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Rheumatoid arthritis (RA) is an autoimmune disease associated with synovitis and cartilage destruction. Ultrasound (US)-driven sonodynamic therapy (SDT) possess a good application prospect in RA therapy because of its non-invasiveness and strong tissue penetration capabilities, which can kill activated synovial inflammatory cells. Nevertheless, the tiny accumulation of sonosensitizers in the joints and the hypoxic synovial microenvironment severely limit the therapeutic effect of SDT. Hence, we developed a sonosensitizer spafloxacin (SPX) doped and human serum albumin (HSA) loaded concave-cubic rhodium (Rh) nanozyme (Rh/SPX-HSA) to realize mutual-reinforcing SDT during ultrasonic activation. On the one hand, SPX would cause mitochondrial dysfunction by inducing excessive reactive oxygen species (ROS) production, thus suppressing fibroblast-like synoviocyte (FLS) under US conditions. On the other hand, concave-cubic rhodium was utilized as a nanozyme with endogenous peroxidase (POD) and catalase (CAT)-like enzyme activities, which not only relieved the hypoxia of the joint to resist angiogenesis, but also enormously ascended the SDT efficacy by rising 1O2 levels. Interestingly, the activity of nanozymes was also improved by the ultrasonic cavitation effect, thereby realizing mutual-reinforcing SDT. Overall, our strategy provided Rh-based to achieve effective SDT under hypoxic microenvironment, which offered a promising prospect for highly efficient treatment of RA.
Rheumatoid arthritis (RA) is an autoimmune disease related to synovitis and accompanied by cartilage damage . Synovial hyperplasia, pannus formation, inflammatory cell infiltration and local hypoxia are the main pathophysiological changes of early RA [, , ]. Studies have shown that abnormal proliferation of fibroblast-like synoviocyte (FLS) is the key factor leading to the occurrence and development of synovitis [5,6]. Specifically, the excessive proliferation of FLS secretes large amounts of pro-inflammatory factors and metalloproteinases, which contribute to cartilage degradation. Furthermore, it can lead to the increased oxygen consumption, which further erodes articular cartilage [, , ]. Currently, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs) and disease-modifying anti-rheumatic drugs (DMARDs) are mainly applied in the clinical treatment of RA . Unfortunately, due to the poor bioavailability and short biological half-life, prolonged repeated use of anti-rheumatic drugs has serious adverse reactions such as drug resistance, vomiting, as well as bone marrow suppression .
Based on ultrasound (US) activated sonosensitizer to trigger the production of reactive oxygen species (ROS), sonodynamic therapy (SDT) is a relatively safe and valid treatment method, which mainly concentrates in the research of solid tumors and has achieved significant therapeutic effects [11,12]. Recently, several novel nanoplatforms have been proposed for SDT-involved combinational therapies to deliver even stronger therapeutic effects [, , ]. For example, Lin et al. designed a new type of Pt–TiO2 heterostructure as bilaterally augmented sonosensitizer for synergistic-enhanced chemo-sonodynamic therapy, demonstrating a notable reduction ability in tumor growth . Interestingly, ultrasound with non-invasiveness, strong tissue penetration, and limited local irradiation can penetrate the inflammatory sites of joints and kill inflammatory cells, thus reducing synovial hyperplasia and minimizing oxidative damage to surrounding normal tissues [, , ], which offers a vast application prospect for SDT to treat RA. Specifically, ultrasonic cavitation effect occurs during the process of SDT, due to the bubbles formation, which is induced by ultrasound waves caused pressure changes in liquid. During the collapse of gas bubbles, high temperature and pressures will be generated, which can further release a large amount of energy to strengthen the strong collisions and aggregation between molecules in the solid-liquid system . However, hypoxia microenvironment of RA caused by the proliferation of FLSs severely limits the efficiency of SDT.
Sparfloxacin (SPX), as a fluoroquinolone antibacterial drug, exhibits remarkable sonosensitive properties . Studies have found that SPX has more retention in joint tissues after systemic administration, which provides the possibility to target the abnormal proliferation of FLS in the synovial tissue of the joint, thus effectively blocking the occurrence and development of joint inflammation. Moreover, it is also noteworthy that hypoxia up-regulates hypoxia-inducible factor (HIF-1α) and increases the expression of vascular endothelial growth factor (VEGF), thereby contributing to angiogenesis. Subsequently, the adjacent cartilage and bone tissue structure can be further digested and destroyed , which will eventually accelerate the progression of RA. In this regard, it is of great significance to deliver O2 to relieve hypoxic inflamed joints for the effective SDT in hypoxia microenvironment.
