Delivery Of Tacrolimus Research Articles

A tacrolimus-eluting nerve guidance conduit enhances regeneration in acritical-sized peripheral nerve injury rat model.

Critical-sized peripheral nerve injuries pose a significant clinical challenge and lead to functional loss and disability. Current regeneration strategies, including autografts, synthetic nerve conduits, and biologic treatments, encounter challenges such as limited availability, donor site morbidity, suboptimal recovery, potential immune responses, and sustained stability and bioactivity. An obstacle in peripheral nerve regeneration is the immune response that can lead to inflammation and scarring that impede the regenerative process. Addressing both the immunological and regenerative needs is crucial for successful nerve recovery. Here, we introduce a novel biodegradable tacrolimus-eluting nerve guidance conduit engineered from a blend of poly (L-lactide-co-caprolactone) to facilitate peripheral nerve regeneration and report the testing of this conduit in 15-mm critical-sized gaps in the sciatic nerve of rats. The conduit's diffusion holes enable the local release of tacrolimus, a potent immunosuppressant with neuro-regenerative properties, directly into the injury site. A series of in vitro experiments were conducted to assess the ability of the conduit to maintain a controlled tacrolimus release profile that could promote neurite outgrowth. Subsequent in vivo assessments in rat models of sciatic nerve injury revealed significant enhancements in nerve regeneration, as evidenced by improved axonal growth and functional recovery compared to controls using placebo conduits. These findings indicate the synergistic effects of combining a biodegradable conduit with localized, sustained delivery of tacrolimus, suggesting a promising approach for treating peripheral nerve injuries. Further optimization of the design and long-term efficacy studies and clinical trials are needed before the potential for clinical translation in humans can be considered.

Pectin-based hydrogel loaded with polymeric nanocapsules for the cutaneous delivery of tacrolimus: A targeted approach for the treatment of psoriasis

This study aimed to develop a novel pectin-based hydrogel (PEC) incorporating nanocapsules-loaded tacrolimus (NCtac), named PEC-NCtac, as a potential strategy for psoriasis treatment. Blank nanocapsules (NC), PEC, PEC-NC, non-encapsulated tacrolimus (TAC), and the commercial TAC ointment (Tacroz®) were used as controls. The objectives involved physicochemical characterizing PEC-NCtac, assessing its cytotoxicity and anti-inflammatory effects, comparing adhesiveness with controls, determining skin penetration and permeation, and evaluating irritation potential. PEC-NCtac had an unimodal size distribution by laser diffraction (mean diameter of 250 nm and polydispersity -SPAN- of 1.68), drug content of 0.81 mg g−1 (HPLC), and pH of 4.51 (potentiometry). The nanoformulation had no significant impact on the viability of HaCat cells and CD4+ T cells when tested 24 h after treatment, with both cell types maintaining nearly 100 % viability. Treatment with NCtac resulted in a reduction in the pro-inflammatory cytokine IL-17A (p < 0.05). Adhesion studies revealed that PEC-NC showed a 1.9-fold higher force work compared to PEC. The combined effect of individual adhesion of NC and PEC when associated (PEC-NC) was evident in both healthy and injured skin (Healthy skin = 73 mN mm; Injured skin = 251 mN mm). PEC-NCtac allowed a decrease in skin drug permeation in the epidermis of injured skin compared to Tacroz® (40 % vs. 70 %, respectively). PEC-NCtac exhibited non-irritating activity in the HET-CAM/CAM-TBS model, while TAC demonstrated slight irritant activity. Furthermore, PEC-NCtac showed superior anti-inflammatory effects compared to TAC (75.0 % vs. 58 %, P value = 0.03). Summarizing, PEC-NCtac appears promising for topical treatment, demonstrating enhanced adhesion, skin penetration, safety profile, and anti-inflammatory activity.

Microsponge-Based Gel Loaded with Immunosuppressant as a Simple and Valuable Strategy for Psoriasis Therapy: Determination of Pro-Inflammatory Response through Cytokine IL-2 mRNA Expression.

