Drug delivery targets and systems for targeted treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease that selectively attacks human joints. The common non-targeted treatment approaches lead to obvious side effect and systemtic complication for RA patients. Therefore, targeted drug delivery for treatment of RA has gained much attetntion in the past few years. In this paper, we reviewed the potential targets (folate receptor, angiogenesis, matrix metalloproteases, selectins, vasoactive intestinal peptide receptor andFc-γ receptor) that could be utilised to facilitate the specific delivery of drugs to the inflammed synovium and also presented different drug delivery systems for targeting RA, including the liposomes, various types of nanoparticles, polymeric micelles and the macromolecular prodrugs. The strategies combining nanotechnologies and ligand mediated active targeting for RA would be emphatically illustrated, which was expected to be helpful for identifying technologies and drug delivery methods for targeted treatment of RA.     

Emerging drugs for rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic, autoimmune disease characterized by symmetric arthritis of diarhthrodial joints leading to progressive erosion of cartilage and bone. The individual and social impacts of RA are of great importance. Objective: To investigate the development of new therapies for RA treatment. Methods: Various databases have been searched for new drugs in clinical trials (Phase I – III) and experimental future therapeutic agents for RA. Results/conclusion: The current management of the disease includes the use of disease modifying anti-rheumatic drugs and the biologic therapies. Progress in our understanding of RA pathophysiology led to the identification of new therapeutic targets. These include pro-inflammatory cytokines, T and B cells, adhesion molecules, chemokines and intra- and extracellular signaling pathways. Therapeutic modulation of the above targets can provide new treatment strategies. This article reviews a few of the new treatment strategies currently being evaluated.     

In vivoand in vitroanti-arthritic efficacy of a herbal formula consisting of Rosae Multiflorae Fructus and Lonicerae Japonicae Flos

OBJECTIVE Rheumatoid arthritis(RA)is the most common inflammatory autoimmune disease,affecting around 1% of the world population.Toll-like receptor 4(TLR4)signalling has been found to be involved in the pathogenesis of RA.It is a potential therapeutic target for RA treatment.A herbal formula(RL)consisting of Rosae Multiflorae Fructus and Lonicerae Japonicae Flos has traditionally been used in treating various inflammatory disorders.In this study,we would evaluate the anti-arthritic effect of RL on collagen-induced arthritis(CIA)in rats and investigate the involvement of TLR4 signaling in the mode of action of RL in vivo and in vitro.METHODS In vivo anti-arthritic efficacy was evaluated using CIA rats induced by bovine typeⅡ collagen.The treatment groups were treated with various concentrations of RL or positive control indomethacin for 35 d.Clinical signs(hind paw volume and arthritis severity scores),changes in serum inflammatory mediators,histological and radiographic changes of joints were investigated.Spleens and peritoneal macrophages were used to determine the effects of RL on innate and adaptive immune responses in CIA rats.The involvement of TLR4 signalling pathways in the anti-arthritic effect of RL was examined in cartilage tissue of CIA rats,murine RAW264.7macrophages and human THP-1 monocytic cells.RESULTS The severity of arthritis in the CIA rats was significantly attenuated by RL.Histological score and radiographic score were efficiently improved by RL.RL could also dose-dependently inhibit pro-inflammatory cytokines in serum of CIA rats.RL significantly inhibited the production of various pro-inflammatory mediators,the expression and/or activity of the components of TLR4 signalling pathways in animal tissue and cell lines.CONCLUSION RL possesses anti-arthritic effect on collagen-induced arthritis in rats.The therapeutic effect of RL may be related to its inhibition on pro-inflammatory cytokines in serum.The inhibition of the TLR4/TAK1/NF-κB and TLR4/TAK1/MAPK pathways participate in the anti-arthritic effects of RL.This provides a pharmacological justification for the use of RL in the control of various arthritic diseases.Further investigation should be done to develop RL into a modern anti-arthritic agent.     

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.     

