BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Xianquan Feng,Lingjun Zeng,Lina Wu,Zhenzhen Chen,Wanjing Lin,Hongtao Song,Fenghua Lan
Immunotherapy has captured attention for its high clinical efficacy. However, its efficacy is limited by inadequate immune activation. Therefore, a platform to activate the immune system and amplify the host's immune response against tumors is urgently needed. Herein, a self-delivery photodynamic nanodrug (VAC@HSA) is reported as inducing immunogenic cell death (ICD), promoting the recruitment of dendritic cells (DCs), and normalizing tumor blood vessels. Firstly, verteporfin with laser assistance releases tumor-associated antigen to induce ICD, while celecoxib downregulates prostaglandin E2 and releases CCL5 to activate DC recruitment. Moreover, vasculature is normalized through axitinib, which contributes to reducing tumor hypoxia and reversing the immunosuppressive effects of vascular endothelial growth factor. This joint action promotes the infiltration of immune effector cells into the tumor. Therefore, the amplified photodynamic nanodrug with excellent biocompatibility effectively inhibits tumor growth and lung metastasis and produces a cascade of immune responses. Our study demonstrates a practically innovative strategy for activating cancer immunotherapy, which can alter the "cold" properties of tumors.
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Qihui Wang,Xinlu Huangfu,Huan Ouyang,Jian Liang,Shengyuan Zhang,Hua Nie,Huang Zeng,Li Yang,Hao Fan,Junwei He
Rheumatoid arthritis (RA) is a chronic inflammatory disorder. Toll-like receptor 4 (TLR4) and cyclooxygenase-2 (COX-2) are key mediators in its pathogenesis. Despite their crucial role, few studies have examined inhibitors targeting the TLR4–COX-2 axis. In this study, a combination of affinity ultrafiltration (AUF), surface plasmon resonance (SPR), serum pharmacochemistry, UHPLC-MS/MS, network pharmacology, cellular thermal shift assay (CETSA), isothermal dose–response (ITDR), and drug affinity–responsive target stability (DARTS) techniques were employed to explore TLR4–COX-2 inhibitors from Dendropanax proteus root extract (DPR). As a result, 10 phenylpropanoids were successfully identified from DPR. These constituents exhibited COX-2 inhibitory activity, with IC₅₀ values ranging from 5.2 to 36.2 μM. Molecular docking and molecular dynamics simulations confirmed their strong binding affinity to COX-2. In TNF-α–stimulated MH7A cells, these constituents significantly decreased COX-2 and PGE2 protein expression at concentrations of 2.5 and 5 μM. DPR modulates TLR4-mediated inflammatory signaling pathway against RA through network pharmacology, which was confirmed by CETSA, ITDR, and DARTS experiments. These phenylpropanoids significantly reduced TLR4 protein expression in TNF-α–stimulated MH7A cells at concentrations of 2.5 and 5 μM. Collectively, phenylpropanoids are the major anti-RA constituents of DPR, exerting their effects by inhibition of the TLR4-COX-2 signaling axis. While these findings are limited to in vitro and in silico models, they provide a strong scientific foundation for future in vivo efficacy studies and structural optimization of these phenylpropanoid leads.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2026
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IF 6
Yuanyuan Liu,Yuanyao Lin,Xuemei He
An ultrasound-responsive PLGA nanosystem co-encapsulating CXB, CAT, and PFP was developed. • Ultrasound triggered PFP phase transition and promoted on-demand CXB release from nanoparticles. • CAT retained catalytic activity and enabled oxygen generation, helping alleviate tumor hypoxia. • The nanosystem potentiated the antitumor activity of imatinib against GIST in vitro and in vivo. • Combined treatment increased apoptosis and suppressed migration and tumor growth in GIST. The therapeutic efficacy of imatinib (IM) in gastrointestinal stromal tumors (GISTs) is often limited by inadequate intratumoral drug accumulation and an abnormal tumor microenvironment. In this study, an ultrasound-responsive poly(lactic-co-glycolic acid) (PLGA) nanoparticle system, designated CXB/CAT@PFP-PLGA NPs, was