Recently, nanozymes have drew extensive attention because of their unique physical and chemical properties such as simple preparation, low cost and high stability even under harsh conditions [23,24]. To date, noble metal nanoparticles (NPs), metal oxides NPs and carbon-based NPs with unique enzyme catalytic activity have been widely employed in biological detection , antibacterial applications , biosensors , environmental monitoring , immunoassays  and cancer treatment . Among the different types of noble metal (Pt, Pd, Ag, and Au) NPs enzymes, rhodium (Rh) exhibits extraordinary catalytic properties in various reactions, particularly in hydrogenation [31,32], NOx reduction , and CO oxidation . A great deal kinds of rhodium NPs have been available till date, including Rh nanocube, nanooctahedron, nanosphere, nanotrisoctahedron, nanotrapezohedron, and nanotetrahexahedron [, , ]. In comparison, Rh nanozyme with unconventional shapes (concave-cubes) represents better catalytic eﬀect because of its high energy facets . Here, we find that Rh nanoparticles exhibit the activities of two enzymes, peroxidase (POD) and catalase (CAT), which are responsible for generating radicals and alleviating hypoxia to kill synovial fibroblasts as well as anti-angiogenesis for the treatment of RA. Importantly, the cavitation effect that occurred in the process of SPX-sensitized SDT would elevate the activity of Rh nanozyme in return, thus realizing mutual-reinforcing SDT against RA.
Secreted protein acidic and rich in cysteine (SPARC) is a small molecule glycoprotein rich in cysteine, which can regulate the production of extracellular matrix and matrix metalloproteinases . Studies have confirmed that it is significantly increased in the microenvironment of a variety of diseases, including atherosclerosis, pancreatic cancer, breast cancer, ovarian cancer and colon cancer [38,39]. Very recently, SPARC is also found to be highly expressed in the synovial fluid and joint tissues of collagen-induced arthritis (CIA) mice . It is worth noting that SPARC exhibits an inherent high affinity for albumin , which enhances the accumulation of human serum albumin (HSA) in inflammatory sites. Add to this, RA joints have higher requirements for albumin than healthy tissues, which is associated with up-regulated metabolism of synovial cells , thereby further boosting the efficiency of nanozyme delivery to joints. Accordingly, HSA-modified Rh/SPX is constructed in order to enable the nanozymes to actively target the inflammatory sites of the joint via pathophysiological features of RA microenvironment, thus avoiding no significant side effects on normal tissues.
In our work, we first successfully prepared SPX doped and HSA loaded concave-cubic rhodium nanozyme (Rh/SPX-HSA) for RA treatment (Scheme 1). After accumulating in the inflamed joints, SPX was released from the Rh nanozyme under US irradiation. Firstly, concave-cubic Rh nanozyme perform intrinsic CAT-like and POD-like activity to simultaneously generate O2 and ·OH. The produced O2 in situ can suppress the expression of HIF-1α, thereby alleviating hypoxia and realizing anti-angiogenesis in the joints. Secondly, sonosensitizer SPX triggered by US could induce excessive 1O2 production in FLS. In this case, combined with ·OH generated by Rh nanozyme, the elevated levels of ROS in RA could activate the mitochondrial caspases-cascade pathway to promote FLS apoptosis, which ultimately inhibited synovial hyperplasia and cartilage destruction. Interestingly, the activity of Rh nanozyme was enhanced by ultrasonic cavitation effect, which would promote the diffusion of H2O2 to increase the interaction between H2O2 and Rh nanozyme, thus accelerating ROS production. In return, Rh-induced self-supply of O2 further enabled the interaction of SPX with O2 for efficient 1O2 generation, which also facilitated the efficiency of SDT. Thus, we believed such novel nanocomposite based on Rh nanozyme and SPX sonosensitizer as well as a properly designed O2 self-replenishment in this research would put forward a new strategy for the mutual-reinforcing SDT, which also provided potentials for highly potent RA therapy.