针对类风湿关节炎分子靶点的治疗药物研究进展

治疗类风湿关节炎(rheum atoid arthritis,RA)的药物虽有很多,但由于RA的发病机制和病因还没有完全阐明,目前还没有一种药物能够根治RA。随着对炎症过程的认识不断深入,特别对信号转导路径的认识,人们一直努力找寻一些调理疾病进程的具有特异性的干扰信号转导路径新的治疗药物。TNF-α阻断剂和IL-1受体拮抗剂等细胞因子拮抗剂在临床试验中治疗RA起到明显的效果。调节滑膜细胞G蛋白-AC-cAMP和Ras-MAPKs信号通路是中药白芍总苷和木瓜总苷发挥抗滑膜细胞增殖的重要分子机制。该文将对一些以细胞因子、炎症介质、细胞表面抗原、信号转导为靶点的药物研究情况进行综述。     

Proximal signaling molecules as potential targets for anti-inflammatory therapy

As a consequence of the limited efficacy and significant toxicity of current anti-inflammatory therapies, there is widespread interest in the development of novel drugs for this application. Progress in our understanding of inflammatory signaling pathways has identified novel targets, notably in pathways involving mitogen-activated protein kinases and T-cell receptor signaling. Recent observations have provided molecular insight into the mechanism of action of well-established anti-inflammatory and immunosuppressive drugs, such as glucocorticoids and azathioprine, and the anti-inflammatory small molecule semapimod (Cytokine PharmaSciences Inc). Data from these studies indicate that therapeutic agents which specifically target proximal signaling molecules might represent a powerful strategy for combating inflammatory diseases.     

Synthesis, physicochemical properties and biological evaluation of aromatic ester prodrugs of 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102): orally active iron chelators with clinical potential.

The synthesis of seven aromatic ester derivatives of 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one is described. These ester prodrugs have been designed to target iron chelators to the liver, the major iron storage organ. In principle this should improve chelation efficacy and minimize toxicity. The distribution coefficients of these ester prodrugs between 1-octanol and MOPS buffer pH 7.4 were measured together with their rates of hydrolysis at pH 2 and pH 7.4, in rat blood and liver homogenate. Esters with heteroaromatic acid moieties were found to be less stable than benzoyl analogues. The in-vivo iron mobilisation efficacy of these ester prodrugs has been compared with that of the parent drug using a 59Fe-ferritin loaded rat model. Many prodrugs were found to enhance the ability of the parent hydroxypyridinone to facilitate 59Fe excretion. However, not all prodrugs provided increased efficacy, demonstrating that lipophilicity is not the only factor which influences drug efficacy. Furthermore, no clear correlation between efficacy and susceptibility to hydrolysis was detected. The picolinic and nicotinic ester derivatives appear to offer the best potential as prodrugs as they have a relatively low LogP value and yet lead to enhanced efficacy over the parent hydroxypyridinone.     

Chemical JAK inhibitors for the treatment of rheumatoid arthritis

Introduction: Considerable advances in the treatment of rheumatoid arthritis (RA) have been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, biological DMARDs require intravenous or subcutaneous injection and some patients fail to respond to these drugs or lose their primary response. Currently, Janus kinase (JAK) inhibitors have been developed as a new class of DMARD that inhibits the non-receptor tyrosine kinase family JAK involved in intracellular signaling of various cytokines and growth factors.

Areas covered: Several JAK inhibitors such as tofacitinib and baricitinib are oral synthetic DMARD that inhibit JAK1, 2 and 3. Both drugs have shown feasible efficacy and tolerable safety. In this article, efficacy and adverse events from the phase III trials of JAK inhibitors are overviewed. In addition, pharmacokinetics and mechanism of action of JAK inhibitors in relevance to efficacy and adverse events are covered.

Expert opinion: JAK inhibitors are novel therapies for RA that inhibit multiple cytokines and signaling pathways. Further studies are needed to determine their risk-benefit ratio and selection of the most appropriate patients for such therapy.     

