Extracellular-vesicles delivered tumor-specific sequential nanocatalysts can be used for MRI-informed nanocatalytic Therapy of hepatocellular carcinoma.
ABSTRACT: Background: Conventional therapeutic strategies for advanced hepatocellular carcinoma (HCC) remains a great challenge, therefore the alternative therapeutic modality for specific and efficient HCC suppression is urgently needed. Methods: In this work, HCC-derived extracellular vesicles (EVs) were applied as surface nanocarrier for sequential nanocatalysts GOD-ESIONs@EVs (GE@EVs) of tumor-specific and cascade nanocatalytic therapy against HCC. By enhancing the intracellular endocytosis through arginine-glycine-aspartic acid (RGD)-targeting effect and membrane fusion, sequential nanocatalysts led to more efficient treatment in the HCC tumor region in a shorter period of time. Results: Through glucose consumption as catalyzed by the loaded glucose oxidase (GOD) to overproduce hydrogen peroxide (H2O2), highly toxic hydroxyl radicals were generated by Fenton-like reaction as catalyzed by ESIONs, which was achieved under the mildly acidic tumor microenvironment, enabling the stimuli of the apoptosis and necrosis of HCC cells. This strategy demonstrated the high active-targeting capability of GE@EVs into HCC, achieving highly efficient tumor suppression both in vitro and in vivo. In addition, the as-synthesized nanoreactor could act as a desirable nanoscale contrast agent for magnetic resonance imaging, which exhibited desirable imaging capability during the sequential nanocatalytic treatment. Conclusion: This application of surface-engineering EVs not only proves the high-performance catalytic therapeutic modality of GE@EVs for HCC, but also broadens the versatile bio-applications of EVs.
Project description:Therapeutic nanocatalysis has emerged as an intriguing strategy for efficient cancer-specific therapy, but the traditional inorganic nanocatalysts suffer from low catalytic efficiency and difficulty in biodegradation, hindering their further clinical translation. Herein, a tumor microenvironment-triggered, biodegradable and biocompatible nanocatalyst employing 2D hydroxide nanosheet is presented, and is shown to have high catalytic capacity to efficiently produce abundant hydroxyl radicals under the tumor microenvironment and consequently kill tumor cells selectively. A polyethylene glycol (PEG)-conjugated Fe<sup>2+</sup>-containing hydroxide nanosheet is successfully constructed via a facile but efficient bottom-up approach that concurrently realizes nanosheet synthesis and PEGylation. Importantly, the nanosheets are featured with high catalytic activity to disproportionate H<sub>2</sub>O<sub>2</sub> in tumors, and consequently generate abundant hydroxyl radicals at a high reaction rate under tumorous acidic condition; the highly toxic hydroxyl radicals, as a result, cause the death of tumor cells in vitro and suppress the tumor growth in vivo without the use of any supplementary toxic agent, only with the biocompatible nanocatalysts. Meanwhile, the desirable biodegradation and biocompatibility of the hydroxide nanosheet render a high degree of safety to the organism. Therefore, this work provides the first paradigm of biodegradable 2D nanocatalytic platform with concurrently high catalytic-therapeutic performance and biosafety for efficient tumor-specific treatment.
Project description:Tumor cells metabolize in distinct pathways compared with most normal tissue cells. The resulting tumor microenvironment would provide characteristic physiochemical conditions for selective tumor modalities. Here we introduce a concept of sequential catalytic nanomedicine for efficient tumor therapy by designing and delivering biocompatible nanocatalysts into tumor sites. Natural glucose oxidase (GOD, enzyme catalyst) and ultrasmall Fe3O4 nanoparticles (inorganic nanozyme, Fenton reaction catalyst) have been integrated into the large pore-sized and biodegradable dendritic silica nanoparticles to fabricate the sequential nanocatalyst. GOD in sequential nanocatalyst could effectively deplete glucose in tumor cells, and meanwhile produce a considerable amount of H2O2 for subsequent Fenton-like reaction catalyzed by Fe3O4 nanoparticles in response to mild acidic tumor microenvironment. Highly toxic hydroxyl radicals are generated through these sequential catalytic reactions to trigger the apoptosis and death of tumor cells. The current work manifests a proof of concept of catalytic nanomedicine by approaching selectivity and efficiency concurrently for tumor therapeutics.The specific metabolism of cancer cells may allow for selective tumor therapeutics. Here, the authors show that a suitable combination of an enzyme and iron nanoparticles loaded on dendritic silica induces apoptosis of cancer cells in response to the glucose-reliant and mild acidic microenvironment.