Sodium hexachlororhodate (III) dodecahydrate was obtained from D&B Biological Science and Technology Co., Ltd (Shanghai, China). Potassium bromide (KBr, 99.0%), polyvinylpyrrolidone (PVP, M.W.≈55,000) and sparfloxacin were obtained from Yuanye Bio-Technology Co., Ltd. Ethylene glycol (EG) was bought from J. T. Baker. H2O2 (30%) was purchased from Jiangtian Chemical Co., Ltd. L-ascorbic acid (AA, 99.0%) and 3,3′,5,5′-tetramethylbenzidine (TMB) were obtained from Heowns Bio-Technology Co.,
Fabrication and characterization of Rh/SPX-HSA
Rh/SPX-HSA was prepared based on a modified polyol process through kinetic control use a syringe pump (Scheme 1). Transmission electron microscopy (TEM) images confirmed the concave nanocubic structure of Rh with an average edge length of about 10nm (Fig. 1a and b), which was consistent with the dynamic light scattering (DLS) results (Figure S1). The concave structure could also be observed clearly under high-resolution TEM (HRTEM) (Fig. 1c), which showed series fringes in the same
In summary, the obtained Rh/SPX-HSA nanocomposite could consume H2O2 at the inflammatory site of the joint through the contained Rh nanozyme, thus advancing the O2 concentration to significantly alleviated the hypoxia of the joints and further enhanced SDT effect. As a result, injections of Rh/SPX-HSA into CIA mice successfully clumped to the inflammatory site of the joint and oxygenated the synovial joint, subsequently down-regulating HIF-1α to prevent angiogenesis. Conversely, the cavitation
The raw/processed data required to reproduce these ﬁndings cannot be shared at this time as the data also forms part of an ongoing study.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This work was supported by the National Natural Science Foundation of China (81701817, 31971106, 81372124), the National Key Research and Development Program of China (2020YFC1512304, 2020YFC1512301), the Young Elite Scientists Sponsorship Program by Tianjin (0701320001), and the Major Special Projects of Tianjin (0402080005).
- Y.J. Kim et al.Ionic complex systems based on hyaluronic acid and PEGylated TNF-related apoptosis-inducing ligand for treatment of rheumatoid arthritis
- C. Li et al.pH-sensitive polymeric micelles for targeted delivery to inflamed joints
J. Contr. Release
- W. Li et al.Exo/endogenous dual-augmented chemodynamic therapy based on bio-reducible and bio-breakable copper (Ⅱ)-based truncated octahedron
Chem. Eng. J.
- Y. Wang et al.Oxygen-supplementing mesoporous polydopamine nanosponges with WS2 QDs-embedded for CT/MSOT/MR imaging and thermoradiotherapy of hypoxic cancer
- Y.a. Tang et al.Albumin-coordinated assembly of clearable platinum nanodots for photo-induced cancer theranostics
- V.A. Myasoedova et al.Matrix metalloproteinases in pro-atherosclerotic arterial remodelingSee AlsoTREMFYA® (guselkumab) Approved by U.S. Food and Drug Administration as the First Selective Interleukin (IL)-23 Inhibitor for Active Psoriatic ArthritisAbstracts zum 40. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh) - PDF Free DownloadMalay - Amboseli National Parks - Manyeleti Game Reserve (2022)
J. Mol. Cell. Cardiol.
- S. Wu et al.Peptide-functionalized metal-organic framework nanocomposite for ultrasensitive detection of secreted protein acidic and rich in cysteine with practical application
- X.Y. Quek et al.Structure sensitivity in the hydrogenation of unsaturated hydrocarbons over Rh nanoparticles
- H. Xu et al.Biocompatible Fe-Hematoporphyrin coordination nanoplatforms with efficient sonodynamic-chemo effects on deep-seated tumors
- M.T. Leech et al.Fibroblasts and synovial immunity
Curr. Opin. Pharmacol.
Route to rheumatoid arthritis by macrophage-derived microvesicle-coated nanoparticles
The pathogenesis of rheumatoid arthritis
N. Engl. J. Med.
One year in review 2017: pathogenesis of rheumatoid arthritis
Clin. Exp. Rheumatol.
Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis
Oridonin inhibits cell proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes
Hypoxia—a key regulator of angiogenesis and inflammation in rheumatoid arthritis
Nat. Rev. Rheumatol.
American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis
Dose-dependent efficacy of gold clusters on rheumatoid arthritis therapy
Tumor targeting DVDMS-nanoliposomes for an enhanced sonodynamic therapy of gliomas
Rapid photo-sonotherapy for clinical treatment of bacterial infected bone implants by creating oxygen deficiency using sulfur doping
Conferring Ti-based MOFs with defects for enhanced sonodynamic cancer therapy
Glutathione-depleting nanoplatelets for enhanced sonodynamic cancer therapy
A novel Pt–TiO2 heterostructure with oxygen-deficient layer as bilaterally enhanced sonosensitizer for synergistic chemo-sonodynamic cancer therapy
Adv. Funct. Mater.
Fe(III)-Porphyrin sonotheranostics: a green triple-regulated ROS generation nanoplatform for enhanced cancer imaging and therapy
Adv. Funct. Mater.
Efficacy of indocyanine green-mediated sonodynamic therapy on rheumatoid arthritis fibroblast-like synoviocytes
Ultrasound Med. Biol.