Lung adenocarcinoma: lessons in translation from bench to bedside

Lung cancer is currently the leading cause of cancer-related death in the United States and worldwide, accounting for approximately a third of all cancer diagnoses and deaths. The American Cancer Society estimates 159,390 deaths from lung cancer in the United States for 2009 alone. The high mortality rate associated with lung cancer has prompted numerous exhaustive efforts to identify novel therapeutic targets and treatment modalities for this deadly disease. The characterization of signaling pathways underlying the development and progression of lung cancer, particularly lung adenocarcinoma, has been instrumental in developing novel therapeutic strategies to target aggressive metastatic disease. This paradigm is best illustrated in lung adenocarcinoma by recent studies of the epidermal growth factor receptor, which has been identified to be a critical diagnostic and therapeutic target. Our understanding of the central role of epidermal growth factor receptor in the development and progression of lung adenocarcinoma has led to the development of molecular agents against this key oncogene that have demonstrated significant clinical efficacy against the disease. Despite these successes, de novo or acquired resistance to these anti-epidermal growth factor receptor agents invariably develops, either through additional mutations in the epidermal growth factor receptor, or abnormal regulation of downstream signaling pathways. Thus, it is necessary to further investigate the molecular determinants of treatment resistance and to develop novel therapeutic strategies directed specifically against the molecular drivers of metastatic chemoresistant lung cancer. Given the heterogeneity and convergence of signaling pathways underlying both disease etiology and chemoresistance, future efforts to administer rationally designed agents against multiple molecular targets could serve to improve both first-line and second-line therapies for patients with lung adenocarcinoma.     

Targeting fibroblast-like synoviocytes in rheumatoid arthritis

Fibroblast-like synoviocytes (FLS) are mesenchymal-derived cells that play an important role in the physiology of the synovium by producing certain components of the synovial fluid and articular cartilage. In rheumatoid arthritis (RA), however, fibroblasts become a key driver of synovial inflammation and joint damage. Because of this, there has been recent interest in FLS as a therapeutic target in RA to avoid side effects such as systemic immune suppression associated with many existing RA treatments. In this review, we describe how approved treatments for RA affect FLS signaling and function and discuss the effects of investigational FLS-targeted drugs for RA.     

MDM2 promotes rheumatoid arthritis via activation of MAPK and NF-κB

Murine double minute-2 (MDM2) has pleiotropic roles in immune activation and regulation. However, the role of MDM2 in rheumatoid arthritis (RA) remains unknown. We undertook this study to investigate the role of MDM2 in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) were isolated from 25 patients with active RA and 25 patients with osteoarthritis (OA). FLS were stimulated in the presence or absence of IL-1β in vitro. Mice with collagen-induced arthritis (CIA) were treated with Nutlin-3a (100 mg/kg) or vehicle twice daily for 2 weeks. MDM2 expression was determined by Western blot. MDM2 was down-regulated by specific gene silencing. The concentrations of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed using enzyme-linked immunosorbent assay (ELISA). The pathways of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) were investigated by Western blot. Arthritis scoring and histological analysis were conducted. MDM2 expression was significantly higher in RA-FLS than in OA-FLS. MDM2 protein expression was positively correlated with disease activity of RA. MDM2 promoted the production of TNF-α, IL-6, MMP1 and MMP13 through MAPK and NF-κB pathways in RA-FLS. Nutlin-3a treatment decreased the arthritis severity and joint damage in CIA. Nutlin-3a also inhibited the activation of MAPK and NF-κB in arthritic joints. In conclusion, MDM2 inhibition exhibits anti-inflammatory activity and MDM2 might be a new therapeutic target for RA.     