Tacrolimus (TL) is a topical calcineurin inhibitor immunosuppressive drug widely used to manage various skin disorders. Herein, we report a TL-loaded microsphere gel formulation with severe atopic dermatitis effects that are required to manage skin disorders. The current study adopted a modified emulsion solvent evaporation technique to synthesize TL-loaded microspheres, which were further converted into gels for skin use. Characterization of the synthesized formulation was performed by differential dynamic light scattering, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, X-ray crystallography, Brunauer-Emmett-Teller (BET) analysis, differential scanning calorimetry, and drug release. A Franz diffusion cell was used to study the diffusion of TL for up to 8 h at pH 6.8 and 5.5. Evaluation of cell viability was determined by MTT assay and showed higher IC50 values compared to the plain drug. RNA extraction, real-time polymerase chain reaction (RT-PCR), and reverse transcription were also performed to determine the expression levels of the anti-inflammatory cytokine IL-2. Particle size determination was performed by a zeta sizer, and the TL microsphere size was 1745 ± 70 nm with a good polydispersity (0.337 ± 0.12). The drug entrapment efficiency was also very good at 60% ± 10, and the drug release was 93.9% ± 3.5 within 8 h. An in vitro diffusion study of the formulation also showed improved permeability at both pH values (4.5 and 5.5). The findings of the hemolytic tests demonstrated that TL-MG at concentrations of 50, 100, and 200 mg/mL did not produce any hemolysis. A dose-dependent pattern of cytotoxicity was found during the cell viability assay, with an IC50 value of 787.55 ± 12.78 µg/mL. There was a significant decrease in the IL-2 level in the TL-MG group compared to the other groups. TL-MG microspheres were nontoxic carriers for tacrolimus delivery, with greater loading capacity, a significant release profile, and enhanced cellular uptake with improved permeability.

A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation.

Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf®) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which leads to erratic bioavailability and toxicity. Local delivery of TAC directly into the graft, instead of systemic delivery, can improve safety, efficacy, and tolerability. Macrophages have emerged as promising therapeutic targets as their increased levels correlate with an increased risk of organ rejection and a poor prognosis post-transplantation. Here, we present a locally injectable drug delivery platform for macrophages, where TAC is incorporated into a colloidally stable nanoemulsion and then formulated as a reversibly thermoresponsive, pluronic-based nanoemulgel (NEG). This novel formulation is designed to undergo a sol-to-gel transition at physiological temperature to sustain TAC release in situ at the site of local application. We also show that TAC-NEG mitigates the release of proinflammatory cytokines and nitric oxide from lipopolysaccharide (LPS)-activated macrophages. To the best of our knowledge, this is the first TAC-loaded nanoemulgel with demonstrated anti-inflammatory effects on macrophages in vitro.

Advancing Nerve Regeneration: Translational Perspectives of Tacrolimus (FK506).

Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.

Application of Nanoprecipitation Technique to Develop Poloxamer-407 Facilitated Solid Lipid Nanoparticles for the Controlled Delivery of Tacrolimus

Currently, the solid lipid nanoparticles (SLNs) are utilized as a novel approach for the controlled drug delivery system (CDDS). Tacrolimus (TCM), a lipophilic drug, can easily be encapsulated in the hydrophobic core of these SLNs using nanoprecipitation technique. The current aim was to develop the controlled release Poloxamer (PLX) facilitated TCM loaded SLNs (PLX/TCM-SLNs), followed by their physicochemical evaluations, including chemical compatibility, particle size, surface charge, surface morphology, nature of SLNs, loading efficiency (LE), entrapment efficiency (EE), in vitro drug release studies, release kinetic modeling, and statistical evaluation. Here we also evaluate physicochemical properties of TCM and investigate solubility profile for improvement and dissolution rate of PLX/TCM-SLNs. PLX was used in the process as a polymer due to its low toxicity and weak immunogenic properties. The prepared formulation was characterized by scanning electron microscopy (SEM) images, and Fourier transform infrared spectroscopy (FTIR) has confirmed the compatibility of the selected ingredients, whereas particle size analysis showed that prepared PLX/TCM-SLNs were of nanosized ( 120.6 ± 9 nm) having zeta potential of −21.3 Mv. On the other hand, SEM had revealed the smooth and uniform surface of the particle, while X-ray diffraction (XRD) confirmed the uniform surface as crystalline structure of TCM in PLX/TCM-SLNs masked. A satisfactory level of EE ( 94.5 ± 2.74 %) has also been noticed. Furthermore, in vitro drug release studies have explored the controlled release of drug during 8 hours, following zero order release kinetics and diffusion type of release mechanism. Outcomes of the studies have advocated the successful preparation of SLNs, as controlled release PLX/TCM-SLNs have been prepared efficiently.