developed for the co-delivery of celecoxib (CXB) and catalase (CAT) to enhance the antitumor efficacy of IM. The nanoparticles were characterized in terms of their physicochemical properties, ultrasound responsiveness, and oxygen-generating capability. Their ability to potentiate IM therapy was evaluated both in vitro and in vivo, while biodistribution and biosafety were assessed in vivo. The results showed that CXB/CAT@PFP-PLGA NPs exhibited a relatively uniform size distribution and successfully co-encapsulated CXB and CAT. Upon ultrasound irradiation, the nanoparticles underwent phase transition, thereby triggering drug release. In vitro, CXB/CAT@PFP-PLGA NPs enhanced the inhibitory effect of IM by reducing cell viability, promoting apoptosis, and inhibiting cell migration. In vivo, the nanosystem improved the antitumor efficacy of IM, accumulated at the tumor site, suppressed tumor growth, and showed no evident systemic toxicity. Collectively, these findings suggest that CXB/CAT@PFP-PLGA NPs may represent a promising strategy for enhancing IM therapy in GIST. Download: Download high-res image (89KB) Download: Download full-size image
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Drug Delivery and Translational Research
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2026
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IF 6.9
Yuan Hao,Zhang Bingwen,Sun Wen,Liu Haofan,Hu Liandong
In this study, celecoxib (CXB) microspheres (CM) and ropivacaine (RPV) microspheres (RM) were prepared respectively. A poly (D, L-lactide-co-glycolide)-block-poly (ethylene glycol)-block-poly (D, L-lactide-co-glycolide) (PLGA–PEG–PLGA, PPP) was synthesized by copolymerizing glycolide and lactide with polyethylene glycol. CM, RM, and hydroxyapatite (HA) were then incorporated into PPP solution to construct the microsphere–hydrogel system (CRMH hydrogels). CM, RM, and CRMH were systematically characterized in terms of morphology, physicochemical properties, pH-buffering capacity, and degradation behavior. The pH-dependent drug release and release kinetics of the individual CM, RM and the CRMH hydrogels were also investigated. In vitro release studies demonstrated that CRMH hydrogels provided coordinated, sustained release of CXB and RPV at pH 6.2. In a rabbit osteoarthritis (OA) model, intra-articular (IA) administration of CRMH hydrogels achieved sustained drug retention and release within the joint cavity, and effectively promoted articular cartilage repair. Overall, the CRMH hydrogels showed promising synergistic therapeutic potential for OA.
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Drug Delivery and Translational Research
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2026
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IF 6.9
Yuan Hao,Zhang Bingwen,Sun Wen,Yang Fujia,Wang Fan,Qu YaMeng,Hu Liandong
Osteoarthritis is associated with a weakly acidic intra-articular microenvironment, which provides an intrinsic trigger for pH-responsive drug delivery systems to achieve site-specific and controlled drug release, thereby enhancing therapeutic efficacy. In this study, celecoxib (CXB)-loaded microspheres (CM-10) for intra-articular injection were fabricated using a microfluidic technique with poly(lactic-co-glycolic acid) (PLGA)/CaCO₃ as the carrier. The microspheres were systematically characterized in terms of morphology, encapsulation efficiency, and physicochemical properties. Their pH-responsive drug release and degradation behaviors were evaluated under different in vitro conditions, and the degradation behavior following intra-articular injection was further investigated. In addition, the pharmacodynamic effects of CM-10 were assessed in an osteoarthritis model. The results demonstrated that CM-10 exhibited pronounced pH-responsive release, with accelerated drug release under acidic conditions and sustained degradation following intra-articular administration. Furthermore, CM-10 effectively promoted articular cartilage repair and improved therapeutic outcomes. These findings indicate that CM-10 has promising potential as a pH-responsive intra-articular drug delivery system for osteoarthritis therapy.
