IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis.

Rationale: Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type. Methods: Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined. Results: IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx. Conclusions: These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.

Transformation of nanoparticles via the transition of functional DNAs responsive to pH and vascular endothelial growth factor for photothermal anti-tumor therapy.

This study presents a novel approach for the development of DNA-functionalized gold nanoparticles (AuNPs) capable of responding to disease-specific factors and microenvironmental changes, resulting in an effective anti-tumor effect via photothermal therapy. The AuNPs are decorated with two types of DNAs, an i-motif duplex and a VEGF split aptamer, enabling recognition of changes in pH and VEGF, respectively. The formation of VEGF aptamers on the AuNPs induces their aggregation, further enhanced by VEGF ligands. The resulting changes in the optical properties of the AuNPs are detected by monitoring the absorbance. Upon irradiation with a near-infrared laser, the aggregated AuNPs generate heat due to their thermoplasmonic characteristic, leading to an anti-tumor effect. This study demonstrates the enhanced anti-tumor effect of DNA-functionalized AuNPs via photothermal therapy in both in vitro and in vivo tumor models. These findings suggest the potential utilization of such functional AuNPs for precise disease diagnosis and treatment by detecting disease-related factors in the microenvironment.

A polymeric iron oxide nanocomplex loaded with sulfasalazine: an approach for inducing ferritinophagy-assisted ferroptosis for anti-cancer therapy.

The approach of using ferroptosis to treat cancer has garnered attention due to its promising potential. However, the effectiveness of this therapy is often limited by the inherent redox system in cancer cells and the presence of ferritin as an iron ion storage molecule. To address this issue, we have designed a polymeric iron oxide nanocomplex loaded with sulfasalazine as a ferritinophagy-assisted ferroptosis inducing agent. The nanocomplex is based on a pH-responsive drug releasing platform that enables improved ferroptosis anti-cancer therapy. The nanocomplex was synthesized using polymerized phenylboronic acid decorated with iron oxide and further loaded with sulfasalazine by interacting with polymerized phenylboronic acid. Upon entering cancer cells, the nanocomplex releases sulfasalazine at the lysosomal acidic pH, which causes the complex to degrade into the labile iron ion (Fe2+). This process inhibits the production of GSH and reproduces the labile iron ion by degrading ferritin. As a result, an excess iron ion pool is formed, and the facilitated Fenton reaction induces an improved ferroptosis anti-cancer effect. Moreover, our research has demonstrated that the nanocomplex effectively regresses tumors, thereby representing significant inhibition of tumor growth using in vivo models. We believe that this ferritinophagy-assisted ferroptosis strategy using the nanocomplex provides a promising solution for iron-based anti-cancer therapy.

IDO-triggered swellable polymeric micelles for IDO inhibition and targeted cancer immunotherapy.

Indoleamine 2,3-dioxygenase (IDO) has been studied as a promising target for cancer immunotherapy. IDO catalyzes the oxidation of tryptophan into kynurenine, which subsequently activates regulatory T cells, thereby promoting an immunosuppressive microenvironment in the tumor tissue. Due to its overexpression in tumor cells, IDO itself could be a tumor-specific stimulus for targeted cancer therapy. Toward this objective, we developed IDO-triggered swellable micelles for targeted cancer immunotherapy. The micelles are prepared by the self-assembly of amphiphilic polymers containing polymerized tryptophan as a hydrophobic block. The micelles exhibited IDO-responsive behavior via solubility conversion of the hydrophobic core triggered by the oxidation of tryptophan residues into kynurenine. The micelles were internalized into tumor cells and disassembled by overexpressed IDO. Loaded with IDO inhibitor, the micelle presented enhanced therapeutic antitumor effect, and effector T-cells were recruited into the tumor tissue. We demonstrated that overexpressed IDO in cancer cells could be utilized as a tumor-specific stimulus, and utilizing an IDO-responsive drug delivery system holds great promise for targeted cancer therapy and immunomodulation.

Transcytosis-Inducing Multifunctional Albumin Nanomedicines with Deep Penetration Ability for Image-Guided Solid Tumor Treatment.