Local delivery of tacrolimus using electrospun poly-ϵ-caprolactone nanofibres suppresses the T-cell response to peripheral nerve allografts

Objective. Repair of nerve gap injuries can be achieved through nerve autografting, but this approach is restricted by limited tissue supply and donor site morbidity. The use of living nerve allografts would provide an abundant tissue source, improving outcomes following peripheral nerve injury. Currently this approach is not used due to the requirement for systemic immunosuppression, to prevent donor-derived cells within the transplanted nerve causing an immune response, which is associated with severe adverse effects. The aim of this study was to develop a method for delivering immunosuppression locally, then to test its effectiveness in reducing the immune response to transplanted tissue in a rat model of nerve allograft repair. Approach. A coaxial electrospinning approach was used to produce poly-ϵ-caprolactone fibre sheets loaded with the immunosuppressant tacrolimus. The material was characterised in terms of structure and tacrolimus release, then tested in vivo through implantation in a rat sciatic nerve allograft model with immunologically mismatched host and donor tissue. Main results. Following successful drug encapsulation, the fibre sheets showed nanofibrous structure and controlled release of tacrolimus over several weeks. Materials containing tacrolimus (and blank material controls) were implanted around the nerve graft at the time of allograft or autograft repair. The fibre sheets were well tolerated by the animals and tacrolimus release resulted in a significant reduction in lymphocyte infiltration at 3 weeks post-transplantation. Significance. These findings demonstrate proof of concept for a novel nanofibrous biomaterial-based targeted drug delivery strategy for immunosuppression in peripheral nerve allografting.

Tacrolimus loaded lipid-polymer hybrid nanoparticles incorporated thermosensitive gel as intravesical drug delivery system

A drug that is administered through a catheter into the bladder is referred to as an intravesical drug delivery system. The aim of this work is to improvise intravesical drug delivery of Tacrolimus loaded lipid polymer hybrid nanoparticles thermosensitive gel for bladder wall to provide control release, increase intravesical residence time and avoid fast removal by urination. The Tacrolimus loaded lipid polymer hybrid nanoparticles mimic cell membrane and enhance cellular uptakes. Our data reveals nanocarrier formation with a mean particle size, zeta potential and entrapment efficiency of optimal formula was found to be 124±0.01 nm,-27.5±0.102mv and 72% ± 0.15% respectively. In situ gelling formulations containing TAC-CS-LPHNs can adhere to the mucosal layer of the bladder and help in the diffusion of therapeutic agent across the bladder wall. To impart mechanical strength and mucoadhesive properties, the chitosan concentration was adjusted to 0.5% and 0.25%.The image of field emission scanning electron microscope shows an irregular surface with filled pores with nanoparticles. The gel was syringeable and had reasonable viscosity within room temperature. A Tissue uptake study reveals that Tacrolimus loaded lipid polymer hybrid nanoparticles have been penetrating bladder tissues and accumulated inside the cytoplasm and nucleus of urothelium epithelial cells. In addition, the bioimaging study shows that the gel resided inside the bladder for up to 2 hrs and completely urinated out of the bladder with negligible distribution to other tissues.

Biodegradable core-multishell nanocarrier: Topical tacrolimus delivery for treatment of dermatitis.

Two challenges in topical drug delivery to the skin include solubilizing hydrophobic drugs in water-based formulations and increasing drug penetration into the skin. Polymeric core-multishell nanocarrier (CMS), particularly the novel biodegradable CMS (bCMS=hPG-PCL1.1K-mPEG2k-CMS) have shown both advantages on excised skin ex vivo. Here, we investigated topical delivery of tacrolimus (TAC; > 500g/mol) by bCMS in a hydrogel on an oxazolone-induced model of dermatitis in vivo. As expected, bCMS successfully delivered TAC into the skin. However, in vivo they did not increase, but decrease TAC penetration through the stratum corneum compared to ointment. Differences in the resulting mean concentrations were mostly non-significant in the skin (epidermis: 35.7±20.9ng/cm2 for bCMS vs. 92.6±62.7ng/cm2 for ointment; dermis: 76.8±26.8ng/cm2vs 118.2±50.4ng/cm2), but highly significant in blood (plasma: 1.1±0.4ng/ml vs 11.3±9.3ng/ml; erythrocytes: 0.5±0.2ng/ml vs 3.4±2.4ng/ml) and liver (0.01±0.01ng/mg vs 0.03±0.01ng/mg). bCMS were detected in the stratum corneum but not in viable skin or beyond. The therapeutic efficacy of TAC delivered by bCMS was equivalent to that of standard TAC ointment. Our results suggest that bCMS may be a promising carrier for the topical delivery of TAC. The quantitative difference to previous results should be interpreted in light of structural differences between murine and human skin, but highlights the need as well as potential methods to develop more a complex ex vivo analysis on human skin to ensure quantitative predictive value.