Targeting endothelial metabolism for anti-angiogenesis therapy: A pharmacological perspective

Current anti-angiogenic therapies in malignant and ocular diseases target growth factor signaling in order to attenuate excessive vascular growth. Although initial responses are promising, overall therapeutic success is limited due to insufficient efficiency, tumor refractoriness and resistance. Emerging evidence suggests that diverse growth factor signaling pathways in endothelial cells (ECs) converge onto cellular metabolism, creating an attractive target for novel alternative anti-angiogenic therapies. Recent studies show that ECs rely on glycolysis for ATP and biomass synthesis, necessary for proliferation and migration, key processes of angiogenesis. In addition, fatty acid β-oxidation (FAO) is essential for de novo nucleotide synthesis during EC proliferation. Initial proof-of-evidence has been given that administration of pharmacological inhibitors of those metabolic pathways can be used to inhibit pathological angiogenesis in vivo. Deciphering the role of other metabolic pathways and exploring the therapeutic potential of blocking these pathways await further investigation.     

Celastrus treatment modulates antigen-induced gene expression in lymphoid cells of arthritic rats

Rheumatoid arthritis (RA) is a debilitating autoimmune disease of global prevalence and the disease process primarily targets the synovial joints. Despite improvements in the treatment of RA over the past decade, there still is a need for new therapeutic agents that are efficacious, less expensive, and free of severe adverse reactions. Celastrus has been used in China for centuries for the treatment of rheumatic diseases. Furthermore, we previously reported that ethanol extract of Celastrus aculeatus Merr. (Celastrus) attenuates adjuvant-induced arthritis (AA) in rats. However, the mechanisms underlying the anti-arthritic activity of Celastrus have not yet been fully defined. We reasoned that microarray analysis might offer useful insights into the pathways and molecules targeted by Celastrus. We compared the gene expression profiles of the draining lymph node cells (LNC) of Celastrus-treated (Tc) versus water-treated (Tw) rats, and each group with untreated arthritic rats (T(0)). LNC were restimulated with mycobacterial heat shock protein-65 (Bhsp65). We identified 104 differentially expressed genes (DEG) (8 upregulated, 96 downregulated) when comparing Tc with T(0) rats, in contrast to 28 (12 upregulated, 16 downregulated) when comparing Tw and T(0) rats. Further, 20 genes (6 upregulated, 14 downregulated) were shared by both Tw and Tc groups. Thus, Celastrus treatment (Tc) significantly downregulated a large proportion of genes compared to controls (Tw). The DEG were mainly associated with the processes of immune response, cell proliferation and apoptosis, and cell signaling. These results provide novel insights into the mechanism of Celastrus anti-arthritic activity, and unravel potential therapeutic targets for arthritis.     

Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment

The tumor microenvironment, characterized by regions of hypoxia, low nutrition, and acidosis due to incomplete blood vessel networks, has been recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also malignant progression and metastasis. However, exploiting such a cumbersome tumor microenvironment for cancer treatment could provide tumor-specific therapeutic approaches. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment in which hypoxia inducible factor (HIF)-1-mediated gene regulation is considered essential for angiogenesis and tumor development. Additional oxygen sensitive signaling pathways including mammalian target of rapamycin (mTOR) signaling and signaling through activation of the unfolded protein response (UPR) also contribute to the adaptation in the tumor microenvironment. This in turn has led to the current extensive interest in the signal molecules related to adaptive responses in the tumor microenvironment as potential molecular targets for cancer therapy against refractory cancer and recurrence in preparation for the aging society. Therefore, we should focus on the drug discovery for targeting the tumor microenvironment to develop tumor-specific cytostatic agents including angiogenesis inhibitors. In this paper, the development of hypoxia-selective prodrugs, HIF-1 inhibitors, and modulators of the tumor microenvironment will be discussed.     

