Friction-adaptive hydrogel coating for mechanical-immune synergy in ligament-to-bone integration.

PurposeOsteoarthritis (OA) joints present abnormal mechanical environments that limit drug retention and therapeutic efficacy. Current intra-articular systems cannot provide both sustained anti-inflammatory delivery and mechanical support. A celecoxib (CXB)-loaded “Nano-in-Nano” Hierarchical Delivery System (NiN-HDS) was developed to simultaneously optimize drug release and joint reinforcement.MethodsIn this study, celecoxib-loaded PLGA nanoparticles (CXB-NPs) were prepared by emulsion solvent evaporation and incorporated into an electrospun nanofiber membrane combined with a genipin-crosslinked gelatin layer to form NiN-HDS. The system was characterized for particle size, zeta potential, porosity, hydrophilicity, swelling, degradation, mechanical properties, and in vitro CXB release. Therapeutic potential was evaluated in a rat OA model using histological and immunohistochemical analyses of cartilage and inflammatory markers.ResultsNiN-HDS maintained nanoparticle stability, with CXB-NPs showing an average particle size of 138.4 ± 4.3 nm and a zeta potential of –58.74 ± 16.58 mV. The system exhibited high porosity (87.16 ± 0.75%) and hydrophilicity (contact angle < 90°), achieved swelling equilibrium at 150 ± 10 min with a swelling ratio of 163.97 ± 9.76%, and degraded over 10 days with 88.53 ± 2.03% mass loss. Mechanical testing demonstrated high strength (Young’s modulus 17.24 ± 2.65 MPa, elongation at break 307.48 ± 32.01%. NiN-HDS provided sustained CXB release over 7 days, reaching 67.16% cumulative release. In vivo, it reduced cartilage damage and suppressed IL-1β and MMP-13 expression, while maintaining mechanical support and controlled drug delivery.ConclusionIn conclusion, we successfully developed NiN-HDS. Our results show that NiN-HDS combines sustained drug delivery with mechanical support, improves cartilage preservation and reduces local inflammation in a rat OA model, indicating that it can serve as a promising strategy for intra-articular therapy of osteoarthritis.

A chemokine "leverage regulation" biomimetic nanoformulation enhances CAR-T cells against solid tumors by reshaping immune cell niches.

Solvent-free aqueous spray drying of poorly soluble drugs enabled by hot-feed micellar solubilization and high-Tg polymer matrices.

Chronic inflammation-responsive hydrogel restores myeloid-T cell crosstalk to reinvigorate antitumor immunity against metastatic colorectal cancer

Deep learning-assisted SERS platform for label-free detection of celecoxib in serum using ag@Pt@porous silicon Bragg mirror composite substrate.

Targeting the aHSC-PGE2-NK cell axis overcomes immunosuppression and inhibits liver metastasis in fibrotic liver.

The solubilization of poorly water-soluble drugs remains a critical challenge in pharmaceutical research. The formulation of solid dispersions employing mesoporous silica nanoparticles (MSN) constitutes a key strategy for enhancing the hydrophilicity and oral bioavailability of Biopharmaceutics Classification System (BCS) Class II drugs. Although several commercial mesoporous silica excipients have been approved for pharmaceutical use, there remains room for improvement regarding drug loading capacity, stability, and controllability of drug release. Methods: for this purpose, dendritic mesoporous silica nanoparticles (DMSN) with a radial dendritic structure and pH-responsive degradation properties were designed and synthesized using celecoxib (CEL) as the model drug, featuring a pore size of 21.51 nm. CEL was loaded onto DMSN and seven commercial solid dispersion excipients using the solvent evaporation method. Results: owing to its high surface area, pore volume, and radial structure, DMSN achieved 39.72% drug loading in an amorphous state, markedly improving wettability, dissolution, and physical stability. Accelerated stability tests showed that DMSN inhibited recrystallization, outperforming traditional solid dispersions. Pharmacokinetic studies in rats demonstrated that the oral bioavailability of CEL-DMSN was 1.29-fold higher than that of commercial celecoxib capsules. Conclusions: in conclusion, these results confirmed the potential of DMSN in enhancing the stability, promoting oral absorption, and reducing gastrointestinal irritation of poorly soluble drugs.