VP1: Combined Local Delivery of Tacrolimus and Stem Cells in Fibrin Gel is a Viable Potential Treatment for Enhancing Peripheral Nerve Regeneration

INTRODUCTION: The immunosuppressive and neuroregenerative potential of tacrolimus (FK506) may overcome the rejection of stem cells to enhance nerve regeneration. The aim of this study was to determine the feasibility and effectiveness of combining local, sustained delivery of tacrolimus (FK506) with stem cells. MATERIALS AND METHODS: The drug release profile of local FK506 over the course of 35 days was evaluated in phosphate-buffered saline (PBS). FK506 was incorporated into fibrin gel in poly(lactic-co-glycolic) acid (PLGA) microspheres in concentrations of 0.01 ng/mL and 100 ng/mL and incubated in phosphate-buffered saline (PBS) at physiological temperature. Microspheres were prepared and characterized according to validated protocols by Tajdaran et al. (2015). Adipose derived mesenchymal stem cells (MSCs) were cultured in collected PBS to mimic systemic exposure representing released concentrations at day 7, 15 and 28 from 0.01 ng/mL and 100 ng/mL microspheres. MSCs were cultured in the following groups: (i) hydrogel only, (ii) PLGA empty microspheres in hydrogel, (iii) Hydrogel Infused with Stem cells and Tacrolimus (HIST) 0.01 ng/mL, and (iv) HIST 100 ng/mL. Staining against CD90 was conducted to confirm stem cell characterization. MSC viability was evaluated at 24h, 48h, 72h, and seven days using Live/Dead staining and MTS assays. RESULTS: Microspheres containing 0.01 ng/mL showed depletion of FK506 by 13 days. FK506 microspheres containing 100 ng/mL revealed a sustained release up to 35 days. An inflation point was observed at day 15 due to erosion of gel, resulting in an increase of FK506 release. CD90 staining confirmed stem cell characterization. MSCs were viable up to seven days and no significant differences in viability were found between groups. CONCLUSION: Encapsulation of 100 ng/mL FK506 microspheres and MSCs in hydrogel is feasible and has strong potential to enhance survival of transplanted cells, which may ultimately lead to improved nerve regeneration.

VP2: Mesenchymal Stem Cells and Local Tacrolimus Delivery Synergistically Enhance Neurite Extension

VP2: Mesenchymal Stem Cells and Local Tacrolimus Delivery Synergistically Enhance Neurite Extension

Helper T Cell (CD4+) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity.

Antibody-mediated rejection (ABMR) is a major cause of dysfunction and loss of transplanted kidney. The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells. However, the prognosis of patients following current treatment is poor. T follicular helper cells (Tfh) play an important role in allograft-specific antibodies secreting plasma cell (PC) development. Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders, such as transplant rejection and autoimmune diseases. Tacrolimus (Tac), the primary immunosuppressant, prevents rejection by reducing T cell activation. However, its administration should be closely monitored to avoid serious side effects. In this study, we investigated whether Tac delivery to helper T (CD4+) cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure. Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development, PC, and donor-specific antibody (DSA) generation without causing severe side effects compared with delivery through the drug administration pathway. This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation. The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.

Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension.

The aim of this study was to investigate the combined effect of mesenchymal stem cells (MSC) and local delivery of tacrolimus (FK506) on nerve regeneration when applied to nerve autografts and decellularized allografts. A three-dimensional in vitro compartmented cell culture system consisting of a neonatal dorsal root ganglion adjacent to a nerve graft was used to evaluate the regenerating neurites into the peripheral nerve scaffold. Nerve autografts and allografts were treated with (i) undifferentiated MSCs, (ii) FK506 (100 ng/mL) or (iii) both (N = 9/group). After 48 hours, neurite extension was measured to quantify nerve regeneration and stem cell viability was evaluated. Stem cell viability was confirmed in all MSC-treated grafts. Neurite extension was superior in autografts treated with FK506, and MSCs and FK506 combined (p < 0.001 and p = 0.0001, respectively), and autografts treated with MSCs (p = 0.12) were comparable to untreated autografts. In allografts, FK506 treatment and combined treatment were superior to controls (p < 0.001 and p = 0.0001, respectively), and treatment with MSCs (p = 0.09) was comparable to controls. All autograft groups were superior compared to their respective allograft treatment group (p < 0.05) in neurite extension. Alone, either MSC or FK506 treatment improved neurite outgrowth, and combined they further enhanced neurite extension in both autografts and allografts.