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Frontiers in Pharmacology
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2026
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IF 5.4
Qing-Qing Liao,Li-Ping Chen,Jia-Qi Zheng,Yu-Jie Yang,Jing-Dan Weng,Teng Xie,Xiao-Dong Sun,Yuan-Yuan Zhang
Introduction The pathology of diabetic foot ulcer (DFU) is characterized by keratinocyte dysfunction, non-resolving inflammation, and oxidative stress. We aim to investigate the effects and mechanisms of piroxicam on DFU healing through regulating mitochondrial function and suppressing inflammation. Methods DFU was established in male C57BL/6 J mice and ovariectomized female mice. Piroxicam (1% or 0.33%) solution or saline was then applied for 9 days. HaCaT cells were induced with high glucose (HG) and subsequently incubated with piroxicam (0, 1.2, 3.7, 11, 33, 100 nM). Results and Discussion Piroxicam significantly promoted DFU healing and inhibited the fibrosis in male diabetic mice at a low dose. Consistently, piroxicam enhanced proliferation and migration, and inhibited inflammation, fibrosis, and cellular senescence in HG-induced HaCaT cells. Mechanistically, piroxicam alleviated HG-induced mitochondrial dysfunction by stabilizing the mitochondrial respiratory chain, increasing biogenesis, and enhancing mitophagy. These effects further attenuated oxidative stress and inhibited the cGAS-STING-NF-κB inflammatory pathway, thereby reducing the release of pro-inflammatory factors. Furthermore, molecular docking revealed that piroxicam bound to ERα, a finding further confirmed by a cellular thermal shift assay. HG induced a significant decrease in nuclear ERα protein levels, which was reversed by piroxicam, especially at 11 and 33 nM. Additionally, piroxicam’s pro-healing and anti-inflammation effects were attenuated in ovariectomized female DFU mice. Piroxicam’s protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen. In conclusion, piroxicam alleviates mitochondrial dysfunction and suppresses inflammatory responses by binding to ERα, which ultimately promotes DFU healing at low doses.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Dong-Wei Shao,Tong Xie,Ya-Tao Wang
Osteoarthritis (OA) is a widespread chronic degenerative joint disease, for which new treatment strategies are urgently needed. In this study, we developed an injectable, pH-responsive hydrogel (HA-TA-CS) aimed at improving joint drug delivery by enhancing retention within the joint cavity, while exhibiting excellent biocompatibility. The hydrogel was loaded with celecoxib for localized, in situ release (HA-TA-CS@Cel). OA is characterized by elevated levels of reactive oxygen species (ROS), which promote oxidative stress, inflammatory cytokine production, and further exacerbate the inflammatory response. HA-TA-CS@Cel effectively mitigates inflammation by scavenging excess ROS through the sustained release of TA and celecoxib. Our results demonstrate that HA-TA-CS@Cel significantly alleviates OA progression. In a mouse OA model, the system reduced pro-inflammatory factors and alleviated disease severity. Furthermore, HA-TA-CS@Cel promoted the polarization of macrophages from the M1 to the M2 phenotype, suggesting its ability to modulate the immune microenvironment and thereby attenuate joint inflammation and slow OA progression. These findings indicate that the injectable HA-TA-CS@Cel hydrogel system holds great promise for treating OA through enhanced cartilage protection and macrophage polarization, with potential applications in other inflammatory diseases.