Transcytosis is an active transcellular transportation pathway that has garnered interest for overcoming the limited deep penetration of nanomedicines in solid tumors. In this study, a charge-convertible nanomedicine that facilitates deep penetration into solid tumors via transcytosis is designed. It is an albumin-based calcium phosphate nanomedicine loaded with IR820 (mAlb-820@CaP) for high-resolution photoacoustic imaging and enhanced photothermal therapy. Biomineralization on the surface stabilizes the albumin-IR820 complex during circulation and provides calcium ions (Ca2+ ) for tissue penetration on degradation in an acidic environment. pH-triggered transcytosis of the nanomedicine enabled by caveolae-mediated endocytosis and calcium ion-induced exocytosis in 2D cellular, 3D spheroid, and in vivo tumor models is demonstrated. Notably, the extravasation and penetration ability of the nanomedicine is observed in vivo using a high-resolution photoacoustic system, and nanomedicine shows the most potent photothermal antitumor effect in vivo. Overall, the strategy provides a versatile theragnosis platform for both noninvasive photoacoustic imaging and high therapeutic efficiency resulting from deep penetration of nanomedicine.

Complexation of drug and hapten-conjugated aptamer with universal hapten antibody for pancreatic cancer treatment.

Owing to a lack of reliable markers and therapeutic targets, pancreatic ductal adenocarcinoma (PDAC) remains the most lethal malignant tumor despite numerous therapeutic advances. In this study, we utilized cell-SELEX to isolate a DNA aptamer recognizing the natural conformation of the target on the cell surface. PAp7T8, an aptamer optimized by size and chemical modification, exhibited specific targeting to pancreatic cancer cells and orthotopic xenograft pancreatic tumors. To confer therapeutic functions to the aptamer, we adopted a drug-conjugated oligobody (DOligobody) strategy. Monomethyl auristatin E was used as a cytotoxic drug, digoxigenin acted as a hapten, and the humanized anti-digoxigenin antibody served as a universal carrier of the aptamer. The resulting PAp7T8-DOligobody showed extended in vivo half-life and markedly inhibited tumor growth in an orthotopic pancreatic cancer xenograft model without causing significant toxicity. Therefore, PAp7T8-DOligobody represents a promising novel therapeutic delivery platform for PDAC.

Deep Learning Enhances Multiparametric Dynamic Volumetric Photoacoustic Computed Tomography In Vivo (DL-PACT).

Photoacoustic computed tomography (PACT) has become a premier preclinical and clinical imaging modality. Although PACT's image quality can be dramatically improved with a large number of ultrasound (US) transducer elements and associated multiplexed data acquisition systems, the associated high system cost and/or slow temporal resolution are significant problems. Here, a deep learning-based approach is demonstrated that qualitatively and quantitively diminishes the limited-view artifacts that reduce image quality and improves the slow temporal resolution. This deep learning-enhanced multiparametric dynamic volumetric PACT approach, called DL-PACT, requires only a clustered subset of many US transducer elements on the conventional multiparametric PACT. Using DL-PACT, high-quality static structural and dynamic contrast-enhanced whole-body images as well as dynamic functional brain images of live animals and humans are successfully acquired, all in a relatively fast and cost-effective manner. It is believed that the strategy can significantly advance the use of PACT technology for preclinical and clinical applications such as neurology, cardiology, pharmacology, endocrinology, and oncology.

Facile preparation of poly(N-isopropylacrylamide)/graphene oxide nanocomposites for chemo-photothermal therapy.

Carbon-based nanomaterials, such as carbon nanotubes, fullerenes, nanodiamonds, and graphene, have been investigated for various biomedical applications, including biological imaging, photothermal therapy, drug/gene delivery, cancer therapy, biosensors, and electrochemical sensors. Graphene oxide (GO) has unique physicochemical properties and can be used to restore conductivity through oxidation. In this study, we developed poly(N-isopropylacrylamide) (PNIPAM)-based nanogel systems containing GO for controlled in vitro drug delivery. The photothermal effects of the PNIPAM/GO- and PNIPAMAAM/GO-based nanogel systems were enhanced. The release of DOX from the PNIPAM/GO-based nanogel was achieved using the photothermal effect of near-infrared irradiation. Using a Cell Counting Kit-8 assay, the cytotoxicity of all conditions demonstrated that the PNIPAM composite-based nanogels were biocompatible with no significance.