Metal–Organic-Framework-derived carbon nanostructure augmented sonodynamic cancer therapy
- Emerging nanotherapeutics alleviating rheumatoid arthritis by readjusting the seeds and soils
2022, Journal of Controlled Release
Rheumatoid arthritis (RA) is a complicated autoimmune disease that results in severe joint inflammation, synovial hyperplasia, pannus formation, cartilage and bone destruction, and other RA-associated complications. Although the pathogenesis of RA remains unclear, increasing reports have shown that inflammation-relevant cells and the microenvironment of inflamed joints play a critical role in the formation and aggravation of RA. Recently, numerous nanotherapeutics have been engineered to overcome these intractable challenges by readjusting inflammation-related seeds (endothelial cells, macrophages, neutrophils, antigen-presenting cells, fibroblasts, osteoclasts, T cells, B cells, and chondrocytes) and inflamed soils (NO, cell-free DNA, hypoxia, ROS, and pro-inflammatory cytokines). In this review, we first present a detailed pathogenesis of RA, with an emphasis on the emerging advances in regulating seeds or remodeling soils for RA treatment. We then outline these intelligent therapeutics via synergistic seed-soil adjustment, particularly for spatiotemporally cascade-responsive or all-in-one integrational nanosystems. Finally, we briefly discuss the ongoing challenges and prospects for the clinical development and translation of seed soil-based therapies.
- Engineering nanomedicines to inhibit hypoxia-inducible Factor-1 for cancer therapy
2022, Cancer Letters
Hypoxia-inducible factor-1 (HIF-1), an essential promoter of tumor progression, has attracted increasing attention as a therapeutic target. In addition to hypoxic cellular conditions, HIF-1 activation can be triggered by cancer treatment, which causes drug tolerance and therapeutic failure. To date, a series of effective strategies have been explored to suppress HIF-1 function, including silencing the HIF-1α gene, inhibiting HIF-1α protein translation, degrading HIF-1α protein, and inhibiting HIF-1 transcription. Furthermore, nanoparticle-based drug delivery systems have been widely developed to improve the stability and pharmacokinetics of HIF-1 inhibitors or achieve HIF-1-targeted combination therapies as a nanoplatform. In this review, we summarize the current literature on nanomedicines targeting HIF-1 to combat cancer and discuss their potential for future development.
- Deep and precise lighting-up/combat diseases through sonodynamic agents integrating molecular imaging and therapy modalities
2022, Coordination Chemistry Reviews
Phototherapy including photodynamic therapy (PDT) and photothermal therapy (PTT) has been widely applied to treat various diseases. Regrettably, phototherapy still has several limitations in practical applications, such as the poor tissue penetration of excitation light, unsatisfactory therapy efficiency, tumor hypoxia and the short lifetime of the generated reactive oxygen species, and undesired damage to normal tissues. By utilizing the cooperation of low-intensity ultrasound (US) and sonosensitizers, the novel treatment approach, sonodynamic therapy (SDT) has the power to overcome the main limitations of phototherapy due to its inherent deep tissue penetrating capability. Despite the achieved great progress and success, SDT still faces the issue of precisely tracing the sonosensitizers and evaluating the therapy efficiency during the sonodynamic therapy. To guide the process of SDT, the design of multifunctional sonosensitizers integration with the modern imaging techniques should be considered. On the other hand, traditional mono-therapy modality of SDT still faces the challenge of limited therapy efficiency and continuous administration during the entire therapy period, which can be effectively resolved by the complement of SDT and other therapy modalities. This review summarizes the applications of SDT in combination with molecular imaging techniques and other therapeutic modalities. Moreover, we further discuss the potential clinical translation and the future prospects of SDT.
- Rheumatoid arthritis microenvironment insights into treatment effect of nanomaterials
2022, Nano Today
Rheumatoid arthritis (RA) causes a huge medical burden due to its high morbidity and disability rate. Emerging evidences demonstrate that RA has a tumor-like microenvironment. The RA microenvironment (RAM) is an extremely complex network system formed by the crosstalk of various extracellular matrix factors and a variety of stromal cells. Traditional anti-inflammatory standard therapies are compromised by the buffer barrier from the RAM and can only provide short-term relief to RA. Well-designed nanomaterials have attracted intensive interests to overcome the buffer barrier of RAM thanks to their function to simultaneously interfering with multiple pathogenic factors of RAM. Moreover, nanomaterials can achieve precise treatment far beyond traditional therapies through passive and active targeting of RAM strategies. Recently, significant progress in nanomaterials, medicine, and biology have greatly promoted the development of RAM-based nanomaterials for RA treatment with high therapeutic effect, low side effects. Here, we firstly systematically introduced the unique features, constitutes of the RAM, and emphasized the key role of the vicious circle of reactive oxygen and nitrogen species (RONS) and inflammatory factors in the RA progress. We further comprehensively summarized the treatment strategies and recent significant advances of nanomaterials for RA treatment. Finally, we put forward the challenges to clinical application of nanomaterials based on RAM, and discussed the future research direction of RA treatment.
