查找使用阿拉丁产品的科研文献

Hyaluronic acid-coated polypeptide nanogel enhances specific distribution and therapy of tacrolimus in rheumatoid arthritis

Li Yuhuan,Wang Xin,Gao Yu,Zhang Ziyi,Liu Te,Zhang Zhuo,Wang Yinan,Chang Fei,Yang Modi

Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels’ disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications.

Flexible microneedles incorporating gold nanorods and tacrolimus for effective synergistic photothermal-chemotherapy of rheumatoid arthritis

Shulin Shen,Aiqun Wan,Yan Wang,Linxiao Liu,Yao Yao,Jiaqi Weng,Tong Zhu,Qingliang Yang,Qinying Yan

Transdermal drug delivery systems for rheumatoid arthritis (RA) have garnered substantial attention due to their great potential to overcome limitations observed in conventional oral or injection strategies, including limited selectivity and adverse effects on extra-articular tissues. Microneedles (MNs) appear to be highly desirable carriers for transdermal drug delivery of RA. However, microneedles typically are unable to keep up with the flexibility of joints, which decreases the effectiveness of administration. In this study, we developed a flexible microneedles (FMNs) delivery system. And gelatin was employed for the fabrication of flexible backings for microneedles owing to its excellent ductility and biocompatibility . We achieved synergistic   photothermal-chemotherapy of RA by incorporating the chemical drug Tacrolimus (TAC) and the photothermal agent gold nanorods (AuNRs) into dissolving microneedles. Results showed a high mechanical strength of the proposed FMNs. In the animal model of adjuvant-induced arthritis (AA), it is indicated that the prepared FMNs inhibited the expression of related inflammatory cytokines such as IL-1ß and TNF-α while enhancing bone repair and other related factors. Thus, the combination therapy of FMNs-mediated hyperthermia and chemotherapy can serve as a novel and synergistic treatment option for RA.

Rescuing vascular dysfunction in dorsal pancreatic arteries prevents tacrolimus-induced glucose metabolism disorder in mice

Fei Lingyan,Wang Honghong,Zhao Dongliang,Wang Xiaohua,Ren Jizhen,Liu Lanyun,Tang Chun,Lei Yan,Wang Qingqing,Nie Yuanpeng,Liu Yang,Li Na,Zhong Ming,Xu Nan,Wei Jin,Persson Pontus B.,Patzak Andraes,Khedkar Pratik H.,Zheng Zhihua,Jiang Shan

Long-term adverse effects of the immunosuppressant tacrolimus (Tac), such as nephrotoxicity, hepatotoxicity and diabetes, have been widely reported. Up to 33.6% of solid organ transplantation patients receiving Tac treatment develop hyperglycemia; however, the underlying mechanisms remain poorly understood. Here, using a mouse model of Tac-induced hyperglycemia, we found that Tac-induced body-weight loss, hyperglycemia, hypoinsulinemia, glucose intolerance and insulin resistance were improved by valsartan, a renin-angiotensin system (RAS) inhibitor. Histological and immunofluorescence analysis of the pancreas showed reduced islet areas and β-cell mass in Tac-treated mice. Moreover, when compared to control mice, isolated islets from Tac-treated mice showed a downregulation of cell-proliferation markers (Ki67, Ccna2 and Ccnd1) while an upregulation of apoptotic markers (DNA fragmentation, Bax and Caspase3). Tac also upregulated hypoxia-related markers in the pancreas, including hypoxia-inducible factor-1α (HIF-1α) and its downstream factors (Adm, Hmox1 and Vegfa), CD31 and pimonidazole adducts. Furthermore, treatment with Tac led to vascular dysfunction in pancreatic arteries. All of these adverse effects could be partially or fully abrogated by valsartan. Tac also increased levels of renin in renal tissue (1.00 ± 0.06 vs 1.29 ± 0.04, p  < 0.05) and serum (28.35 ± 4.29 ng/mL vs 51.99 ± 4.95 ng/mL, p  < 0.05). Inhibition of RAS by valsartan protected against Tac-induced vascular dysfunction in renal interlobar arteries. Collectively, our data illustrate a previously undescribed mechanism, in which Tac-induced vascular dysfunction in renal interlobar arteries leads to RAS activation. Blocking RAS by valsartan alleviates vascular dysfunction in dorsal pancreatic arteries and hypoxia in islets, which in turn prevents Tac-induced β-cell dysfunction and glucose metabolism disorder.

