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Rheumatoid arthritis (RA) is a progressive autoimmune inflammatory disorder characterized by cellular infiltration in synovium causing joint destruction and bone erosion. The heterogeneous nature of the disease manifests in different clinical forms, hence treatment of RA still remains obscure. Treatments are limited owing to systemic toxicity by dose-escalation and lack of selectivity. To overcome these limitations, Smart drug delivery systems (SDDS) are under investigation to exploit the arthritic microenvironment either by passive targeting or active targeting to the inflamed joints via folate receptor, CD44, angiogenesis, integrins. This review comprehensively deliberates upon understanding the pathophysiology of RA and role of SDDSs, highlighting the emerging trends for RA nanotherapeutics.
Nanobiotech Lab, Kirori Mal College, University of Delhi, India
Vikas Shukla
Nanobiotech Lab, Kirori Mal College, University of Delhi, India
Vijay Kumar
Nanobiotech Lab, Kirori Mal College, University of Delhi, India
Marie-Curie Fellow, Percuros B.V, The Netherlands
Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, The Netherlands
Anita Kamra Verma*
Nanobiotech Lab, Kirori Mal College, University of Delhi, India
*Address all correspondence to: akverma@kmc.du.ac.in
1. Introduction
Rheumatoid arthritis (RA) is an autoimmune-mediated systemic, chronic inflammatory disorder characterized by progressive inflammation of joints, cell infiltration, pannus formation, synovial dysplasia resulting in cartilage destruction and bone erosion [1]. The worldwide prevalence rate of RA in adult population has been predicted between 0.5–1% and 0.92% in India [2]. Generally, prevalent in women when compared to men (3,1) at any age group. According to recent statistics given in 2019 by the Global RA network and WHO, 23 million people are affected by RA, globally [3]. RA etiology is implicated to be linked to metabolic, genetic, environmental factors, and life style of the patient [4]. While it is considered non-lethal, RA is debilitating and severely compromises the quality of life, further reducing life expectancy in patients.
Despite tremendous progress in evolving efficient pharmacological molecules for RA therapy, their efficacious delivery at the diseased joint remains a long-lasting challenge. Over the last two decades, disease-modifying anti-rheumatic drugs (DMARDs: such as methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), leflunomide (LFM), have attracted attention for effective attenuation of disease progression. Patient compliance is the primary treatment goal with glucocorticoids(GCs); e.g., prednisolone, dexamethasone, hydrocortisone, triamcinolone acetonide, and NASAID (such as ibuprofen, diclofenac, indomethacin etc) result in reducing pain and curbing disease progression [5]. Unfortunately, the associated toxicity caused by dose-escalation and long-term use with undesirable side-effects are limiting the therapeutic success. Continued medication of NSAIDs causes gastro-intestinal and renal toxicity; glucocorticoids cause hypertension, hyperglycemia, muscle wasting, osteoporosis, etc.; nausea and vomiting are common side-effects of conventional DMARDs, including gastro-intestinal irritations, headaches, insomnia, cytopenia, skin and hair damage, etc.; giving biologicals run the risk of anaphylaxis, infections, malignancy, psoriasis and other autoimmune disorders [6, 7]. Biosimilars/biologicals/Biological response modifiers like infliximab, adalimumab, rituximab etc. that have approval of Food and Drug Administration (FDA), were considered for their selective site-specific action, achieved extensive success in clinics for RA treatment. Prior reports suggest combination therapy with biologics, and synthetic DMARDs were found to be highly effective [8].
To circumvent the off-target drug induced systemic toxicity, direct drug delivery via the intra-articular injection to the affected joints was explored. Nevertheless, this mode of administration has several limitations, as it necessitates repeat injections in the joint, risk of infection, and joint disability. Therefore, a concerted effort for development of novel therapies are clearly warranted with a focus on targeting the inflamed joints.
Nanotherapeutics has emerged as an innovative approach enabling efficient delivery of drug for mitigating several diseases. The past decade, has seen an avalanche of publications that have increased our understanding of the patho-physiology of the affected synovial tissue in RA and equivalent progress in nanotechnology and material chemistry, generating tremendous interest in developing Smart drug delivery system (SDDS). Entrapping the anti-inflammatory drugs in SDDS strategically has potential to overcome all the barriers of normal delivery, projecting it as a promising option for site-specific delivery. Currently, RA targeting nanotherapeutics has progressed rapidly because the inflammatory microenvironments of arthritic joints mimic the tumor environment that has typical angiogenic features of neo-vessels coupled with impaired peripheral lymphatic drainage [9, 10]. This review comprehensively deliberates upon the understanding the pathophysiology of RA and role of SDDSs, highlighting the emerging trends for RA nanotherapeutics.