Colon-targeted delivery of tacrolimus using pH-responsive polymeric nanoparticles for murine colitis therapy

The present study aimed at constructing an oral nanoparticle delivery system loaded with tacrolimus (FK506) for effective treatment of inflammatory bowel disease. A FK506/HP-β-CD inclusion compound was prepared by grinding to increase drug solubility. To address the side- effects in non-target organs and systemic toxicity of FK506, pH-responsive Eudragit S100 (ES100) and hyaluronic acid (HA) with high affinity to CD44 receptor were adsorbed onto the surface of chitosan (CS) nanoparticles loaded with FK506/HP-β-CD through electrostatic interactions to obtain FK506@ES100/HA/CS/HP-β-CD nanoparticles (FK506@EHCh NPs). Caco-2 cells and Raw 264.7 macrophages were used to confirm the lack of cytotoxicity and good uptake ability of the newly generated nanoparticles. FK506@EHCh NPs significantly suppressed secretion of TNF-α, IL-1β and IL-6 by LPS-activated Raw 264.7 macrophages. A dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) murine model was established to further confirm the colon targeting and in vivo efficacy of oral IR-775@EHCh NPs. Based on the collective results, we conclude that packaging FK506 into active targeting nanocarriers sensitive to pH facilitates concentration of the drug within the sites of intestinal inflammation and improves the drug levels in target tissues, thus avoiding systemic side-effects and improving efficacy. In view of the promising results obtained in this study, the potential of EHCh nanoparticles for drug delivery and targeted treatment of inflammatory bowel disease warrants further investigation.

Formulation development, optimization, and in vitro assessment of thermoresponsive ophthalmic pluronic F127-chitosan in situ tacrolimus gel

To overcome problems associated with topical delivery of tacrolimus (TCS), a thermoresponsive in situ gel system containing pluronic F127 (PL), and chitosan (CS) was developed, to enhance the precorneal retention, and to sustain the release of the drug. The PL-CS in situ gel was optimized using a 2-factor-3-level central composite experimental design by selecting the concentration of PL and CS as independent variables while gelation time, gelation temperature, and spreadability as dependent variables. The optimized formulation developed using 22.5 g PL and 0.5 g CS, gels at 33.6 °C, in 22.93 seconds, and showed the spreadability of 6.2 cm. In vitro studies conducted for the optimized gel revealed the sustained release of TCS (81.73% in 4 h) and improved corneal permeation (74.13% in 4 h), compared with TCS solution. The mechanism of release of TCS followed the Higuchi model with Fickian diffusion transport. Further, histopathology and HET-CAM studies revealed that the developed gel was nonirritating and safe for ocular administration.

Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration.

The application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.

Glycol chitosan-based tacrolimus-loaded nanomicelle therapy ameliorates lupus nephritis

BackgroundRecently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Faslpr mutation were also treated with HGC vehicle and used as healthy controls.ResultsWeekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone.ConclusionOur study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.

Surface functionalized mesoporous silica nanoparticles for intravitreal application of tacrolimus.