Malignant gliomas, including glioblastoma multiforme (GBM) and grade 4 astrocytoma, are the most common types of brain tumors in adults. Standard treatment for gliomas includes adjuvant chemotherapy, typically based on temozolomide, combined with radiotherapy. However, its effectiveness is severely hindered by the limited ability of drugs to cross the blood–brain barrier and by the hyperactivation of the canonical Wnt signaling pathway, which drives tumor cell survival. Therefore, innovative drug combinations and novel delivery strategies are crucial for overcoming these barriers. Polymeric micelles represent a promising approach for enhancing drug delivery to brain tumors. This study aimed to obtain micelles containing cannabidiol (CBD), celecoxib (CELE), and temozolomide (TMZ), as well as their combinations, and to verify their anti-glioma properties. The study involved optimizing the micelle composition, incorporating active ingredients, and assessing the temporal stability of the resulting nanocarriers under varying temperature conditions. The GBM cell line U-138 MG and astrocytoma cell line U-87 MG were used to evaluate the biologic effects of the tested micelles. Cytotoxicity was assessed using the MTT assay, and flow cytometry was used to analyze the effect of the micelles on apoptosis. Western blot analysis was employed to assess the impact of the tested nanoformulations on the Wnt/β-catenin signaling pathway. The optimized micelles demonstrated strong cytotoxic and proapoptotic effects, accompanied by attenuation of the Wnt/β-catenin pathway. These preliminary findings support the therapeutic potential of polymeric micelles for treating malignant gliomas; however, further in vitro and in vivo studies are required to confirm their clinical applicability.

A c*-guided high-temperature rheological approach and solid-state NMR (ssNMR) 1H T1ρ and 1H T1 relaxation time measurements were used to estimate the miscibility of celecoxib (CEL)/polyvinylpyrrolidone (PVP) amorphous solid dispersions (ASDs) prepared by melt quench and spray drying. The ssNMR spin diffusion method is capable of investigating the miscibility of ASDs processed by the two methods, as it measures as-is ASD powders, while the c*-guided high-temperature rheological approach cannot, since it erases the processing history. Our results indicate a general agreement of the estimated miscibility of ASDs prepared by the two processing methods. The crystallization tendency is significantly different when the polymer concentration c is below and above c*. When c < c*, the onset of crystallization in dilute CEL/PVP ASDs is approximately identical to that of neat amorphous CEL. However, when c > c*, the first evidence of CEL crystallization is significantly delayed, indicating a reduced crystallization propensity. These results confirm that the efficient and material-sparing rheological approach can be used to estimate the miscibility (limit) and predict stability against crystallization for both melt-extruded and spray-dried ASDs. Our findings are useful in the rational and efficient design of robust ASDs with a desirable stability against crystallization during long-term storage.

BackgroundOsteoarthritis (OA) is a chronic degenerative disease that severely affects the physical function and quality of life of patients. Non-steroidal anti-inflammatory drugs (NSAIDs) are standard treatments for OA, alleviating joint pain and inflammation. Meanwhile, long-term oral administration and intra-articular injection will bring inevitable side effects. In this study, a dissolving microneedle composite drug delivery system co-loaded with celecoxib and shikonin (SKN-CXB@MN) was prepared, which can efficiently deliver drugs through the skin and exert therapeutic effects on OA from multiple targets including analgesia, anti-inflammation, and cartilage protection.MethodsThe material properties of SKN-CXB@MN were assessed through experiments on morphology, mechanical properties, solubility, drug release performance, and skin recovery. The biocompatibility of SKN-CXB@MN was determined using CCK-8 assays and live-dead staining. The protective effect of SKN-CXB@MN on IL-1β-induced chondrocytes were investigated through in vitro anti-apoptosis assays. The analgesic, anti-inflammatory, and cartilage-protective effects of SKN-CXB@MN were evaluated by measuring the joint swelling degree, PWT, weight bearing of RL, histology, and immunohistochemical staining in the OA rat model.ResultsMaterials characterization reveals that SKN-CXB@MN possesses sufficient mechanical strength to penetrate the skin. Upon application, the microneedles dissolve completely and release 85% of CXB and 75% of SKN within 15 min . In vitro biocompatibility assays confirm that SKN-CXB@MN is non-cytotoxic to chondrocytes and does not affect cell proliferation. Anti-apoptosis experiments show that SKN-CXB@MN inhibits IL-1β-induced chondrocyte apoptosis. In an OA rat model, SKN-CXB@MN alleviates knee joint swelling and pain, reduces cartilage degeneration, decreases chondrocyte apoptosis, and suppresses the inflammatory response.ConclusionThe dual-drug loaded SKN-CXB@MN system facilitates targeted drug delivery, thereby reducing systemic side effects. The synergistic effects of Celecoxib (CXB) and Shikonin (SKN) not only substantially alleviate pain and inflammation but also retard cartilage degeneration by modulating chondrocyte apoptosis and extracellular matrix metabolism. These multifaceted mechanisms indicate that the SKN-CXB@MN formulation could be a promising therapeutic option for osteoarthritis management.