Project description:Emerging nanocatalytic tumor therapies based on nontoxic but catalytically active inorganic nanoparticles (NPs) for intratumoral production of high-toxic reactive oxygen species have inspired great research interest in the scientific community. Nanozymes exhibiting natural enzyme-mimicking catalytic activities have been extensively explored in biomedicine, mostly in biomolecular detection, yet much fewer researches are available on specific nanocatalytic tumor therapy. This study reports on the construction of an efficient biomimetic dual inorganic nanozyme-based nanoplatform, which triggers cascade catalytic reactions for tumor microenvironment responsive nanocatalytic tumor therapy based on ultrasmall Au and Fe3O4 NPs coloaded dendritic mesoporous silica NPs. Au NPs as the unique glucose oxidase-mimic nanozyme specifically catalyze β-D-glucose oxidation into gluconic acid and H2O2, while the as produced H2O2 is subsequently catalyzed by the peroxidase-mimic Fe3O4 NPs to liberate high-toxic hydroxyl radicals for inducing tumor-cell death by the typical Fenton-based catalytic reaction. Extensive in vitro and in vivo evaluations have demonstrated high nanocatalytic-therapeutic efficacy with a desirable tumor-suppression rate (69.08%) based on these biocompatible composite nanocatalysts. Therefore, this work paves a way for nanocatalytic tumor therapy by rationally designing inorganic nanozymes with multienzymatic activities for achieving high therapeutic efficacy and excellent biosafety simultaneously.
Project description:Bimetallic nanocatalysts, with efficient and controllable catalytic performance, have a promising application in chemical production. In this study, surface Pt-rich bimetallic AuPt nanoparticles with different Pt/Au ratios were prepared and tested in selective hydrogenation reactions of substituted nitroaromatics. Au nanoparticles were first prepared with n-butyllithium as a rapid reducer, which were further used as seeds in the slow growth process of Pt atoms. Because of the employed sequential reduction method and the following atom diffusion, surface Pt-rich bimetallic AuPt nanoparticles were obtained. Compared with the uniform AuPt alloy nanocatalysts synthesized by the co-reduction method with n-butyllithium as the reducer and monometallic Pt nanocatalysts, the obtained surface Pt-rich AuPt bimetallic nanocatalysts presented an enhanced catalytic selectivity or activity. The performance enhancement is assigned to the optimized Au/Pt interaction in the surface Pt-rich bimetallic nanostructures. This work demonstrates that the optimization of the stoichiometry and construction of bimetallic materials is a feasible method to synthesize controllable and efficient nanocatalysts.
Project description:For the practical application of nanocatalysts, it is desirable to understand the spatiotemporal fluctuations of nanocatalytic activity at the single-nanoparticle level. Here we use time-lapsed superresolution mapping of single-molecule catalysis events on individual nanoparticles to observe time-varying changes in the spatial distribution of catalysis events on Sb-doped TiO2 nanorods and Au triangle nanoplates. Compared with the active sites on well-defined surface facets, the defects of the nanoparticle catalysts possess higher intrinsic reactivity but lower stability. Corners and ends are more reactive but also less stable than flat surfaces. Averaged over time, the most stable sites dominate the total apparent activity of single nanocatalysts. However, the active sites with higher intrinsic activity but lower stability show activity at earlier time points before deactivating. Unexpectedly, some active sites are found to recover their activity ("self-healing") after deactivation, which is probably due to desorption of the adsorbate. Our superresolution measurement of different types of active catalytic sites, over both space and time, leads to a more comprehensive understanding of reactivity patterns and may enable the design of new and more productive heterogeneous catalysts.