Ultrasensitive Sandwich-Type SERS-Biosensor-Based Dual Plasmonic Superstructure for Detection of Tacrolimus in Patients

Xiaoyue Zheng,Jiazhou Ye,Weiwei Chen,Xiaoyuan Wang,Jianhua Li,Fengmei Su,Caiping Ding,Youju Huang

Tacrolimus (FK506) is widely used in the prevention of organ transplant rejection and the treatment of autoimmune diseases, but it is difficult to detect within the low and narrow concentration range in practical clinical fields. A magnetic plasmonic superstructure-targets-plasmonic superstructure-based sandwich-type SERS biosensor is presented here to ultrasensitively detect FK506 in the blood of organ transplant patients. The spiky Fe3O4@SiO2@Ag flower magnetic superstructure and hollow Ag@Au superstructure enhanced the SERS signals by providing rich sharp tips, cavities, and abundant hot spot gaps. And the magnetic feature makes it easy to concentrate and separate the biological target. Using the designed sandwich-type SERS biosensor, FK506 could be detected within a range of 0.5–20 ng/mL with a detection limit of 0.33 ng/mL. All results indicated that the sandwich-type SERS biosensor has good stability, sensitivity, and anti-interference properties. It is noteworthy that this allowed us to successfully analyze FK506 in the blood of transplant patients, which is in strong agreement with the clinical results. Consequently, the attractive sandwich-type SERS biosensor can be used for the detection of FK506 in real samples, which is promising for clinical diagnosis.

Tacrolimus Induced Hypertension and Vascular Remodeling Includes Mechanisms of Cellular Senescence—The Protective Effect of Valsartan

Lingyan Fei,Xiaohua Wang,Lingyi Kong,Tianjiao Cui,Pratik H Khedkar,Yunxiu Xiang,Dongliang Zhao,Junxuan Fang,Yulin Liang,Yangyang Zhang,Nan Xu,Xingyu Qiu,Liang Zhao,Gensheng Zhang,Yan Lei,Chun Tang,Kongyang Ma,Liwei Lu,Jin Wei,En Yin Lai,Pontus B Persson,Andreas Patzak,Zhihua Zheng,Shan Jiang

Aim Calcineurin inhibitors (CNI) such as tacrolimus (Tac) are the first‐line treatment to prevent transplant rejection. However, CNI have adverse effects on blood vessels and renal function, which may be linked to cellular senescence. Valsartan, a common angiotensin II type 1 receptor (AT 1 R) blocker, exhibits anti‐senescence properties. We tested the hypothesis that tacrolimus causes hypertension and microvascular remodeling that involves induction of senescence, and that valsartan is protective. Methods Microperfusion and wire myography were employed to assess the contractile and dilatory functions of renal afferent arterioles (Af‐Art) and mesenteric arteries, respectively. The expression of components of the renin‐angiotensin system (RAS) and senescence‐associated biomarkers was investigated using qPCR and immunohistochemistry. Results Long‐term administration of Tac activated the RAS. Tac‐induced microvascular remodeling in mesenteric arteries and Af‐Art was mitigated by treatment with valsartan. Mice treated with Tac exhibited increased vasoconstriction in response to angiotensin II and reduced dilation to acetylcholine. Both effects were abolished by valsartan. Additionally, senescence‐associated biomarkers were upregulated in mesenteric and renal resistance arteries from Tac‐treated mice. Co‐administration of Tac with valsartan or ABT‐263, a senolytic agent, rescued Tac‐induced microvascular injury and reduced hypertension (conscious mice, noninvasive tail‐cuff system). Treatment with the antihypertensive drug amlodipine normalized blood pressure and downregulated senescence‐associated beta‐galactosidase in mesenteric arteries. Conclusion These findings suggest that cellular senescence contributes to Tac‐induced microvascular injury and hypertension and demonstrate the effectiveness of senolytic treatment for protection. Valsartan could reduce senescence indirectly by lowering blood pressure; a direct anti‐senescence effect might also play a role in this context.