Hexa-BODIPY-cyclotriphosphazene based nanoparticle for NIR fluorescence/photoacoustic dual-modal imaging and photothermal cancer therapy.

Theranostic, which integrates the diagnosis and tumor treatment in tandem, is an emerging strategy in cancer treatment. Here, we report a novel and unique theranostic nanoparticle, HBCP NP, based on hexa-BODIPY cyclophosphazene (HBCP). Due to the unique bulky molecular structure of HBCP, this nanoparticle can simultaneously perform near-infrared (NIR) fluorescence imaging and photoacoustic imaging (PAI). Interestingly, since reactive oxygen species (ROS) generation of HBCP NPs is completely inhibited, 'safe' fluorescence imaging is possible without the risk of cell damage even under laser irradiation. Finally, NIR fluorescence imaging and PAI in 4T1 tumor-bearing mice demonstrated selective accumulation of HBCP NPs at tumor sites. In addition, HBCP NPs exhibited excellent photothermal effects under high-power laser irradiation, achieving effective tumor growth inhibition.

Guided Bone Regeneration with a Nitric-Oxide Releasing Polymer Inducing Angiogenesis and Osteogenesis in Critical-Sized Bone Defects.

Synthetic scaffolds, as bone grafts, provide a favorable environment for the repair and growth of new bone tissue at defect sites. However, the lack of angio- and osteo-induction limits the usefulness of artificial scaffolds for bone regeneration. Nitric oxide (NO) performs essential roles in healing processes, such as regulating inflammation and addressing incomplete revascularization. In this study, a polymer capable of controlled NO release is developed to promote the osteogenic capacity in artificial scaffolds. The biological efficiency of the NO compound is assessed by its effect on pre-osteoblasts and macrophages in vitro and the extent of vascularization and bone formation in the calvaria defect model in vivo. The compound does not inhibit cell adhesion or proliferation. NO treatment significantly increases both alkaline phosphatase activity and mineralization in pre-osteoblasts. Macrophages treated with NO secrete high levels of anti-inflammatory factors and adopt the pro-regenerative phenotype. In the critical-sized defect model, the collagen scaffold containing the NO compound enhances neovascularization and bone formation. The developed NO-releasing system promotes osteogenesis and regeneration of damaged bone tissue. As the multiple functions of NO involve macrophage modulation and angiogenesis, such release systems may be valuable for guiding bone regeneration in critical-sized defects.

Enhanced Tumoricidal Immune Responses by Transarterial Chemotherapy Using Novel Nanocomplexes in a Rat Liver Cancer Model.

BACKGROUND/AIM: Locoregional treatments for hepatocellular carcinoma (HCC) induce immunogenic cell death and a tumor-specific immune response, but infiltration and activation of immune cells in the liver have not been clearly described. Transarterial chemoembolization (TACE) or transarterial chemotherapy (TAC) without embolization have been used to treat intermediate or advanced stage HCC patients. The identification of intrahepatic immune cell changes after locoregional therapy provides a theoretical basis for the combination with immune checkpoint inhibitors (ICIs) in HCC. This study aimed to determine the anticancer effect and changes in the liver immune cell population and function after direct injection of polymerized phenylboronic acid-conjugated doxorubicin (pPBA-Dox) nanocomplexes into the liver through TAC. MATERIALS AND METHODS: pPBA-Dox nanocomplexes were delivered directly to the liver cancer in a rat model by transarterial methods. Anticancer effect was confirmed by magnetic resonance imaging (MRI), and the immune cell population and functional changes were confirmed by flow cytometry (FACS). RESULTS: We first established a rat liver cancer model by implanting McA-RH7777 into rats and confirmed the formation of liver cancer through MRI, pathological examinations, and biochemical tests. Transarterial injection of pPBA-Dox nanocomplexes had a stronger anticancer effect than conventional Dox alone. Higher numbers of CD8+ and CD4+ T cells with activated phenotypes were infiltrated into the tumor microenvironment after transarterial pPBA-Dox treatments than after Dox alone treatment, suggesting the induction of stronger local immune responses by pPBA-Dox than Dox alone. CONCLUSION: This study provides a theoretical basis for TAC combined with ICIs and insight into novel targeted therapies using nanocomplexes for the treatment of HCC.