Although polymerscan prevent the crystallization ofglassy drugsin amorphous solid dispersions, their stabilization mechanism requiresfurther clarification for an efficient formulation design. This studyexamined the impact of adding trace amounts (2 or 5 w/w %) of vinylpyrrolidone–vinylacetate copolymer (PVPVA) on the physical stability of celecoxib (CEL)glass using differential scanning calorimetry and broadband dielectricspectroscopy. Long-term isothermal crystallization studies from 35to 60 °C revealed that CEL glass was significantly stabilizedby the addition of trace amounts of PVPVA. Its stabilization was attributedto the effect of PVPVA on the nucleation process rather than on crystalgrowth. The addition of PVPVA slowed down the α-relaxation ofCEL, whereas it accelerated Johari–Goldstein relaxation. Moreover,the addition of PVPVA effectively slowed down γ- and δ-relaxations. Of these, suppression of γ-relaxationmobility had the most important effect, as it is related to the formationof hydrogen bonding between CEL and PVPVA molecules to inhibit nucleation.Moreover, the change in molecular cooperativity of the CEL glass uponadding PVPVA contributed to the inhibition of nuclei formation dueto the decreased nucleation temperature. This study provides detailedinsights into the physical stabilization mechanisms of glass usingpolymeric excipients.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic effects, although the possible COX-independent impact on the kidneys is largely unknown. Kidney damage is often associated with defective autophagy and autophagy dysregulation has been associated with kidney fibrosis and the pro-fibrotic EGR1 transcription factor activation. The non-selective COX inhibitor indomethacin (IND) can be nephrotoxic, but the impact of selective COX-2 inhibitor celecoxib (CEL) or the non-selective naproxen (NAP) on renal autophagy and EGR1 remain obscure. Here, we investigated the dose-dependent effect of CEL and NAP administration on human proximal tubule epithelial (HK-2) cells and murine inner medullary collecting duct (IMCD) cells in comparison to the effects of IND. To elucidate chronic renal effects, we also treated rats similarly for two weeks. We found that high doses of CEL and NAP, but not IND, disrupted autophagy, increased oxidative stress, and activated pro-fibrotic pathways in both HK-2 and IMCD cells with induced EGR1, accompanied by ACTA2 upregulation. We found similar effects in the renal medulla of rats treated with high-dose CEL and NAP. In addition, autophagy dysfunction was evident through increased LC3-II/I and p62 accumulation. Histology confirmed dose-dependent tubular damage and nuclear EGR1 accumulation in CEL and NAP treated rats, accompanied by induced HMOX1 and AKT phosphorylation. Our study reveals dose-dependent tubulotoxic effects of NSAIDs unrelated to their COX-selectivity, suggesting an interplay between pro-fibrotic transcription factor EGR1, autophagy pathways and oxidative stress. These findings underscore the need for meticulous dose optimization especially in kidney disease patients in order to reduce nephrotoxicity.

The multidimensional complexity between metabolism and inflammation within the obese tumor microenvironment (OTME) poses substantial barriers to postsurgical immunotherapy and wound management. Herein, we engineered a multifunctional hydrogel (Lipo/CXB@Hydrogel) through covalent conjugation of dopamine-crosslinked oxidized hyaluronic acid and a ROS-sensitive linker, co-delivering the non-steroidal anti-inflammatory drug celecoxib (CXB) and the lipid metabolism modulator Lipofermata (Lipo) to facilitate T cell immunotherapy and wound healing. The unique multi-dynamic-bond crosslinked structure endows the hydrogel with excellent self-healing, tissue adhesiveness and mechanical properties. The implanted Lipo/CXB@Hydrogel degrades and releases CXB to suppress hyperinflammation and enhance intratumoral cytotoxic T lymphocyte (CTL) infiltration, while Lipo inhibits the predatory uptake of fatty acids by tumor cells in the OTME for competing metabolic resources of intratumoral infiltrated CTLs. Importantly, such a cascaded immunological effect of Lipo/CXB@Hydrogel treatment amplifies CTL proliferation and activity specifically through targeting the arachidonic acid (AA)/COX-2/PGE2 signaling axis, a central hub linking lipid metabolism and inflammation, initiating a long-lasting immune response to suppress colorectal tumor postsurgical recurrence and metastasis in obesity contexts. Moreover, the hydrogel can easily repeatedly close the reopened wounds and promote skin regeneration. Thus, this multifunctional hydrogel may provide a promising strategy for postsurgical obese tumor immunotherapy and wound closure.