Effects of nanoparticles with hydrotropic nicotinamide on tacrolimus: permeability through psoriatic skin and antipsoriatic and antiproliferative activities

Tao Wan,Wenhui Pan,Yueming Long,Kaiyue Yu,Sibo Liu,Wenyi Ruan,Jingtong Pan,Mengyao Qin,Chuanbin Wu,Yuehong Xu

Tacrolimus cationic nanoemulsion enhances ocular surface retention for the treatment of dry eye disease and allergic conjunctivitis

Junming Li,Xinxin Liang,Shuo Ma,Jingxin Gou,Tian Yin,Haibing He,Xing Tang,Jiansong Zhao,Yu Zhang

Tacrolimus (TAC), as a new potent immunosuppressant, holds promise for treating immune-mediated ocular surface diseases, especially in dry eye disease (DED) and allergic conjunctivitis (AC). However, the low water solubility of TAC results in commercial formulations (Talymus®) as suspensions with limited corneal retention time and low penetration efficiency. In addition, the irritation of TAC reflexes tearing and rapid drug clearance, thereby reducing bioavailability. To address these challenges, we developed a TAC cationic nanoemulsion (TAC-CNE) with good biocompatibility. The oil-phase encapsulation improved water solubility while reduced irritation of TAC, and enabled sustained drug release via diffusion kinetics. Furthermore, cationic surface modification promoted electrostatic interactions with negatively charged ocular mucin proteins. This interaction, combined with the appropriate viscosity, can prolong the ocular surface retention time and thereby improve bioavailability. In addition, TAC-CNE was prepared through a simple high-pressure homogenization method, exhibiting stability over 6 months under storage conditions. In vivo and in vitro evaluations demonstrated the superior therapeutic efficacy of TAC-CNE in DED and AC. In particular, TAC-CNE was more prominent in safety, which solved the problems of ocular irritation of commercial preparations. Our findings highlight TAC-CNE as a promising strategy to overcome the limitations of commercial formulations, offering a new treatment choice for DED and AC. Download: Download high-res image (132KB) Download: Download full-size image

Polymer-free tacrolimus microsphere implants for long-acting prevention of corneal neovascularization in rats by subconjunctiva injection

Jinbin Liu,Huanglan Yan,Dengning Xia

Corneal neovascularization (CNV) severely compromises vision and remains difficult to manage with current pharmacotherapies, which are often limited by rapid drug clearance, poor tissue penetration, and adverse effects. Although polymer-based drug carriers can provide sustained drug release, they frequently suffer from low drug-loading capacity, suboptimal release kinetics, or induce inflammatory responses. Tacrolimus (FK506), a potent immunosuppressant with anti-inflammatory activity, is similarly limited by poor water solubility and rapid ocular clearance when administered as eye drops. In this study, we developed a polymer-free tacrolimus microsphere system using an emulsion-solvent evaporation method. The resulting microspheres exhibited uniform morphology (6.8 ± 1.0 μm) with a high drug-loading capacity (up to 98 ± 2 %) and a dense amorphous internal structure. In vitro , the microsphere showed a sustained release profile, reaching 85 % cumulative release by Day 30. In a rat CNV model, subconjunctival injection of tacrolimus microsphere maintained elevated drug concentrations in the cornea (81.0 ± 21.2 ng/g) and sclera (114.2 ± 34.9 ng/g) for at least one month and significantly suppressed CNV progression, reduced corneal opacity, and decreased the expression of inflammatory (TNF-α, IL-1β) and angiogenic (VEGF) markers. Histological analysis further confirmed improved corneal architecture, minimal inflammatory infiltration, and reduced neovascularization. In contrast, tacrolimus eye drops demonstrated limited therapeutic benefit and rapid clearance. Overall, these findings highlight polymer-free tacrolimus microsphere as a promising long-acting delivery platform for effective CNV management upon subconjunctiva injection, with the potential to improve therapeutic outcomes by enabling sustained drug release and reducing administration frequency.

Transforming sutures from passive tools into active immunomodulatory platforms: Prolonging corneal graft survival using reloadable tacrolimus-eluting sutures

Mengzhen Xie,Yueze Hong,Ao Li,Haoyu Zou,Jianying Liu,Fanjun Zhang,Lei Tian,Shang Li,Ying Jie,Yunbing Wang

Corneal allograft rejection remains a major cause of transplant failure. To address the limitations of topical immunosuppressants—such as poor bioavailability and patient non-compliance—this study introduces a transformative strategy: engineering surgical sutures into active, reloadable immunomodulatory platforms. We developed a novel tacrolimus-eluting suture by modifying its surface with poly(dopamine) and anchoring a cyclodextrin-tacrolimus inclusion complex. This design enables sustained local drug release directly at the graft-host junction. Crucially, the system is reloadable; after initial depletion, the drug payload can be non-invasively replenished via cyclodextrin, allowing it to match the prolonged risk period of post-transplantation. In vitro studies confirmed sustained release over one week, and ex vivo corneal penetration models validated efficacy. By integrating long-term, localized immunosuppression into the standard-of-care suture, this platform offers a groundbreaking approach to prolong graft survival and personalize postoperative management.