Recent progress in therapeutic strategies and biomimetic nanomedicines for rheumatoid arthritis treatment
2022, Expert Opinion on Drug Delivery
Research articleExcavating bioactivities of nanozyme to remodel microenvironment for protecting chondrocytes and delaying osteoarthritis
Bioactive Materials, Volume 6, Issue 8, 2021, pp. 2439-2451
Osteoarthritis (OA) is the main cause of disability in the elderly. Effective intervention in the early and middle stage of osteoarthritis can greatly prevent or slow down the development of the disease, and reduce the probability of joint replacement. However, there is to date no effective intervention for early and middle-stage OA. OA microenvironment mainly destroys the balance of oxidative stress, extracellular matrix synthesis and degradation of chondrocytes under the joint action of biological and mechanical factors. Herein, hollow Prussian blue nanozymes (HPBzymes) were designed via a modified hydrothermal template-free method. The aim of this study was to investigate the effects of HPBzymes on chondrocytes and the progression of OA. The intrinsic bioactivities of HPBzymes were excavated in vitro and in vivo, remodeling microenvironment for significantly protecting chondrocytes and delaying the progression of traumatic OA by inhibiting reactive oxygen species (ROS) and Rac1/nuclear factor kappa-B (NF-κB) signaling in a rat model. HPBzyme significantly diminished interleukin (IL)-1β-stimulated inflammation, extracellular matrix degradation, and apoptosis of human chondrocytes. HPBzyme attenuated the expression of Rac1 and the ROS levels and prevented the release and nuclear translocation of NF-κB. Deeply digging the intrinsic bioactivities of nanozyme with single component to remodel microenvironment is an effective strategy for ROS-associated chronic diseases. This study reveals that excavating the bioactivities of nanomedicine deserves attention for diagnosis and treatment of severe diseases.
Research articleRuthenium(II) complexes coordinated to graphitic carbon nitride: Oxygen self-sufficient photosensitizers which produce multiple ROS for photodynamic therapy in hypoxia
Biomaterials, Volume 276, 2021, Article 121064
The photodynamic therapy (PDT) of cancer is limited by tumor hypoxia as PDT efficiency depends on O2 concentration. A novel oxygen self-sufficient photosensitizer (Ru-g-C3N4) was therefore designed and synthesized via a facile one-pot method in order to overcome tumor hypoxia-induced PDT resistance. The photosensitizer is based on [Ru(bpy)2]2+ coordinated to g-C3N4 nanosheets by Ru–N bonding. Compared to pure g-C3N4, the resulting nanosheets exhibit increased water solubility, stronger visible light absorption, and enhanced biocompatibility. Once Ru-g-C3N4 is taken up by hypoxic tumor cells and exposed to visible light, the nanosheets not only catalyze the decomposition of H2O2 and H2O to generate O2, but also catalyze H2O2 and O2 concurrently to produce multiple ROS (•OH, •O2−, and 1O2). In addition, Ru-g-C3N4 affords luminescence imaging, while continuously generating O2 to alleviate hypoxia greatly improving PDT efficacy. To the best of our knowledge, this oxygen self-sufficient photosensitizer produced via grafting a metal complex onto g-C3N4 is the first of its type to be reported.
Research articlePlasma-activated thermosensitive biogel as an exogenous ROS carrier for post-surgical treatment of cancer
Biomaterials, Volume 276, 2021, Article 121057
Post-surgical residual tumor cells are the primary cause of relapse and progression of cancer but unfortunately, there are limited therapeutic options. In this work, a fillable plasma-activated biogel is produced on a thermosensitive biogel [(Poly-DL-lactide)-(poly-ethylene glycol)-(poly-DL-lactide), PLEL] with the aid of a discharge plasma for local post-operative treatment of cancer. In vivo data show that the plasma-activated PLEL biogel (PAPB) eliminates residual tumor tissues after removal surgery and also inhibits in situ recurrence while showing no evident systemic toxicity. Moreover, the PAPB possesses excellent storage capability, allows for slow release of plasma-generated reactive oxygen species (ROS), and exhibits good ROS-mediated anticancer effects in vitro. Our results reveal that the novel plasma-activated biogel is an effective therapeutic agent for local post-operative treatment of cancer.