Breast cancer affects one in eight Canadian women over their lifetime. Triple-negative breast cancer (TNBC) represents 10%-20% of all advanced stage breast cancers, often developing multidrug resistance (MDR), commonly resulting in treatment failure. Jadomycin B (JB), a natural product of Streptomyces venezuelae, maintains cytotoxicity against MDR TNBCs, and its activity is enhanced when combined with selective cyclooxygenase-2 inhibitor, celecoxib (CXB) in vitro. Our objectives were to evaluate the toxicity and anticancer effects of JB combined with CXB using zebrafish larval xenografts as a model system. Fluorescent human TNBC MDA-MB-231 cells (231-enhanced green fluorescent protein (EGFP)) were generated and characterized for zebrafish larval xenografts. A maximum tolerated dose (MTD) in zebrafish larvae were determined for JB (20 µM) and CXB (5 µM). Zebrafish embryos were xenotransplanted with 50-100 231-EGFP cells and treated with the MTDs of JB and CXB alone or in combination. The combination of JB and CXB resulted in a 75% reduction in 231-EGFP fluorescence intensity, significantly higher than reductions caused by either drug alone (39% for JB, 15% for CXB) (p<0.05). This study demonstrates that combining JB with CXB enhances anticancer activity in a zebrafish larval xenograft model of human TNBC, validating effects previously determined in vitro.

Celecoxib (CXB), a COX-2-selective nonsteroidal anti-inflammatory drug, exhibits promising anticancer activity but suffers from poor aqueous solubility and low bioavailability. In this study, a heparin–Brij S10 amphiphilic conjugate (Hep-Brij) was synthesized via cystamine linkage to develop self-assembled micelles for enhanced CXB delivery. The Hep–Brij micelles displayed a uniform nanoscale size (116.8 nm), negative surface charge (–26.3 mV), and high encapsulation efficiency (99.07%) with a drug loading of 4.71%. The micellar system demonstrated pH-responsive release, showing faster CXB liberation at physiological pH (7.4) and slower release under acidic conditions (pH 5.0), indicating potential for controlled and site-specific drug delivery. Hemocompatibility and cytocompatibility assays confirmed excellent biocompatibility below 200 µg/mL. Remarkably, CXB-loaded Hep–Brij micelles achieved a 59.3-fold lower IC50 value (0.89 ± 0.07 µg/mL) against MCF-7 breast cancer cells compared to free CXB (52.78 ± 1.26 µg/mL), underscoring enhanced intracellular uptake and cytotoxicity. The synergistic contributions of heparin and Brij S10 underpin the superior therapeutic outcome. These results demonstrate that Hep–Brij micelles represent a safe and potent nanoplatform for improving CXB delivery and efficacy in breast cancer therapy.

ABSTRACT Celecoxib (CXB) is a lipophilic drug classified as a Biopharmaceutical Classification System (BCS) Class II compound, characterized by poor aqueous solubility and low oral bioavailability, which hinders its ability to penetrate through the stratum corneum. To address these concerns, nanoemulgel (NEG) has emerged as a promising carrier for enhancing transdermal delivery of lipophilic drugs. This study aimed to develop, characterize, and investigate the release profile of the CXB‐loaded NEG incorporating fractionated medium chain triglycerides (FMCTs) as the carrier oil, which mainly contains caprylic and capric acids, which are known for their superior solubilizing capacity and skin penetration enhancement. Herein, the CXB‐loaded nanoemulsion (NE) was prepared with a combination of oil, surfactants and water using the spontaneous emulsification method. The resulting CXB‐NE was then characterized according to its particle size, polydispersity index, zeta potential to evaluate its physicochemical properties. The optimized formulation was incorporated with Carbopol 940 gel to develop CXB‐NEG, which was evaluated for in vitro release study. The results showed that CXB‐NEG F1 formulated with a blend of MCT and PKOlein demonstrated a smaller particle size (146.80 nm) compared to CXB‐NEG F2 containing MCT alone (161.90 nm). Both formulations exhibited good stability with PDI less than 0.30 and zeta potential exceeding −30 mV. Notably, CXB release from NEG‐F1 was approximately 10‐fold higher (50.35%) than the release from conventional gel (5.03%), followed by NEG‐F2 with 42.60% release. These findings suggested that incorporating a blend of MCT and PKOlein in CXB‐NEG F1 enhances particle size reduction, stability, and drug release performance. These enhancements improve skin permeation, supporting the formulation's suitability for transdermal delivery and indicating the effectiveness of FMCTs as permeation enhancers.