Chitosan nanoparticles-incorporated polylactic acid/tacrolimus nanofiber composite membrane for tracheal scar inhibition and tracheal wound healing promotion

Guangchao Lv,Shiyun Feng,Shifang Sang,Hui Zhao,Kaizhong Wang

Postoperative tracheal stenosis caused by excessive scar formation is a major complication of complex thoracic surgeries (e.g., sleeve lobectomy, lung transplantation) with limited effective preventive strategies. We hypothesized that a composite membrane integrating chitosan (CS), polylactic acid (PLA), and tacrolimus (TAC) via simultaneous electrospinning and electrospraying would inhibit tracheal scarring and promote tracheal wound healing by synergizing their respective advantages. Herein, we fabricated the CS nanoparticle-incorporated PLA/TAC nanofiber (CS/PLA/TAC) composite membrane and characterized its physicochemical properties (morphology, mechanical strength, wettability). In vitro, the membrane achieved sustained TAC release over 28 days, selectively promoting normal tracheal fibroblast proliferation, migration, invasion, and early collagen secretion, while suppressing hypertrophic scar fibroblast proliferation and collagen production by downregulating transforming growth factor-β and α-smooth muscle actin. It also exhibited strong antibacterial activity and good biocompatibility, which showed no significant liver or kidney impairment. In a mouse tracheal trauma model, the membrane effectively inhibited scar formation, regulated collagen deposition, and promoted normal tissue regeneration. These findings validate our hypothesis and highlight the CS/PLA/TAC composite membrane as a promising biomaterial for preventing postoperative tracheal stenosis and enhancing healing in clinical thoracic surgery.

Enteric Polymer Based on pH-Responsive Aliphatic Polycarbonate Functionalized with Vitamin E To Facilitate Oral Delivery of Tacrolimus

Menglin Wang,Jin Sun,Yinglei Zhai,He Lian,Cong Luo,Lin Li,Yuqian Du,Dong Zhang,Wenya Ding,Shuhong Qiu,Yuhai Liu,Longfa Kou,Xiangfei Han,Rongwu Xiang,Yongjun Wang,Zhonggui He

To improve the bioavailability of orally administered drugs, we synthesized a pH-sensitive polymer (poly(ethylene glycol)–poly(2-methyl-2-carboxyl-propylene carbonate)–vitamin E, mPEG–PCC–VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113–PCC32–VE4 exhibited low critical micelle concentration of 1.7 × 10–6 mg/mL and high drug loading ability for tacrolimus (21.2% ± 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113–PCC32–VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs.

Preparation, characterization and in vivo evaluation of amorphous tacrolimus nanosuspensions produced using CO2-assisted in situ nanoamorphization method

Yingli Wang,Xiangfei Han,Jing Wang,Yongjun Wang

Unlike conventional ‘top-down’ and ‘bottom-up’ techniques, a novel low-cost CO 2 -assisted in situ nanoamorphization (ISN) method has been developed to prepare amorphous drug nanosuspensions. In order to improve the dissolution rate and oral bioavailability of tacrolimus (FK506), herein FK506 nanosuspensions with different particle size were successfully prepared using ISN method through adjusting the amount of acid-base pair and the stabilizer, the mean particle sizes of obtained FK506 nanosuspensions were 167.3   ±   2.8   nm (FK506-NA), 302.8   ±   2.0   nm (FK506-NB) and 513.5   ±   15.1   nm (FK506-NC), respectively. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) confirmed the amorphous state of FK506 in all nanosuspensions that would be beneficial to the improvement of drug bioavailability because the amorphous drug form is more soluble and has a higher dissolution rate than the crystalline state. In vitro dissolution studies showed that the dissolution rate order of different formulation is as follows: FK506-NB   >   FK506-NA   >   FK506-NC   >   FK506-D (without acid-base pair included)   >   Prograf ® (commercial hard capsule). In vivo pharmacokinetic studies showed that all FK506 nanosuspensions clearly increased the oral bioavailability of FK506 in comparison with Prograf ® , especially for FK506-NB. The C max and AUC 0–12   h of FK506-NB were about 2.05-fold ( p   <   0.01) and 1.5-fold ( p   <   0.05) higher than that of Prograf ® . These findings suggest that this simple and versatile ISN technique has great potential for use in the preparation of nanosuspensions to increase drug oral bioavailability.