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ULTRASONICS SONOCHEMISTRY
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2025
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IF 9.7
Hong-Fu Zhao,Si-Yi Han,Lu Xiao,Bo-Kang Yu,Ning Xia,Ying-Hua Zhang
Corn silk ( Zea mays L. ), an accessory product of maize, is an unconventional component with potential bioactive compounds. In this study, isoorientin was extracted from maize whiskers by ultrasound-assisted extraction, and the response surface optimization resulted in an extraction amount of 1.26 mg/g. A quantitative structure-effect relationship (QSAR) prediction model was developed, and the R 2 and RMSE of the XGBoost regression algorithm were 0.9582 and 0.01823, respectively. Interpretative analyses of the prediction model were carried out by using the SHAP visualization, which showed that the charge, structure, and lipid solubility of the molecules play a key role. Several anti-inflammatory compounds were screened by combining molecular docking and molecular dynamics. After oral toxicity testing, it was determined that isoorientin performed the best and had a semi-inhibitory concentration of 18.38 μg/mL. This study improves the high-value utilization of maize whiskers and provides a theoretical basis for the rapid screening of food-borne anti-inflammatory compounds.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 5.4
Aoyu Zhang,Shuying Li,Jie Qiao,Chuanqi Zhong,Zhiwen Zhang,Xiguang Ye,Jun Jin,Shiyan Shang,Song Wu,Qing Zhang,Gongxu Yang
Ethnopharmacological relevance The therapeutic effect of Psoralea corylifolia L. on knee joint pain was recorded as early as the Ming Dynasty in the Compendium of Materia Medica, which notes its actions of tonifying the kidney, strengthening tendons, and bones. Isopsoralen (ISO), derived from the Psoralea corylifolia L., has shown efficacy in improving osteoarthritis (OA) in both traditional use and our previous screening, demonstrating effects in alleviating joint inflammation and protecting cartilage. Aim of the study OA is a common disabling disease. Its progression connects local joint pathology to systemic metabolic and inflammatory states, extending to gut microbiota and metabolites. This study examines the therapeutic mechanism of isopsoralen against OA using a DMM-induced model. Materials and methods ISO's targets were predicted by network pharmacology approaches. Therapeutic effects were evaluated through behavioral tests, micro-CT, histology, Western blot, and PCR, while safety was assessed via liver/kidney staining. 16S rDNA sequencing and targeted metabolomics were employed to analyze gut microbiota structure and short-chain fatty acids (SCFAs). Pseudo germ-free mice and fecal microbiota transplantation (FMT) were used to validate the role of gut microbiota. Results Network pharmacology indicated ISO's multi-target action against OA. ISO downregulated the MAPK/NF-κB pathway, attenuated subchondral bone abnormalities, and alleviated joint degeneration in DMM mice. It also modulated gut microbiota composition and SCFA levels. FMT confirmed the essential role of gut microbiota in ISO's efficacy. Furthermore, no hepatorenal toxicity was observed. Conclusion ISO alleviates OA by modulating gut microbiota/SCFAs and inhibiting the MAPK/NF-κB pathway, thereby reducing inflammation and improving bone abnormalities, without hepatorenal toxicity.
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BIOMATERIALS
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2026
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IF 12.9
Shuang Wang,Tianwu Chen,Yong Li,Lei Zhang,Jing Wang,Changsheng Liu
The long-term success of anterior cruciate ligament (ACL) reconstruction depends on the stable integration between artificial grafts and host bone. Despite their favourable mechanical strength, polyethylene terephthalate (PET) artificial ligaments often suffer from micromotion-induced fibrosis and persistent foreign body reactions (FBR), which together hinder osteointegration. Here, we develop a dual-network hydrogel coating with time-staged local immunomodulatory capability, enabling functional “mechano-immune” synergy at the graft-bone interface. Catechol-functionalized hyaluronic acid (HAMA-DOP) forms strong adhesive interactions with PET through π-π stacking, hydrogen bonding, and reversible covalent bonds. Subsequent oxidative crosslinking into a dense quinone-based secondary network enhances shear resistance and fatigue durability, while supporting self-healing. Pluronic F127 diacrylate (PF127-DA) introduces a thermoresponsive structure allowing the hydrogel to transition from injectable fluid at 4 °C to a stable gel at 37 °C, enabling localized and phase-specific release of celecoxib (CXB). This facilitates early suppression of inflammation and sustained promotion of regeneration. In vivo studies reveal a dose-dependent regulatory effect of CXB, where low-dose delivery promotes M2 macrophage polarization, H-type vessel formation, and bone bridging, while high doses impair immune homeostasis and osteointegration. This work establishes a robust, biologically responsive interface strategy, advancing the design of innovative coatings for enhanced outcomes in artificial ligament integration.
