Mutual-reinforcing sonodynamic therapy against Rheumatoid Arthritis based on sparfloxacin sonosensitizer doped concave-cubic rhodium nanozyme (2022)

Table of Contents
Biomaterials Abstract Introduction Section snippets Chemicals Fabrication and characterization of Rh/SPX-HSA Conclusion Data availability Declaration of competing interest Acknowledgments References (55) Biomaterials J. Contr. Release Chem. Eng. J. Biomaterials Biomaterials J. Mol. Cell. Cardiol. Biosens. Bioelectron. Catal. Today Biomaterials Curr. Opin. Pharmacol. Lancet Route to rheumatoid arthritis by macrophage-derived microvesicle-coated nanoparticles Nano Lett. 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 Immunol. Rev. Oridonin inhibits cell proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes Inflammation 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 Arthritis Rheum. Dose-dependent efficacy of gold clusters on rheumatoid arthritis therapy ACS Omega Tumor targeting DVDMS-nanoliposomes for an enhanced sonodynamic therapy of gliomas Biomaterials Science Rapid photo-sonotherapy for clinical treatment of bacterial infected bone implants by creating oxygen deficiency using sulfur doping ACS Nano Conferring Ti-based MOFs with defects for enhanced sonodynamic cancer therapy Adv. Mater. Glutathione-depleting nanoplatelets for enhanced sonodynamic cancer therapy Nanoscale 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 Adv. Mater. Cited by (8) Phototherapy Using a Fluoroquinolone Antibiotic Drug to Suppress Tumor Migration and Proliferation and to Enhance Apoptosis Recent progress in therapeutic strategies and biomimetic nanomedicines for rheumatoid arthritis treatment Recommended articles (6) Related content
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Biomaterials

Volume 276,

September 2021

, 121063

Abstract

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.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease related to synovitis and accompanied by cartilage damage [1]. Synovial hyperplasia, pannus formation, inflammatory cell infiltration and local hypoxia are the main pathophysiological changes of early RA [[2], [3], [4]]. 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 [[6], [7], [8]]. 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 [9]. 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 [10].

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 [[13], [14], [15]]. 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 [16]. 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 [[17], [18], [19]], 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 [20]. 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 [21]. 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 [22], 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 [25], antibacterial applications [26], biosensors [27], environmental monitoring [28], immunoassays [29] and cancer treatment [30]. 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 [33], and CO oxidation [33]. A great deal kinds of rhodium NPs have been available till date, including Rh nanocube, nanooctahedron, nanosphere, nanotrisoctahedron, nanotrapezohedron, and nanotetrahexahedron [[34], [35], [36]]. In comparison, Rh nanozyme with unconventional shapes (concave-cubes) represents better catalytic effect because of its high energy facets [34]. 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 [37]. 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 [40]. It is worth noting that SPARC exhibits an inherent high affinity for albumin [41], 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 [42], 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.

Section snippets

Chemicals

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

Conclusion

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

Data availability

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.

Acknowledgments

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).

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    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 [[17], [18], [19]], 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

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