Chronic inflammation is the hallmark of RA that advances to destructive synovitis [11]. It develops in a genetically susceptible person largely due to environmental factors and related epigenetic mechanisms [12]. It predominantly indicates leukocyte infiltration, dysregulated angiogenesis, proliferation of lining layer, that alters the synovial tissue into an invasive pannus. The microvasculature of synovium is dysregulated, hence, in spite of enhanced flow of blood, the increased metabolic needs outdo the vascular blood supply, thereby creating an intense hypoxic microenvironment. However, rheumatoid factor (RF) and anticitrullinated peptide antibodies(ACPA) are induced and must exist before the onset of this disease. The heterogeneous nature of the disease manifests in different clinical forms, hence treatment of RA still remains obscure. It is well documented that synovial microenvironment has abundance of macrophages, multifaceted crosslink of immune cells secreting granulocyte colony-stimulating factor, pro-inflammatory cytokines, tumor necrosis factor(TNF-α), interleukin (IL-1), IL-6, chemokines, and degrading like MMPs that are particularly responsible for RA pathogenesis [13, 14]. Figure 1 illustrates the network of cytokines secreted by multitude of cells involved in RA development that can be useful for assessment of disease progression along with biomarkers present on these cells.
Figure 1.
Schematic illustration indicating the key events and signaling cascades involved in RA pathophysiology. Leukocytes infiltrate synovium and stimulate the inflammatory cascade, characterized by cross-talk of SF and macrophages, monocytes, mast cells, dendritic cells, as well as B and T cells. Endothelial cells facilitate angiogenesis. The advanced stage includes hyperplastic synovium, cartilage damage, bone erosion, and systemic consequence. Bone resorption by osteoclasts practically creates bone erosions. The obliteration of the subchondral bone can ultimately lead to the degeneration of the articular cartilage that is a result of reduced osteoblasts and an increase in the number of osteoclasts and synoviocytes.
2.1 Synovial fibroblasts (SF)
Proliferation and infiltration of SF is the key trigger for disease progression in RA. Under normal conditions fibroblasts are responsible for maintaining tissue homeostasis by modulating the inflammatory response [15]. Transcription factors like activator protein-1 and NF-κB, responsible for proliferation, activation, differentiation of fibroblasts, expression of MMPs, other matrix-degrading enzymes like cysteine proteases and aggrecanases have been observed in the synovium [5]. The genetic analysis of synovium would be useful for biological therapy as synovial tissue has a robust immune-inflammatory gene expression [16].
2.2 B cells
B cells contribute to antibody production i.e. RF and anticyclic citrullinated peptide antibody (ACPA), and other effector roles to entail disease progression [17]. RF and/or ACPA promotes severe bone and joint erosions as the citrullinated proteins aggravate RA progression [18]. B cells are pointedly responsible for regulation of inflammatory response by serving as antigen-presenting cells and releasing pro−/anti-inflammatory cytokines that additionally control T cell differentiation and proliferation, and activation of macrophages [5].
2.3 T cells
Activated T cells comprise ≥50% of RA synovial cells, and majority are memory CD4 T cells. In terms of T cell subsets, the Th1(T helper 1) and Th17(T regulatory) are predominant, but lack Th2 subsets [5]. T cells release cytokines as their effector functions; Th1 release interferon gamma(IFN-γ), that further activate macrophages and increases its phagocytic activity. Likewise, effector cytokines of Th17 cells are IL-17A, IL-17F, IL-21, and IL-22, responsible for cell recruitment, secretion of pro-inflammatory cytokines, initiation of differentiation of B-cell, and activate NK cells [19]. IL-17 may emerge as a beneficial target for RA therapies.
2.4 Macrophages
Macrophages are tightly regulated by microenvironment signals including presence of injured cells, microbial debris, pro/anti-inflammatory cytokine or mechanical forces [19]. Depending on the cues, macrophages tend to polarize into characterized phenotypes like pro-inflammatory or immunomodulatory [20]. Taking advantage of the fundamental homing capability of macrophages to migrate to the injured/inflamed arthritic synovium, macrophages can be exploited as delivery vehicles to target specific macrophage populations to carry payloads.