Project description:In hepatocellular carcinoma (HCC) patients with extrahepatic metastasis, the lung is the most frequent site of metastasis. However, how the lung microenvironment favors disseminated cells remains unclear. Here, it is found that nidogen 1 (NID1) in metastatic HCC cell-derived extracellular vesicles (EVs) promotes pre-metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of tumor cells and extrahepatic metastasis. EV-NID1 also activates fibroblasts, which secrete tumor necrosis factor receptor 1 (TNFR1), facilitate lung colonization of tumor cells, and augment HCC cell growth and motility. Administration of anti-TNFR1 antibody effectively diminishes lung metastasis induced by the metastatic HCC cell-derived EVs in mice. In the clinical perspective, analysis of serum EV-NID1 and TNFR1 in HCC patients reveals their positive correlation and association with tumor stages suggesting the potential of these molecules as noninvasive biomarkers for the early detection of HCC. In conclusion, these results demonstrate the interplay of HCC EVs and activated fibroblasts in pre-metastatic niche formation and how blockage of their functions inhibits distant metastasis to the lungs. This study offers promise for the new direction of HCC treatment by targeting oncogenic EV components and their mediated pathways.
Project description:Direct ethanol fuel cells (DEFC) still lack active and efficient electrocatalysts for the alkaline ethanol oxidation reaction (EOR). In this work, a new instant reduction synthesis method was developed to prepare carbon supported ternary PdNiBi nanocatalysts with improved EOR activity. Synthesized catalysts were characterized with a variety of structural and compositional analysis techniques in order to correlate their morphology and surface chemistry with electrochemical performance. The modified instant reduction synthesis results in well-dispersed, spherical Pd<sub>85</sub>Ni<sub>10</sub>Bi<sub>5</sub> nanoparticles on Vulcan XC72R support (Pd<sub>85</sub>Ni<sub>10</sub>Bi<sub>5</sub>/C<sup>(II-III)</sup>), with sizes ranging from 3.7?±?0.8 to 4.7?±?0.7 nm. On the other hand, the common instant reduction synthesis method leads to significantly agglomerated nanoparticles (Pd<sub>85</sub>Ni<sub>10</sub>Bi<sub>5</sub>/C<sup>(I)</sup>). EOR activity and stability of these three different carbon supported PdNiBi anode catalysts with a nominal atomic ratio of 85:10:5 were probed via cyclic voltammetry and chronoamperometry using the rotating disk electrode method. Pd<sub>85</sub>Ni<sub>10</sub>Bi<sub>5</sub>/C<sup>(II)</sup> showed the highest electrocatalytic activity (150 mA?cm<sup>-2</sup>; 2678 mA?mg<sup>-1</sup>) with low onset potential (0.207 V) for EOR in alkaline medium, as compared to a commercial Pd/C and to the other synthesized ternary nanocatalysts Pd<sub>85</sub>Ni<sub>10</sub>Bi<sub>5</sub>/C<sup>(I)</sup> and Pd<sub>85</sub>Ni<sub>10</sub>Bi<sub>5</sub>/C<sup>(III)</sup>. This new synthesis approach provides a new avenue to developing efficient, carbon supported ternary nanocatalysts for future energy conversion devices. Graphical AbstractThe modified instant reduction method for synthesis of ternary Pd<sub>85</sub>Ni<sub>10</sub>Bi<sub>5</sub>/C<sup>(II)</sup> nanocatalyst using Vulcan XC72R as carbon support initiates an agglomeration reduction, provides low average particle size, and enables enhanced activity for the alkaline ethanol oxidation reaction (EOR) compared to the common instant reduction method and to a commercial Pd/C catalyst.