Research articleChemotherapy-enabled/augmented cascade catalytic tumor-oxidative nanotherapy
Biomaterials, Volume 277, 2021, Article 121071
Catalytic cascade transformations, which occur in spatially constrained tumor environment to generate therapeutic moieties from prodrugs or intrinsic species, are highly desirable for precise cancer therapy. Nevertheless, it is high challenging to engineer a cascade nanoreactor with tumor microenvironment (TME)-responsive capability for synergistic tumor therapy. Inspired by the biocatalytic cascades in biological processes, here, a tumor-specific nanoreactor was established to activate cascade reactions for oxidative stress-augmented chemotherapy by the integration of an artificial enzyme, Pt(IV)-based prodrug (Pt(IV)), with Cu(II)-based metal-organic frameworks (CuMOF). Upon internalization of [emailprotected](IV) by tumor cells, in addition to chemotherapeutic effect, the activated cisplatin by glutathione (GSH) reduction is capable of acting as an artificial enzyme to elevate the hydrogen peroxide (H2O2) level through cascade reactions for augmenting the therapeutic efficacy of Cu+-mediated chemodynamic therapy (CDT). Meanwhile, [emailprotected](IV) specifically deplete overexpressed GSH at tumor sites, thus amplifying tumor oxidative stress, and finally leading to augmented antitumor efficacy. The orchestrated cooperative effect of chemotherapy and oxidative stress presents splendid therapeutic efficacy on tumor-bearing mice with negligible adverse effects. Therefore, this cascade nanoreactor provides exciting opportunities to develop complementary therapeutic modalities for precise cancer treatment.
Research articleXenoextracellular matrix-rosiglitazone complex-mediated immune evasion promotes xenogenic bioengineered root regeneration by altering M1/M2 macrophage polarization
Biomaterials, Volume 276, 2021, Article 121066
Xenogenic extracellular matrix (xECM)-based organ transplantation will be a promising approach to address the problem of donor shortage for allotransplantation, which has achieved great success in organ regeneration. However, current approaches to utilize xECM-based organ have limited capacity to yield the host a biofriendly microenvironment for long-term immunity homeostasis, compromising the application of these xenografts for repairing and replacing damaged tissues. As the key innate immune cells, macrophages directly determine the prognosis of xenografts in long term. However, it has not been fully elucidated that how to modulate their biological behavior for microenvironment homeostasis in tissue reconstruction. In this study, we report a robust strategy to impart an immunosuppressive surface to naturally sponge-like porous xECM scaffolds by loading rosiglitazone (RSG) to activate peroxisome proliferators receptors-γ (PPAR-γ). The resultant xECM-RSG complex, enabling RSG to be delivered sequentially and continuously to cells without obvious systemic side effects, is recognized as “self” to escape immune monitoring in local immunoregulation by downregulating the expression of proinflammatory NOS2+ M1 macrophages and oxygen species (ROS) through suppressing NF-κB expression, greatly facilitating the regeneration of enthesis anchoring between the transplanted xenograft and host in both heterotopic and orthotopic models. The newly formed bio-root is morphologically and biomechanically equivalent to native tooth root with a significant expression of odontogenic differentiation-related critical proteins. Therefore, the PPAR-γ-NF-κB axis activated by the xECM-RSG complex enables the xenografts to converse towards M2 macrophages with a modest immunosuppressive capacity for facilitating in xECM-based tissue or organ regeneration.
Research articlePrecise magnetic resonance imaging-guided sonodynamic therapy for drug-resistant bacterial deep infection
Biomaterials, Volume 264, 2021, Article 120386
The precise treatment of drug-resistant deep bacterial infections remains a huge challenge in clinic. Herein, a polymer-peptide-porphyrin conjugate (PPPC), which can be real-time monitored in infectious site, is developed for accurate and deep sonodynamic therapy (SDT) based on “in vivo self-assembly” strategy. The PPPC contains four moieties, i.e., a hyperbranched polymer backbone, a self-assembled peptide linked with an enzyme-cleavable peptide-poly (ethylene glycol) terminal, a bacterial targeting peptide, and a porphyrin sonosensitizer (MnTCPP) segment. Once PPPC nanoparticles reach the infectious area, the protecting PEG layers are removed due to the over-expressed gelatinase, leading to the secondary assembly into large nanoaggregates and resultant enhanced accumulation of sonosensitizer. The nanoaggregates exhibit enhanced interaction with bacterial membrane and decrease the minimum inhibitory concentration (MIC) significantly. Meanwhile, compared with free MnTCPP, the concentration of which can not be accurately quantified, the accumulation amount of MnTCPP in PPPCs at infectious site can be in situ monitored by magnetic resonance imaging (MRI) using T1 combined with T2. When the concentration of PPPC-1 reaches MIC, the drug-resistant bacterial infection area is exposed to ultrasound irradiation, causing the precise and efficient elimination of bacteria. Therefore, the MRI-guided SDT system shows extraordinary tissue penetration depth, drug concentration monitoring, morphology-transformation induced accumulation and improved treatment capacity toward drug-resistant bacteria.