Tacrolimus (TAC), a potent immunosuppressive macrolide, has been investigated for ocular diseases due to promising results in the treatment of anterior and posterior segments eye diseases. Mesoporous and functionalized silica nanoparticles show potential as TAC delivery platforms owing to their interesting characteristic as large surface area, uniform pore size distribution, high pore volume, and excellent biocompatibility. The purpose of this study was to incorporate TAC in functionalized silica nanoparticles with 3-aminopropyltriethoxysilane (MSNAPTES) and investigate the safety and biocompatibility of the systems. The MSNAPTES and MSNAPTES TAC nanoparticles were characterized. The in vitro cytotoxicity of MSNAPTES and MSNAPTES load with TAC (MSNAPTES-TAC) in retinal pigment epithelial cells (ARPE-19) was determined, chorioallantoic membrane (CAM) assay model was used to investigate the in vivo biocompatibility, and safety of intravitreal injection was evaluated using clinical examination (assessment of intraocular pressure and indirect fundus ophthalmoscopy), electroretinographic (ERG) and histologic studies in rats' eyes. The elemental analysis (CHN), thermogravimetric (TGA), photon correlation spectroscopy and Fourier transform infrared (FTIR) analysis confirmed the presence of functionalized agent and TAC in the MSNAPTES nanoparticles. TAC loading was estimated at 7% for the MSNAPTES TAC nanoparticles. MSNAPTES and MSNAPTES TAC did not present in vitro cytotoxicity. The drug delivery systems showed good biocompatibility on CAM. No retinal abnormalities, vitreous hemorrhage, neovascularization, retinal detachment, and optic nerve atrophy were observed during the in vivo study. Follow-up ERGs showed no changes in the function of the retina cells after 15 days of intravitreal injection, and histopathologic observations support these findings. In conclusion, MSNAPTES TAC was successfully synthesized, and physicochemical analyses confirmed the presence of TAC in the nanoparticles. In vitro and in vivo studies indicated that MSNAPTES TAC was safe to intravitreal administration. Taking into account the enormous potential of MSNAPTES to carry TAC, this platform could be a promising strategy for TAC ocular drug delivery in the treatment of eye diseases.

Positively charged polymeric nanoparticles improve ocular penetration of tacrolimus after topical administration

Tacrolimus (TAC) is an immunosuppressant with potential use in ophthalmology, especially as a steroid sparing agent. The efficacy of TAC has been investigated in the treatment of different anterior segment inflammatory disorders. However, its use is limited by its poor corneal penetration, which has led to the development of different nanocarriers. In order to overcome this limitation, we prepared positively charged polymeric nanoparticles loaded with tacrolimus (TAC-NPs) for topical ocular application. TAC-NPs were prepared by interfacial polymer deposition following solvent displacement method, using Eudragit® RL100, a cationic polymer. The formulation was characterized and the ocular safety was assessed in vivo by Draize eye test and histopathological analysis. TAC was quantified in aqueous humor to determine the in vivo release of the nanoparticles. TAC-NPs presented suitable physical-chemical characteristics for ocular application, including monomodal size distribution with a mean diameter of 104 ± 1 nm, positive zeta potential and mucoadhesive properties. The monitoring of the physical-chemical characteristics and the multiple light scattering analysis of TAC-NPs suggested their long-term stability. The in vivo safety investigation of TAC-NPs and blank-NPs showed no signs of ocular irritation on the ophthalmological examination and histopathological study, indicating the biocompatibility of this carrier. The nanoparticles were able to deliver TAC for over 36 h with a better performance than the drug suspension. The in vivo release profile of TAC-NPs indicated slower elimination with 1.7-fold higher maximum concentration of TAC and 5.3-fold higher AUC, suggesting increased ocular penetration and bioavailability in addition to extended delivery. TAC-NPs improved the ocular delivery of tacrolimus after topical administration, without causing any ocular irritation. It shows the potential of this carrier as an alternative for ocular delivery of tacrolimus in the treatment of anterior segment inflammatory conditions.

Topical delivery of Tacrolimus using liposome containing gel: An emerging and synergistic approach in management of psoriasis

Psoriasis is a chronic relapsing inflammatory and hyperproliferative skin disease affecting quality of life. It affects an estimated 8 million Americans and more than 125 million people worldwide. The estimated cost to treat psoriasis in USA is over 13 billion US dollars per year. Treatment of psoriasis may include topical steroid-sparing agent, topical corticosteroids, phototherapy or biologics. Tacrolimus has 10-fold greater immunosuppressive activity than the ciclosporin A which has been recommended for effective treatment of psoriasis. However, it has been widely investigated using conventional formulation approaches which limit its clinical outcomes. It has poor cutaneous bioavailability when administered topically using conventional delivery approach, thus it has poor efficacy against the psoriasis. Low aqueous solubility and high degradation of Tacrolimus make it difficult to formulate as a liquid preparation. Moreover, Tacrolimus has narrow therapeutic index and thus it is essential to prevent its possible toxic effects when a modified release dosage form is administered. The present hypothesis aims to put forward to incorporate Tacrolimus into a novel lipid based nanocarrier system, which would be further loaded into a hydrogel base and evaluated for its target specific topic delivery. Due to the structural similarity of the lipid nanocarriers and skin, these vesicles would target the skin tissues effectively and treat psoriasis with minimum or no side effects. Thus, the proposed formulation would be a considerable value addition to the current therapeutic approaches used for psoriasis management.