Injectable immunogel based on polymerized phenylboronic acid and mannan for cancer immunotherapy.

The recent development and prospects of cancer immunotherapy have led to diversification of the types of therapeutic agents used. By simultaneously administering various agents, a more effective therapeutic effect can be expected due to the synergistic effects of multiple therapeutics. In particular, if a substance with adjuvanticity and tumor antigen is delivered at the same time, enhanced cancer immunotherapy can be achieved through high cross-presentation and antigen-presenting cell (APC) maturation. To this end, we developed a polymerized phenylboronic acid (pPBA)-based immunogel for the simultaneous delivery of mannan, which has adjuvanticity and tumor antigen. The immunogel was formed by simple mixing of the polysaccharide mannan with pPBA through the formation of phenylboronic ester between the diol of mannose monomers and phenylboronic acids of pPBA. The immunogel was slowly degraded by hydrolysis to release the loaded tumor antigen. In addition, the released mannan played a key role in both APC maturation in vitro and the upregulation of cross-presentation. Finally, the pPBA-mannan immunogel exhibited a significant anticancer effect in the 4 T1 cell-inoculated mouse model, implying the potential of a codelivery system of antigens and adjuvants for effective cancer immunotherapy.

Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.

There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor-related deaths. Despite the high potential of nitric oxide (NO) in anti-cancer therapy owing to its biocompatibility and tumor cell-specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox-triggered self-immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin-prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on-demand NO delivery systems for anti-metastatic therapy and other treatments.

Latent Class Analysis of Health Behavior Changes Due to COVID-19 among Middle-Aged Korean Workers.

The purpose of this study was to identify the latent class for changes in health behavior due to COVID-19, reveal the characteristics of participants by type, and identify predictive factors for these types. The participants of this study were office workers between the ages of 40 and 60 and secondary data from the 2020 Community Health Survey of G city was utilized. Latent class analysis was performed on physical activities such as walking and exercise, eating fast food or carbonated drinks, eating delivered food, drinking alcohol, and smoking. Three types of health behavior changes due to COVID-19 were found: (1) decrease in all health behavior type, (2) increase in fast food and delivered food type, and (3) increase in smoking maintenance type. Second, the variables predicting the three types after controlling for general characteristics were health problems, social distancing among the COVID-19 quarantine rules, refraining from going out, and meeting with friends and neighbors and had an impact on COVID-19 life. It is necessary to strengthen non-face-to-face health promotion activities along with quarantine rules for COVID-19. In addition, there is a need for a health management plan for people with non-visible risk factors such as obesity and high blood pressure.

Engineered extracellular vesicle-based sonotheranostics for dual stimuli-sensitive drug release and photoacoustic imaging-guided chemo-sonodynamic cancer therapy.