© 2021 Elsevier Ltd. All rights reserved.
Mutual-reinforcing sonodynamic therapy against Rheumatoid Arthritis based on sparfloxacin sonosensitizer doped concave-cubic rhodium nanozyme (2022) ›
ScienceDirectCorporate sign inSign in / registerViewPDFAccess throughyour institutionBiomaterialsVolume 276, September 2021, 121063https://doi.org/10.1016/j.biomaterials.2021.121063Get rights and contentAbstractRheumatoid arthritis (RA) is an autoimmune disease associated with synovitis and cartilag...
Ultrasound (US)-driven sonodynamic therapy (SDT) possess a good application prospect in RA therapy because of its non-invasiveness and strong tissue penetration capabilities, which can kill activated synovial inflammatory cells.. Overall, our strategy provided Rh-based to achieve effective SDT under hypoxic microenvironment, which offered a promising prospect for highly efficient treatment of RA.. Based on ultrasound (US) activated sonosensitizer to trigger the production of reactive oxygen species (ROS), sonodynamic therapy (SDT) is a relatively safe and valid treatment method, which mainly concentrates in the research of solid tumors and has achieved significant therapeutic effects [11,12].. Interestingly, ultrasound with non-invasiveness, strong tissue penetration, and limited local irradiation can penetrate the inflammatory sites of joints and kill inflammatory cells, thus reducing synovial hyperplasia and minimizing oxidative damage to surrounding normal tissues [, , ], which offers a vast application prospect for SDT to treat RA.. Studies have found that SPX has more retention in joint tissues after systemic administration, which provides the possibility to target the abnormal proliferation of FLS in the synovial tissue of the joint, thus effectively blocking the occurrence and development of joint inflammation.. Importantly, the cavitation effect that occurred in the process of SPX-sensitized SDT would elevate the activity of Rh nanozyme in return, thus realizing mutual-reinforcing SDT against RA.. Accordingly, HSA-modified Rh/SPX is constructed in order to enable the nanozymes to actively target the inflammatory sites of the joint via pathophysiological features of RA microenvironment, thus avoiding no significant side effects on normal tissues.. Interestingly, the activity of Rh nanozyme was enhanced by ultrasonic cavitation effect, which would promote the diffusion of H 2 O 2 to increase the interaction between H 2 O 2 and Rh nanozyme, thus accelerating ROS production.. Thus, we believed such novel nanocomposite based on Rh nanozyme and SPX sonosensitizer as well as a properly designed O 2 self-replenishment in this research would put forward a new strategy for the mutual-reinforcing SDT, which also provided potentials for highly potent RA therapy.. In summary, the obtained Rh/SPX-HSA nanocomposite could consume H 2 O 2 at the inflammatory site of the joint through the contained Rh nanozyme, thus advancing the O 2 concentration to significantly alleviated the hypoxia of the joints and further enhanced SDT effect.. Kim et al. Ionic complex systems based on hyaluronic acid and PEGylated TNF-related apoptosis-inducing ligand for treatment of rheumatoid arthritis C. Li et al. pH-sensitive polymeric micelles for targeted delivery to inflamed joints W. Li et al. Exo/endogenous dual-augmented chemodynamic therapy based on bio-reducible and bio-breakable copper (Ⅱ)-based truncated octahedron Y. Wang et al. Oxygen-supplementing mesoporous polydopamine nanosponges with WS2 QDs-embedded for CT/MSOT/MR imaging and thermoradiotherapy of hypoxic cancer Y.a.. Regrettably, phototherapy still has several limitations in practical applications, such as the poor tissue penetration of excitation light, unsatisfactory therapy efficiency, tumor hypoxia and the short lifetime of the generated reactive oxygen species, and undesired damage to normal tissues.. On the other hand, traditional mono-therapy modality of SDT still faces the challenge of limited therapy efficiency and continuous administration during the entire therapy period, which can be effectively resolved by the complement of SDT and other therapy modalities.. Recently, significant progress in nanomaterials, medicine, and biology have greatly promoted the development of RAM-based nanomaterials for RA treatment with high therapeutic effect, low side effects.. The resultant xECM-RSG complex, enabling RSG to be delivered sequentially and continuously to cells without obvious systemic side effects, is recognized as “self” to escape immune monitoring in local immunoregulation by downregulating the expression of proinflammatory NOS2+ M1 macrophages and oxygen species (ROS) through suppressing NF-κB expression, greatly facilitating the regeneration of enthesis anchoring between the transplanted xenograft and host in both heterotopic and orthotopic models.
