Targeted delivery of hyaluronic acid-coated solid lipid nanoparticles for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44, which is over-expressed on the surface of synovial lymphocytes, macrophages and fibroblasts in inflamed joints in RA. As predicted, HA-SLNs/PD particles accumulated in affected joint tissue after intravenous injection into mice with collagen-induced arthritis (CIA), and HA-SLNs/PD persisted longer in circulation and preserved bone and cartilage better than free drug or drug encapsulated in SLNs without HA. HA-SLNs/PD reduced joint swelling, bone erosion and levels of inflammatory cytokines in serum. These results suggest that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders.     

Drug targeting by solid lipid nanoparticles for dermal use

Long term topical glucocorticoid treatment can induce skin atrophy by the inhibition of fibroblasts. We, therefore, looked for the newly developed drug carriers that may contribute to a reduction of this risk by an epidermal targeting. Prednicarbate (PC, 0.25%) was incorporated into solid lipid nanoparticles of various compositions. Conventional PC cream of 0.25% and ointment served for reference. Local tolerability as well as drug penetration and metabolism were studied in excised human skin and reconstructed epidermis. With the latter drug recovery from the acceptor medium was about 2% of the applied amount following PC cream and ointment but 6.65% following nanoparticle dispersion. Most interestingly, PC incorporation into nanoparticles appeared to induce a localizing effect in the epidermal layer which was pronounced at 6 h and declined later. Dilution of the PC-loaded nanoparticle preparation with cream (1:9) did not reduce the targeting effect while adding drug-free nanoparticles to PC cream did not induce PC targeting. Therefore, the targeting effect is closely related to the PC-nanoparticles and not a result of either the specific lipid or PC adsorbance to the surface of the formerly drug free nanoparticles. Lipid nanoparticle-induced epidermal targeting may increase the benefit/risk ratio of topical therapy.     

Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by inflammation of the joints and destruction of cartilage and bone, often compromising both the quality and duration of life. The disease pathology is complex, involving the infiltration and activation of various populations of immune cells along with the release of destructive inflammatory mediators into the synovium of affected joints. Although it is still debatable whether activated macrophages are the primary promoters of RA, emerging data clearly show that the biological activity of this subset of inflammatory cells greatly contributes to both the acute and chronic stages of the disease. The further discovery of folate receptor expression on these activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring RA has opened the possibility of exploiting folic acid to target attached drugs to this population of pathologic cells. Indeed, recent studies have shown that folate-linked imaging and therapeutic agents can be selectively delivered to arthritic joints, allowing both visualization and treatment of RA, with little or no collateral toxicity to normal tissues. This review will first summarize data documenting specific expression of the folate receptor on activated macrophages and then focus on the development of folate-targeted diagnostic and therapeutic agents for guided intervention into rheumatoid arthritis.     

Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery

The purpose of this study was to construct isotretinoin-loaded SLN (IT-SLN) formulation with skin targeting for topical delivery of isotretinoin. PRECIROL ATO 5 was selected as the lipid of SLN. Tween 80 and soybean lecithin were used as the surfactants to stabilize SLN. The hot homogenization method was performed to prepare the drug-loaded SLN. The various formulations were characterized by photon correlation spectroscopy and all the SLN formulations had low average size between 30 and 50 nm. Transmission electron microscopy studies showed that the IT-SLN formulation had a spherical shape. All the formulations had high entrapment efficiency ranging from 80% to 100%. The penetration of isotretinoin from the IT-SLN formulations through skins and into skins were evaluated in vitro using Franz diffusion cells fitted with rat skins. The in vitro permeation data showed that all the IT-SLN formulations can avoid the systemic uptake of isotretinoin in skins, however the control tincture had a permeation rate of 0.76+/-0.30 microg cm(-2)h(-1) through skins. The IT-SLN consisting of 3.0% PRECIROL ATO 5, 4.0% soybean lecithin and 4.5% Tween 80 could significantly increased the accumulative uptake of isotretinoin in skin and showed a significantly enhanced skin targeting effect. The studied IT-SLN showed a good stability. These results indicate that the studied IT-SLN formulation with skin targeting may be a promising carrier for topical delivery of isotretinoin.     