Sonodynamic therapy has shown promise as an effective alternative to conventional photodynamic therapy owing to its ability to treat deep-seated tumors. However, the development of stimuli-responsive sonosensitizers with high biocompatibility faces a significant challenge. Methods: In this study, we developed dual stimuli-responsive sonosensitizers with desirable biosafety using extracellular vesicles (EVs), a class of naturally occurring nanoparticles. Indocyanine green (ICG), which functions as both a sonosensitizer and photoacoustic (PA) imaging agent, was loaded into EVs, together with paclitaxel (PTX) and sodium bicarbonate (SBC), to achieve pH-responsive PA imaging-guided chemo-sonodynamic combination therapy. Results: The EVs significantly improved the cellular uptake of ICG, thus triggering enhanced sonodynamic effects in breast cancer cells. SBC-, ICG-, and PTX-loaded EV [SBC-EV(ICG/PTX)] efficiently released the PTX in response to acidic pH in the endo/lysosomes because CO2 bubbles generated from the SBC caused the EV membranes to burst. The drug release was further facilitated by ultrasound (US) treatment, demonstrating dual pH/US-responsive drug release. The ICG- and PTX-loaded EVs exhibited efficient anticancer activity against breast tumor cells owing to the combination of chemo-sonodynamic therapy. High-resolution PA imaging visualized the preferential tumor accumulation of SBC-EV(ICG/PTX) in tumor-bearing mice. Notably, a single intravenous injection of SBC-EV(ICG/PTX) with US irradiation significantly suppressed tumor growth in mice without systemic toxicity. Conclusions: Our findings demonstrate that dual stimuli-responsive SBC-EV(ICG/PTX) are promising sonotheranostic nanoplatforms for safe and efficient chemo-sonodynamic combination cancer therapy and photoacoustic imaging.

Immunostimulation of tumor microenvironment by targeting tumor-associated macrophages with hypoxia-responsive nanocomplex for enhanced anti-tumor therapy.

Tumor-associated macrophages (TAMs), which dampen the therapeutic efficacy of cancer immunotherapy, are the key players in the immunosuppressive tumor microenvironment (TME). Therefore, reprogramming TAMs into tumoricidal M1 macrophages possesses considerable potential as a novel immunotherapy. However, the low bioavailability of polarization agents and limited accumulation of TAMs restrict their anti-tumor efficacy. In this study, we developed a polymer-based hypoxia-responsive nanocomplex to target TAMs in hypoxia for enhanced cancer immunotherapy. We synthesized a hypoxia-cleavable polymer poly(ethylene glycol)-azo-poly(l-lysine) (PEG-azo-PLL) and formulated a nanocomplex by simple mixing PEG-azo-PLL and poly(I:C). By mimicking in vitro hypoxia conditions, PEG-azo-PLL/poly(I:C) complexes could transform the physicochemical properties to enhance the delivery efficiency of poly(I:C) to tumor hypoxia, where M2-like TAMs are accumulated. Furthermore, PEG-azo-PLL/poly(I:C) could successfully reduce the population of M2-like TAMs in hypoxic tumors and promoted infiltration of CD8+ T cells in vivo, resulting in the favorable conversion of immunosuppressive TME. Finally, PEG-azo-PLL/poly(I:C) could elicit a significant in vivo anti-tumor effect in B16F10-bearing mice in addition to a prolonged survival time, demonstrating that the hypoxia-responsive nanocomplex PEG-azo-PLL/poly(I:C) is a promising approach for TAM reprogramming immunotherapy for solid tumors.

Copper-Catalyzed Covalent Dimerization of Near-Infrared Fluorescent Cyanine Dyes: Synergistic Enhancement of Photoacoustic Signals for Molecular Imaging of Tumors.

Photoacoustic (PA) imaging relies on the absorption of light by chromophores to generate acoustic waves used to delineate tissue structures and physiology. Here, we demonstrate that Cu(II) efficiently catalyzes the dimerization of diverse near-infrared (NIR) cyanine molecules, including a peptide conjugate. NMR spectroscopy revealed a C-C covalent bond along the heptamethine chains, creating stable molecules under conditions such as a wide range of solvents and pH mediums. Dimerization achieved >90% fluorescence quenching, enhanced photostability, and increased PA signals by a factor of about 4 at equimolar concentrations compared to the monomers. In vivo study with a mouse cancer model revealed that dimerization enhanced tumor retention and PA signal, allowing cancer detection at doses where the monomers are less effective. While the dye dimers highlighted peritumoral blood vessels, the PA signal for dimeric tumor-targeting dye-peptide conjugate, LS301, was diffuse throughout the entire tumor mass. A combination of the ease of synthesis, diversity of molecules that are amenable to Cu(II)-catalyzed dimerization, and the high acoustic wave amplification by these stable dimeric small molecules ushers a new strategy to develop clinically translatable PA molecular amplifiers for the emerging field of molecular photoacoustic imaging.