Inhaltsverzeichnis Was ist Akne inversa?Die wenig bekannten Symptome von Akne inversaWie lautet die Diagnose von Akne inversa?Worin liegen die Akne inversa Ursachen?Die bekannten Hautbereiche, an welchen Akne inversa auftrittWeshalb Akne inversa im Gesicht entstehtDie wenige bekannten Gründe für Akn...
Die wenig bekannten Symptome von Akne inversa Wie lautet die Diagnose von Akne inversa?. Die bekannten Hautbereiche, an welchen Akne inversa auftritt Weshalb Akne inversa im Gesicht entsteht Die wenige bekannten Gründe für Akne inversa im Intimbereich Warum entsteht Akne inversa am Po?. Des Weiteren fördern die Glimmstängel die Entstehung von Akne inversa.. Die Erscheinung von Akne inversa im Gesicht ist eher eine Seltenheit.. Frauen sind dabei von Akne inversa in der Scheide, Männer hingegen von Akne inversa Leistengegend betroffen.. Die Entstehung von Akne inversa am Po geht auf die feine Behaarung des Gesäßes zurück.. Die Antwort auf die Frage “Was hilft gegen Akne inversa?” kann dir niemand pauschal beantworten.. Demzufolge existiert jedoch eine gute Nachricht: Wenn deine Ernährung die Hautkrankheit begünstigt, dann kannst du Akne inversa mit einer Ernährungsumstellung auch heilen.
Master of Narrative Therapy and Community WorkInterested in the 2023 Masters program?Express your interest and receive notifications when applications open!Click hereThe Master of Narrative Therapy and Community Work is a collaboration between Dulwich Centre and University of Melbourne (Department o...
The Master of Narrative Therapy and Community Work is a collaboration between Dulwich Centre and University of Melbourne (Department of Social Work).. The Master of Narrative Therapy and Community Work has been specifically designed to develop participants’ practice-skills, encourage innovation, and enable a rigour in relation to practice-research-theory.. Advanced Narrative Skills Development The Art of Narrative Practice Narrative Practice and Research Synthesis. An undergraduate degree in a related discipline; and Evidence of two years of relevant work experience; and Evidence of completion of prior narrative therapy studies at Dulwich Centre or equivalent; and Completion of the personal statement document (maximum 500 words) A professional referee report Please note, it is necessary to be working/volunteering in a context in which you are able to put narrative ideas into practice for at least 5 hours per week during the duration of the Masters.. Recognition of Prior Learning for those who have completed long-term training programs with Dulwich Centre (International Training Program or Graduate Certificate programs in Hong Kong, Greece or Singapore) means that they are only required to attend one of the intensive teaching blocks in Australia, and to pay reduced fees.. In this subject, students acquire skills in engaging with ten key practice maps of narrative therapy, including externalising, re-authoring, re-membering, definitional ceremony, documentation, absent but implicit, failure conversations map, responding to trauma, engagement with folk culture metaphors (tree of life/team of life/kite of life) and enabling contribution or social action.. Teaching focuses on some of the different methods of innovating that have contributed to new forms of narrative practice, such as co-research, partnerships, cross-cultural invention, folk cultural innovation, synthesis of practice with readings from outside the field, responding to challenges in relation to politics of experience and translations across languages.. In 2023, Dulwich Centre Foundation will offer a scholarship of $3000 to a transgender participant of the Master of Narrative Therapy and Community Work who has indicated they would like to receive the funds.. In addition, alongside the funds, recipients of this scholarship will receive supervision sessions with a Dulwich Centre Faculty member who has significant experience in narrative practice through a trans lens.. Dulwich Centre is delighted to announce this new scholarship which is available to practitioners from Hong Kong who wish to attend the Master of Narrative Therapy and Community Work (University of Melbourne/Dulwich Centre).. There is a long history of collaboration between Dulwich Centre and narrative practitioners in Hong Kong, in fact, more practitioners from Hong Kong have completed the Dulwich Centre International training program than from any other city or country!. The Centre for Youth Research and Practice (Hong Kong Baptist University) and Dulwich Centre currently run a Graduate Certificate in narrative therapy.. Graduates of this course receive recognition of prior learning towards the new Master of Narrative Therapy and Community Work.. demonstrated an interest and commitment to narrative practice • demonstrated a commitment to working with people experiencing social hardship • demonstrated creativity and innovation in their work