Celecoxib (CLX), a selective COX-2 inhibitor and BCS Class II drug, is widely used for osteoarthritis and rheumatoid arthritis but having poor aqueous solubility (4.2 µg/mL) and limited dissolution, restricting its oral bioavailability. This study aimed to enhance CLX solubility and dissolution using integrated computational and experimental approaches. Simulated crystal morphology revealed a dominant (1 0 0) face, indicating a plate-like crystal habit that may hinder dissolution. Molecular dynamics simulations further identified hydroxypropyl β-cyclodextrin (HP-βCD) as the most compatible polymer, exhibiting the lowest interaction parameter (χ = − 5.86) and mixing energy (Emix = − 3.47 kcal/mol). Physical mixtures (PM1–PM4) were prepared at a 1:1 drug-to-polymer ratio and evaluated for solubility and recrystallization inhibition. PM1 (CLX–HP-βCD) showed the highest solubility (64.18 µg/mL) and longest induction time (140 s), indicating improved supersaturation stability. Lyophilized solid dispersions (SD1–SD4) were then developed and characterized using solubility studies, FTIR spectroscopy, microscopy, and in vitro dissolution testing. SD1 exhibited the greatest solubility enhancement (645 µg/mL), over 150-fold higher than pure CLX. FTIR and microscopy confirmed molecular dispersion and amorphization within the hydrophilic matrix. In vitro dissolution testing showed SD1 achieved 78.5% drug release in 3 h, with release kinetics best described by first-order (R2 = 0.9661) and Korsmeyer–Peppas (n = 0.879) models. These dispersions were compressed into tablets (T1–T4) and assessed for mechanical properties and drug release. T1 demonstrated the highest release (99.88% in 3 h), with release kinetics fitting first-order (R2 = 0.8996) and Hixson–Crowell (R2 = 0.9351) models. Overall, HP-βCD-based lyophilized solid dispersion emerged as a highly effective system for enhancing the solubility, dissolution, and ultimately the oral bioavailability of celecoxib.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-20755-7.

A celecoxib (CELE)-graftedchitosan copolymer was synthesized usinga thioketal linkage for oxidative stress-mediated delivery of chlorine6 (Ce6) and enhanced photodynamic therapy (PDT) against oral squamouscarcinoma. CELE was conjugated to the amine groups of chitosan usingthioketal dicarboxylic acid as a linker, resulting in the synthesisof a CELE-grafted chitosan (ChitoCELE) copolymer. The ChitoCELE copolymerwas reconstituted in water, and Ce6 was subsequently incorporatedto produce Ce6-incorporated ChitoCELE nanophotosensitizers. Thesenanophotosensitizers exhibited a spherical morphology with a diameterof less than 200 nm. Disintegration of the nanophotosensitizers wasobserved upon exposure to hydrogen peroxide, leading to an increaseddrug release rate. These results indicated that the nanophotosensitizersare sensitive to oxidative stress in vitro. The intracellularuptake of Ce6, production of reactive oxygen species (ROS), and PDT-inducedcytotoxicity were all higher following treatment with the nanophotosensitizerscompared to treatment with free Ce6. Interestingly, CELE enhancedROS production when combined with Ce6, indicating that CELE and ChitoCELEconjugates can amplify the PDT efficacy of Ce6-incorporated nanophotosensitizers.In an in vivo tumor xenograft model using KB oralsquamous carcinoma cells, the nanophotosensitizers were preferentiallydelivered to solid tumors and efficiently suppressed tumor growth.

A self-delivery albumin nanomedicine amplified photodynamic therapy against esophageal cancer through COX-2/PGE2 interruption and regulation of mitochondrial respiratory