegia (n = 3, 8.1%). Left subclavian artery revascularization and proximal landing zone were not associated with the composite outcome. Low mean arterial pressure (MAP; ≤ 60 mmHg, [hazard ratio, 13.018; 95% confidence interval, 2.435 to 69.583, p = 0.003]) was the most significant predictor and high transfusion requirement in the first 24 hours was associated with event-free survival (log rank p = 0.018). CONCLUSION: Endovascular treatment achieves high technical success rates and acceptable clinical outcome. High transfusion volume and low MAP were associated with poor clinical outcomes.