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2026
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IF 4.3
Zhiling Chen,Huiling Zhou,Jie Song,Ben Xu,Can Wang,Fengchun He,Guisen Zhang,Tao Zhuang
Because the monotherapy of currently available pain killers often shows serious adverse effects or limited efficacy for treating neuropathic pain, multimodal analgesia has been highly recommended to gain improved antinociceptive effects and reduce dose-dependent side effects. Drug-drug co-amorphous systems emerge as a useful strategy for ameliorating the physicochemical properties of drug substances and achieving clinical benefits compared with individual components. New drug-drug co-amorphous products IMI-CEL at different ratios were prepared from imipramine hydrochloride (IMI) and a poorly water-soluble anti-inflammatory drug–celecoxib (CEL) by melt-quenching method, which were characterized by XRPD, DSC and IR. Co-amorphous product IMI-CEL (1:1) displayed notable improvement in the solubility (64.4 times) and dissolution rate (3.1 times) than crystalline CEL in pH 6.8 buffer, and IMI-CEL exhibited good physical stability under long-term storage conditions. Isobolographic analysis demonstrated that IMI-CEL (1:1) showed synergistic analgesic effects in paclitaxel-induced neuropathic pain in mice. Moreover, the oral bioavailability of 1:1 IMI-CEL was improved 1.396 times in rats when compared to the single drug. Above results suggested the potential of IMI-CEL to produce synergistic analgesic effects through developing drug-drug co-amorphous systems.
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Advanced Science
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2026
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IF 14.1
Tianhua Xiao,Zunlei Gong,Chuke Chen,Hui Yu,Yu Cai,Can Liu,Hongkai Huang,Ying Li,Jinyuan Guan,Le Wang,Chengyun Ning,Guoxin Tan,Lei Zhou
Radiotherapy (RT) is widely used as an adjuvant treatment after surgical resection for osteosarcoma, but its efficacy is often limited by insufficient radiosensitization and an immunosuppressive tumor microenvironment that restricts systemic antitumor immunity and promotes recurrence and metastasis. Here we report an injectable metal‐drug supramolecular condensate formed from hafnium ions and alendronate (Hf‐ALN) and loaded with the COX‐2 inhibitor celecoxib (CXB) for synergistic radioimmunotherapy of postoperative osteosarcoma. The condensate forms through coordination‐driven liquid‐liquid phase separation between Hf 4+ ions and alendronate, enabling local retention within postoperative bone defects and sustained therapeutic release. Upon X‐ray irradiation, the Hf component amplifies radiation energy deposition and reactive oxygen species generation, thereby enhancing radiation‐induced DNA damage and immunogenic cell death. Meanwhile, the acidic tumor microenvironment triggers responsive release of CXB and ALN; CXB inhibits the COX‐2/PGE 2 immunosuppressive pathway, while ALN promotes macrophage repolarization toward the M1 phenotype, collectively remodeling the tumor immune microenvironment. This strategy enhances dendritic cell maturation, activates cytotoxic CD8 + T cells, and reduces regulatory T‐cell infiltration. In orthotopic osteosarcoma models, CXB@Hf‐ALN combined with RT suppresses tumor recurrence, preserves bone integrity, inhibits pulmonary metastasis, and prolongs survival with minimal systemic toxicity, offering a promising strategy to improve postsurgical RT outcomes in osteosarcoma. This work designed an injectable metal‐drug supramolecular condensate formed from hafnium ions and alendronate (Hf‐ALN) and loaded with the COX‐2 inhibitor celecoxib (CXB) for synergistic radioimmunotherapy of postoperative osteosarcoma. Mechanistically, upon X‐ray irradiation, Hf enhances radiation energy deposition, ROS generation, and DNA damage, while CXB blocks COX‐2/PGE 2 and ALN repolarizes M1 macrophages, remodeling immune microenvironment to inhibit recurrence/metastasis and preserve bone integrity.
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