Visfatin as a therapeutic target for rheumatoid arthritis

Introduction: The rising prevalence of musculoskeletal pathologies in developed countries has caused a dramatic impact on social welfare. Amidst these musculoskeletal pathologies is Rheumatoid arthritis (RA), a chronic systemic autoimmune disease that mostly affects the synovium. RA metabolic-associated alterations, including distorted adipokine production, enhance RA inflammatory environment. Among the altered adipokines, visfatin is particularly involved in RA inflammation and catabolism and stands out as an essential enzyme linked to critical cell features.

Areas covered: We discuss the potential mechanism supporting the contribution of visfatin to RA and the association between RA and obesity. We discuss the repurposing of cancer-tested drugs to inhibit visfatin in the context of RA. Additionally, we address the possibility of combining these drugs with current RA therapy. Finally, we explore the future of visfatin as an RA biomarker or therapeutic target.

Expert opinion: Inhibition of visfatin has become an interesting therapeutic approach for RA pathology. Such a feat has already been attained in oncology using small molecule inhibitors, which suggest that a similar course of action would be worth pursuing in the RA context. Visfatin will become an important biomarker and therapeutic target for RA.     

Preparation and passive target of 5-fluorouracil solid lipid nanoparticles

This work studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with 5-fluorouracil (5-FU). The goal was to design longer drug residence in vivo and passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects. Based on the optimized results of uniform design experiment, 5-FU-SLNs were prepared by multiple emulsion-ultrasonication (w/o/w). The SLNs were found to be relatively uniform in size (182.1?±?25.8?nm) with a negative zeta potential (?27.89?±?5.1 mV). The average drug entrapment efficiency and loading were 74% and 10%, respectively. Compared with the 5-FU solution (t_1/2β, 0.593h; MRT, 0.358h) after intravenous injection to rats, the pharmacokinetic parameters of 5-FU-SLNs exhibited a longer retention time. (t_1/2β, 4.0628h; MRT, 3.5321h). The area under curve of plasma concentration-time (AUC) of 5-FU-SLNs was 1.48 times greater than that of free drugs. The overall targeting efficiency (TE^C) of the 5-FU-SLNs was enhanced from 13.25–20.45% in the lung and from 11.48–23.16% in kidney while the spleen distribution of 5-FU was significantly reduced as compared with that of the 5-FU solution. These results indicated that 5-FU-SLNs were promising passive targeting therapeutic agents for curing primary lung carcinoma.     

Adsorption kinetics of plasma proteins on solid lipid nanoparticles for drug targeting

The interactions of intravenously injected carriers with plasma proteins are the determining factor for the in vivo fate of the particles. In this study the adsorption kinetics on solid lipid nanoparticles (SLN) were investigated and compared to the adsorption kinetics on previously analyzed polymeric model particles and O/W-emulsions. The adsorbed proteins were determined using two-dimensional polyacrylamide gel electrophoresis (2-DE). Employing diluted human plasma, a transient adsorption of fibrinogen was observed on the surface of SLN stabilized with the surfactant Tego Care 450, which in plasma of higher concentrations was displaced by apolipoproteins. This was in agreement with the "Vroman-effect" previously determined on solid surfaces. It says that in the early stages of adsorption, more plentiful proteins with low affinity are displaced by less plentiful with higher affinity to the surface. Over a period of time (0.5 min to 4 h) more interesting for the organ distribution of long circulating carriers, no relevant changes in the composition of the adsorption patterns of SLN, surface-modified with poloxamine 908 and poloxamer 407, respectively, were detected. This is in contrast to the chemically similar surface-modified polymeric particles but well in agreement with the surface-modified O/W-emulsions. As there is no competitive displacement of apolipoproteins on these modified SLN, the stable adsorption patterns may be better exploited for drug targeting than particles with an adsorption pattern being very dependent on contact time with plasma.     

Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting

The poor orally available lopinavir was successfully encapsulated in glyceryl behenate based solid lipid nanoparticles (Lo-SLN) for its ultimate use to target intestinal lymphatic vessels in combined chemotherapy—the so-called Highly Active Anti-Retroviral Therapy (HAART). SLN with mean particle size of 230 nm (polydispersity index, PDI < 0.27) and surface electrical charge of approx. ?27 mV, were produced by hot homogenization process followed by ultrasonication. Particles were characterized using differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and atomic force microscopy (AFM) to confirm their solid character and the homogeneous distribution of drug within the lipid matrix. In vitro release studies at pH 6.8 phosphate buffer (PBS) and at pH 1.2 HCl 0.1 N showed a slow release in both media. From the intestinal lymphatic transport study it became evident that SLN increased the cumulative percentage dose of lopinavir secreted into the lymph, which was 4.91-fold higher when compared with a conventional drug solution in methyl cellulose 0.5% (w/v) as suspending agent (Lo-MC). The percentage bioavailability was significantly enhanced. The AUC for the Lo-SLN was 2.13-fold higher than that obtained for the Lo-MC of similar concentration. The accelerated stability studies showed that there was no significant change in the mean particle size and PDI after storage at 25 ± 2 °C/60 ± 5% RH. The shelf life of optimized formulation was assessed based on the remained drug content in the stabilized formulation and was shown to be 21.46 months.     

免疫抑制剂治疗类风湿关节炎的研究进展

类风湿关节炎（rheumatoid arthritis,RA）是风湿免疫科一种常见的全身性自身免疫性疾病。根据病情进展的不同程度,治疗方案亦不同,包括改善病情抗风湿药（disease-modifying anti-rheumatic drugs,DMARDs）、非甾体抗炎药（non-steroidal anti-inflammatory drugs,NSAIDs）、生物制剂、植物制剂等药物治疗以及辅助疗法,如针对性的锻炼、改善膳食、热敷冷敷等。目前的治疗方法对于RA的病情是有明显改善的,其中免疫抑制剂（immunosupressive agents,ISA）起到了不可忽视的作用,故从免疫抑制的角度论述,它能够有效控制病情进展,达到缓解疾病、提高生活质量的目标,得到了广泛的应用和发展。本文简述了选择性免疫抑制剂和非选择性免疫抑制剂治疗类风湿关节炎的作用机制以及临床应用,为免疫抑制剂治疗RA方面提供理论依据。     

氟尿苷二丁酸酯固体脂质纳米粒的制备和肝靶向性研究

采用薄膜-超声分散法制备氟尿苷二丁酸酯(FUDRB)固体脂质纳米粒(FUDRB-SLN)和半乳糖苷(G₂)修饰的FUDRB-SLN(FUDRB-G₂SLN)。透射电镜研究其形态及粒径分布；凝胶色谱法测定载药量、包封率。结果表明，FUDRB-SLN和FUDRB-G₂SLN的粒径分别为(137.5±11.1)nm和(95.0±10.7)nm，载药量分别为9.64%和8.56%，包封率分别为99.81%和96.23%。为比较其肝靶向作用，小鼠尾静脉给药后，HPLC法测定氟尿苷(FUDR)在血清及肝、 肾、 肺匀浆中的浓度，计算出FUDR-sol、 FUDRB-SLN和FUDRB-G₂SLN的肝靶向效率分别为2.56、 5.90和8.28。FUDRB-G₂SLN组480 min时在肝脏中仍可检测到FUDR。这些结果说明FUDRB-SLN和FUDRB-G₂SLN在小鼠体内具有良好的肝靶向性，G₂修饰的SLN是一种良好的药物载体，可使药物选择性地导向肝细胞，且具有缓释作用。     