Phenylboronic acid-based core-shell drug delivery platform clasping 1,3-dicarbonyl compounds by a coordinate interaction.

Along with the successful commercialization of chemotherapeutics, such as doxorubicin and paclitaxel, numerous natural compounds have been investigated for clinical applications. Recently, curcumin (CUR), a natural compound with various therapeutic effects, has attracted attention for cancer immunotherapy. Most chemotherapeutics, however, have poor water solubility due to their hydrophobicity, which makes them less suited to biomedical applications; CUR is no exception because of its low bioavailability and extremely high hydrophobicity. In the present study, we developed an easy but effective strategy using the interaction between the 1,3-dicarbonyl groups of drugs and phenylboronic acid (PBA) to solubilize hydrophobic drugs. First, we verified the coordinate interaction between 1,3-dicarbonyl and PBA using 3,5-heptanedione as a model compound, followed by CUR as a model drug. A PBA-grafted hydrophilic polymer was used to form a nanoconstruct by coordination bonding with CUR, which then made direct administration of the nanoparticles possible. The nanoconstruct exhibited remarkable loading capability, uniform size, colloidal stability, and pH-responsive drug release, attributed to the formation of core-shell nanoconstructs by coordinate interaction. The therapeutic nanoconstructs successfully showed both chemotherapeutic and anti-PD-L1 anticancer effects in cellular and animal models. Furthermore, we demonstrated the applicability of this technique to other 1,3-dicarbonyl compounds. Overall, our findings suggest a facile, but expandable strategy by applying the coordinate interaction between 1,3-dicarbonyl and PBA, which enables high drug loading and stimuli-responsive drug release.

A photoacoustic finder fully integrated with a solid-state dye laser and transparent ultrasound transducer.

The standard-of-care for evaluating lymph node status in breast cancers and melanoma metastasis is sentinel lymph node (SLN) assessment performed with a handheld gamma probe and radioisotopes. However, this method inevitably exposes patients and physicians to radiation, and the special facilities required limit its accessibility. Here, we demonstrate a non-ionizing, cost-effective, handheld photoacoustic finder (PAF) fully integrated with a solid-state dye laser and transparent ultrasound transducer (TUT). The solid-state dye laser handpiece is coaxially aligned with the spherically focused TUT. The integrated finder readily detected photoacoustic signals from a tube filled with methylene blue (MB) beneath a 22 mm thick layer of chicken tissue. In live animals, we also photoacoustically detected both SLNs injected with MB and subcutaneously injected melanomas. We believe that our radiation-free and inexpensive PAF can play a vital role in SLN assessment.

Polymeric Aggregate-Embodied Hybrid Nitric-Oxide-Scavenging and Sequential Drug-Releasing Hydrogel for Combinatorial Treatment of Rheumatoid Arthritis.

Selective depletion of overproduced nitric oxide (NO) with nanoscavengers is a promising approach for treating rheumatoid arthritis (RA), preventing both oxidative/nitrosative stress and the upregulation of immune cells. However, its practical applications are limited owing to the minimum time interval between intra-articular injections and unwanted off-target NO depletion. Herein, the rational design of an injectable in situ polymeric aggregate-embodied hybrid NO-scavenging and sequential drug-releasing (M-NO) gel platform for the combinatorial treatment of RA by incorporating a "clickable" NO-cleavable cross-linker (DA-NOCCL) is reported. This network is held together with polymeric aggregates to achieve a self-healing capability for visco-supplementation and on-demand dual drug (both hydrophilic and hydrophobic)-releasing properties, depending on the NO concentration. Moreover, consecutive NO-scavenging action reduces pro-inflammatory cytokine levels in lipopolysaccharides-stimulated macrophage cell lines in vitro. Finally, the intra-articularly injected M-NO gel with anti-inflammatory dexamethasone significantly alleviates the symptoms of RA, with negligible toxicity, in animal models. It is believed that this novel M-NO gel platform will provide a guideline for the combinatorial treatment of RA and various NO-related diseases.