Project description:BACKGROUND:Combined hepatocellular-cholangiocarcinoma (cHCC-CC) can present as a hypervascular or peripherally enhancing tumor in dynamic imaging. We evaluated the effect of transarterial chemoembolization (TACE) on prognosis according to post-operative recurrence imaging patterns. METHODS:We retrospectively analyzed 42 cHCC-CC and 59 hepatocellular carcinoma (HCC-control) patients at the Asan Medical Center. We classified recurrent cHCC-CC according to enhancement pattern (globally enhancing: GE cHCC-CC, peripherally enhancing: PE cHCC-CC) and evaluated tumor response, time-to-local progression (TTPlocal), and overall survival (OS). RESULTS:The GE cHCC-CC group had a significantly higher best objective response rate (complete remission + partial response) than the PE cHCC-CC group (36% vs 0%, P = 0.005), and it was comparable to that of the HCC-control group (35.6%, P = 0.97). TTPlocal in the GE cHCC-CC group was significantly shorter than in the HCC-control group (6.6 vs 27.1 months, P < 0.001), and was not significantly different from that in the PE cHCC-CC group (5.3 months, P = 0.12). OS was 12.4 months, 52.8 months, and 67.5 months in the PE cHCC-CC, GE cHCC-CC, and HCC-control groups, respectively (Ps < 0.05). The adjusted hazard ratios (HRs) for TTPlocal and OS revealed an independent association with enhancement pattern of recurrent cHCC-CC (TTPlocal: HR 2.46; 95% CI 1.10-5.46; P = 0.03; OS: HR 5.97; 95% CI 2.38-14.96; P < 0.001). CONCLUSIONS:The GE cHCC-CC group showed better response and prognosis after TACE than the PE cHCC-CC group, but poorer response and prognosis than the HCC-control group. Enhancement patterns at recurrence were crucially associated with tumor response and overall survival.
Project description:Extracellular microvesicles (EVs) have been recognized for many potential clinical applications including biomarkers for disease diagnosis. In this study, we identified a major population of EVs by simply screening fluid samples with a nanosizer. Unlike other EVs, this extracellular nanovesicle (named HG-NV, HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) can be detected with a nanosizer with minimal in vitro manipulation and are much more homogenous in size (8-12 nm) than other EVs. A simple filtration platform is capable of separating HG-NVs from peripheral blood or cell culture supernatants. In comparison with corresponding exosome profiles, HG-NVs released from both mouse and human breast tumor cells are enriched with RNAs. Tumor derived HG-NVs are more potent in promoting tumor progression than exosomes. In summary, we identified a major subset of EVs as a previously unrecognized nanovesicle. Tumor cell derived HG-NVs promote tumor progression. Molecules predominantly present in breast tumor HG-NVs have been identified and characterized. This discovery may have implications in advancing both microvesicle biology research and clinical management including potential used as a biomarker.
Project description:Hepatocellular carcinoma (HCC) is a common and deadly cancer. Most cases of HCC arise in a cirrhotic/fibrotic liver, indicating that environment may play a paramount role in cancer genesis. Previous studies from our group and others have shown that, in desmoplastic cancers, there is a rich intercellular communication between activated, cancer-associated fibroblasts and cancer cells. Moreover, extracellular vesicles (EVs), or exosomes, have been identified as an important arm of this intercellular communication platform. Finally, these studies have shown that EVs can carry microRNA (miR) species in vivo and deliver them to desmoplastic cancers. The precise role played by activated liver fibroblasts/stellate cells in HCC development is insufficiently known. Based on previous studies, it appears plausible that activated fibroblasts produce signals carried by EVs that promote HCC genesis. In the current study, we first hypothesized and then demonstrated that stellate cell-derived EVs 1) can be loaded with an miR species of choice (miR-335-5p); 2) are taken up by HCC cells in vitro and more importantly in vivo; 3) can supply the miR-335-5p cargo to recipient HCC cells in vitro as well as in vivo; and 4) inhibit HCC cell proliferation and invasion in vitro as well as induce HCC tumor shrinkage in vivo. Finally, we identified messenger RNA targets for miR-335 that are down-regulated after treatment with EV-miR-335-5p. This study informs potential therapeutic strategies in HCC, whereby stellate cell-derived EVs are loaded with therapeutic nucleic acids and delivered in vivo. (Hepatology 2018;67:940-954).