Anti-TNF agents for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease with a prevalence of approximately 1% and an annual incidence of 0.04%. Up to 50% of patients with RA are unable to work 10 years after diagnosis. The disease is associated with significant morbidity and mortality with associated medical costs to the UK of between £240 m and £600 m per year.Non steroidal anti-inflammatory drugs (NSAIDs) have little effect on the underlying course of RA, but they have some anti-inflammatory and analgesic properties. Disease modifying antirheumatic drugs (DMARDs) have been shown to slow progression of RA and are currently recommended early in the course of treatment of RA which is when disease progression is most rapid.Etanercept and infliximab belong to a new group of parentally administered antitumour necrosis factor (TNF) drugs.Etanercept is licensed in the UK for the treatment of active rheumatoid arthritis in patients who have not responded to other DMARDs and in children with polyarticular-course juvenile arthritis who have not responded to or are intolerant of methotrexate. In adults it produces significant improvements in all measures of rheumatic disease activity compared to placebo. In patients whose disease remains active despite methotrexate treatment, further improvement in control is obtained with the addition of etanercept without an increase in toxicity. In one small trial, etanercept was found to be more effective than placebo in a selected group of children.Infliximab is a monoclonal antibody which is currently licensed in the UK for Crohn''s disease and, in combination with methotrexate for the treatment of rheumatoid arthritis in patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate. In clinical trials infliximab produced significant improvements in all measures of rheumatic disease activity compared with placebo. Infliximab in combination with methotrexate was shown to be superior to methotrexate or infliximab alone.There are currently no predictors of a good response to anti-TNF drugs and a percentage of patients fail to respond to treatment (25% to 38% of etanercept patients; 21% to 42% of infliximab patients). Infliximab monotherapy induces the production of anti-infliximab antibodies, which may reduce its effectiveness. Adding methotrexate to infliximab therapy may prevent this response.Anti-TNF drugs may affect host defences against infection and malignancy; whether these agents affect the development and course of malignancies and chronic infections is unknown and safety and efficacy in patients with immunosuppression or chronic infections has not been investigated. With infliximab, upper respiratory tract infections, general infections and those requiring antimicrobial treatment were more common in patients than placebo. Likewise, upper respiratory tract infections were more common in patients treated with etanercept than with placebo. Injection site reactions occur with both infliximab (16%–20%) and etanercept (37%).There are approximately 600 000 patients with RA in the UK, and of these between 2% and 3.5% may have severe disease which has failed to respond to conventional treatment and who might be eligible for anti-TNF therapy. If between 50% and 70% of patients treated with anti-TNF drugs respond and continue on long-term treatment then the recurrent annual cost to the NHS could be between £48 m and £129 m.     

New therapeutic approaches for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic polyarthritis leading to joint destruction and remarkable disability. Current therapies have various degrees of efficacy, but toxicity frequently limits their long-term use. Although the etiology of the disease remains unknown, our increasing knowledge of the mechanisms underlying pathogenic events in rheumatoid synovitis has enabled selective targeting of the pathogenic elements of disease. Several new drugs have recently been introduced for the treatment of RA. These include cyclooxygenase type 2 inhibitors, adhesion molecules, T cells, B cells, cytokine/receptor, chemokines, angiogenesis, oral tolerance antigens, costimulatory molecules, and new disease-modifying antirheumatic drugs. Continuing research into the pathogenesis of RA will undoubtedly identify even more effective therapeutic approaches for the management of this disease in the future. In conclusion, the proof of principle has been established that selective targeting of pathogenic elements of disease results in substantial improvement in signs and symptoms as well as disease progression. Improved efficacy is expected with more aggressive targeting of the pathogenic elements.     

Treatment of rheumatoid arthritis: new therapeutic approaches with biological agents

Rheumatoid arthritis is a chronic polyarthritis leading to joint destruction and remarkable disability. Current therapies have various degrees of efficacy, but toxicity frequently limits their long-term use. Furthermore, treatment of refractory rheumatoid arthritis includes increasing disease-modifying antirheumatic drugs dosage, using combination therapy, and adding or increasing the posology of corticosteroids. Although the etiology of the disease remains unknown, our increasing knowledge of the mechanisms underlying pathogenic events in rheumatoid synovitis, has provided opportunities to specifically target cell surface markers or cytokines involved in the inflammatory response. The objective of this review is to describe the different therapeutic approaches with biological agents that are either being utilized or are under development. Some of these products reflect the evolving capacity for the biotechnology industry to synthesize and humanize therapeutic agents: anti-tumor necrosis factor (TNF) alpha monoclonal antibodies (MoAb) and recombinant TNF-receptor construct appear to be validated tools. These treatments alone, or in combination with methotrexate are very effective in rheumatoid patients. Data from clinical trials and issues related to mechanisms of action, potential toxicity, and future perspectives for these novel therapeutic options are considered in this review. Anti-cytokine treatment include other interesting approaches to interfere with on-going inflammatory processes, such as the use of recombinant human interleukin (IL)1 receptor antagonist, or recombinant human IL10. T cell constimulatory blockade, induction of apoptosis in the synovial tissue, and gene therapy could represent future strategies in rheumatoid disease.     