Rationale and risks of novel immunomodulatory therapies in rheumatoid arthritis

The need for new therapies for the treatment of rheumatoid arthritis (RA) has arisen during an era where clinicians have realized that RA is a far more ominous condition than was thought previously. The last decade has revealed numerous studies depicting the limited long-term efficacy and tolerability of conventional disease-modifying antirheumatic drug (DMARD) therapies. Moreover, DMARDs have not been shown to be truly capable of modifying articular, functional and radiographic outcomes in patients with RA. These issues have been raised amidst significant advances in our understanding of the immunopathogenesis of RA and advances in biotechnology. Such advances have led to a revised approach to using conventional DMARDs, while new pharmacologic and biospecific interventions are being developed. This chapter will discuss the clinical and biologic rationale for novel therapies for patients with RA and the hazards imposed by the therapeutic manipulation of various immune effector mechanisms in patients with RA.     

Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy

INTRODUCTION: The IGF system controls growth, differentiation, and development at the cellular, organ and organismal levels. IGF1 receptor (IGF1R) signaling is dysregulated in many cancers. Numerous clinical trials are currently assessing therapies that inhibit either growth factor binding or IGF1R itself. Therapeutic benefit, often in the form of stable disease, has been reported for many different cancer types. AREAS COVERED: Canonical IGF signaling and non-canonical pathways involved in carcinogenesis. Three recent insights into IGF1R signaling, namely hybrid receptor formation with insulin receptor (INSR), insulin receptor substrate 1 nuclear translocation, and evidence for IGF1R/INSR as dependence receptors. Different approaches to targeting IGF1R and mechanisms of acquired resistance. Possible mechanisms by which IGF1R signaling supports carcinogenesis and specific examples in different human tumors. EXPERT OPINION: Pre-clinical data justifies IGF1R as a target and early clinical trials have shown modest efficacy in selected tumor types. Future work will focus upon assessing the usefulness or disadvantages of simultaneously targeting the IGF1R and INSR, biomarker development to identify potentially responsive patients, and the use of IGF1R inhibitors in combination therapies or as an adjunct to conventional chemotherapy.     

The kinase NIK as a therapeutic target in multiple myeloma

INTRODUCTION: Multiple myeloma (MM) is a neoplasm derived from B lymphocytes and often results in uncontrolled clonal expansion of antibody-secreting cells. While current treatments are able to prolong survival, MM remains incurable. Excessive NF-κB activity in MM contributes to tumor progression and survival. AREAS COVERED: The contribution of NF-κB-inducing kinase (NIK) to alternative NF-κB signaling, where it is the key kinase, and classical NF-κB signaling. Modulation of NIK by natural and chemical factors and current and potential therapies for MM that target NIK. EXPERT OPINION: Mutations affecting the activation of NIK have been identified in MM samples and cell lines, suggesting that NIK may be an important target for therapy of MM. NIK contributes to activation of both NF-κB pathways in MM, giving us the opportunity to limit two pathways contributing to oncogenic survival with a single therapeutic. Many of the mutations identified in MM cells result in the same outcome, hyperactive NIK, thus a single therapeutic may be effective in many patients even though they carry differing mutations. As NIK appears only to activate classical NF-κB when overexpressed, and in normal cells NIK levels are usually low, it is possible that therapeutics designed to limit the amount of NIK may not produce serious side effects in healthy cells.     

Prodrugs for targeted tumor therapies: recent developments in ADEPT, GDEPT and PMT

The treatment of cancer with common anti-proliferative agents generally suffers from an insufficient differentiation between normal and malignant cells which results in extensive side effects. To enhance the efficacy and reduce the normal tissue toxicity of anticancer drugs, numerous selective tumor therapies have emerged including the highly promising approaches ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy) and PMT (Prodrug Monotherapy). These allow a selective release of cytotoxic agents from non-toxic prodrugs at the tumor site either by targeted antibody-enzyme conjugates, enzyme encoding genes or by exploiting physiological and metabolic aberrations in cancerous tissue. Herein, recent developments in the design and biological evaluation of prodrugs for use in ADEPT, GDEPT and PMT are reviewed. As a highlight, a series of novel glycosidic prodrugs based on the natural antibiotics CC-1065 and the duocarmycins will be discussed which show a therapeutic window of up to one million. Notably, the corresponding drugs have tremendously high cytotoxicities with IC(50) values of down to 110 fM.