New therapeutic targets for rheumatoid arthritis

New insights into the pathogenesis of rheumatoid arthritis (RA) and consequently new targets of therapy are covered in a broad overview fashion. Shortterm significant beneficial effect on RA disease activity has been established in a small but rapidly growing number of doubleblind placebocontrolled trials now including recombinant human IL1 receptor antagonist, chimeric (mouse/human) monoclonal antibodies (mAb) against TNFa (cA2), humanised (human/mouse) antiTNFa mAb (CDP571) and recombinant human TNFreceptorFc fusion protein (TNFR : Fc). Placebocontrolled trials of antiT cells agents such as chimeric antiCD4 mAb (cMT412) and antiCD5 immunoconjugate, did not demonstrate clinical benefit. A placebocontrolled study of the antiT cell derived cytokine IL2 (DAB486IL2) showed only modes clinical improvement. Other antiT cell approaches such as autologous T cell vaccination and induction of tolerance by oral type II collagen have been unsuccessful. The one controlled trial with an antiinflammatory cytokine, recombinant human IFNg, showed modest clinical benefits. Controlled trials with IL4 and IL10 and with antiadhesion molecules are awaited.     

Bacteria and bacterial toxins as therapeutic agents for solid tumors

Patients with advanced solid tumors frequently relapse and succumb to their metastatic disease after developing resistance to conventional treatment modalities such as chemotherapy and radiotherapy. In these patients, novel strategies of targeting widespread tumors are urgently needed. The increasing knowledge of the underlying pathogenetic mechanisms has led to the identification of numerous molecules that are overexpressed in various tumors and accumulate at the cell surface. The use of genetically modified bacteria and their toxins targeting these surface molecules has emerged as a promising new treatment strategy in refractory cancers. This review focuses on bacterial toxins such as Diphtheria toxin (DT), Pseudomonas exotoxin A (PE) and Clostridium perfringens enterotoxin (CPE). In addition, the use of anaerobic bacteria such as Clostridium, Salmonella and Bifidobacterium spp. as drug-delivery systems targeting hypoxic tumor areas will be discussed as a new therapeutic modality of advanced solid tumors.     

A potential new therapeutic system for glaucoma: solid lipid nanoparticles containing methazolamide

Methazolamide (MTA) is an antiglaucoma drug; however, there are many side effects of its systemic administration with insufficient ocular therapeutic concentrations. The aim of this study was to formulate MTA-loaded solid lipid nanoparticles (SLNs) and evaluate the potential of SLNs as a new therapeutic system for glaucoma. SLNs were prepared by a modified emulsion-solvent evaporation method and their physicochemical characteristics were evaluated. The pharmacodynamics was investigated by determining the percentage decrease in intraocular pressure. The ocular irritation was studied by Draize test. Despite a burst release of SLNs, the pharmacodynamic experiment indicated that MTA-SLNs had higher therapeutic efficacy, later occurrence of maximum action, and more prolonged effect than drug solution and commercial product. Formulation of MTA-SLNs would be a potential delivery carrier for ocular delivery, with the advantages of a more intensive treatment for glaucoma, lower in doses and better patient compliance compared to the conventional eye drops.     

A potential new therapeutic system for glaucoma: solid lipid nanoparticles containing methazolamide

Methazolamide (MTA) is an antiglaucoma drug; however, there are many side effects of its systemic administration with insufficient ocular therapeutic concentrations. The aim of this study was to formulate MTA-loaded solid lipid nanoparticles (SLNs) and evaluate the potential of SLNs as a new therapeutic system for glaucoma. SLNs were prepared by a modified emulsion–solvent evaporation method and their physicochemical characteristics were evaluated. The pharmacodynamics was investigated by determining the percentage decrease in intraocular pressure. The ocular irritation was studied by Draize test. Despite a burst release of SLNs, the pharmacodynamic experiment indicated that MTA–SLNs had higher therapeutic efficacy, later occurrence of maximum action, and more prolonged effect than drug solution and commercial product. Formulation of MTA–SLNs would be a potential delivery carrier for ocular delivery, with the advantages of a more intensive treatment for glaucoma, lower in doses and better patient compliance compared to the conventional eye drops.