2.5 Osteoclasts
Enhanced osteoclast activity triggered by disproportionate ratio of Osteoprotegerin (OPG) and receptor activator of nuclear-factor kappa-beta ligand (RANKL) are critical factors for RA progression. When RANKL is overexpressed by activated macrophages, osteoblasts and lymphocytes, it stimulates an imbalance between osteoclast multiplication and anomalous activation triggered by the binding of RANKL to RANK on the mature osteoclasts and on the cell-membranes of precursor cells of osteoclast [21]. In addition, MMP-9 and MMP-14 secreted by the osteoblasts, triggers matrix degradation in cartilage, formation of pannus, and osteoclast migration to surface of the bone. Osteoclasts significantly cause erosion of subchondral bone, articular cartilage, and the synovium.
2.6 Enzymes and other effector molecules
MMPs are the enzymes that irreversibly cause extracellular matrix (ECM) degradation, and slow-destruction of cartilage and bone in diseased joints. MMPs are zinc-dependent endopeptidases that are categorized into five sub-classes: i) gelatinases (MMP-2 and 9), ii) collagenases (MMP-1, −8 and 13), iii) stromelysins (MMP-3, −10 and − 11), iv) matrilysins (MMP-7 and -26) and v) membrane-type MMPs (MMP-14 to −17, −24 and − 25) [22, 23]. MMP-1, 2, 3, and 9 have been directly implicated in RA progression [24]. MMPs, in combination with lipases and esterases, accelerate degradation of ECM, articular cartilage and surface of the subchondral bone [25]. Ever-increasing emerging targets including these enzymes provide more options for anti-arthritic therapy with the help of targeted SDDS for RA.
Enhancement of therapeutic efficiency by ‘intelligent/smart’ carriers that release drugs in a controlled manner at the site of action to achieve minimal side effects are categorized as “Smart Drug delivery system” (SDDS). Maintaining optimum size and surface properties, the materials can be engineered to create nanoparticles that can maneuver the microenvironment and respond to endogenous stimuli, like increased concentration of some enzymes, redox gradient-enhanced level of glutathione, or variations in interstitial pH [26] and/ or exogenous stimuli that include temperature changes, applying magnetic field or light, and giving high energy radiation.
3.1 pH-responsive
pH, an important parameter linked to pathophysiological conditions, like inflammation can be exploited for enhanced therapeutic efficiency [27]. Reports priori give clarity that pH in normal tissue and blood is maintained around 7.4, but in arthritic microenvironment, extracellular pH values are intrinsically acidic, usually pH 6.8 [28]. The acidic pH can be attributed to the excess infiltration and activation of proinflammatory cells in the synovium, causing increased demand for oxygen and energy. Augmented consumption of glucose via glycolysis consequently enhances production of lactic acid, that causes local acidosis [29, 30]. Hence, the nanoparticles should be strategically designed to sensitively distinguish pH changes in inflammatory area where high disease activity and joint destruction correlates with low synovial pH. These pH-responsive nanoparticles encapsulating therapeutic molecules like NSAIDs, DMARDs etc. can be promising for RA treatment. Even at the cellular level, pH-sensitive SDDS can either stimulate drug release into lysosomes, or the late endosomes or may even trigger the escape of nanoparticles from lysosomes into the cytosol [31]. Appropriate size will enable efficient penetration in the inflamed joints, facilitated by angiogenesis during RA progression, that causes endothelial cell discontinuity leading to enhanced vascular permeability [32].
Two strategies are rationally used to design of pH-sensitive SDDS, one using materials with acid-sensitive bonds, that can be cleaved by low pH conditions allowing the release of encapsulated molecules from the nanoparticles; and secondly, using polymers (polyacids or polybases) that have ionizable groups, that undergo pH-dependent transformation and change in solubility [33]. Researchers have engineered a dual-strategy by attributing targeting abilities by surface functionalization and simultaneously using pH responsiveness to enhance therapeutic selectivity in RA.
3.2 Redox-responsive
Intracellular microenvironment can be exploited using redox responsive NPs. Reactive oxygen species (ROS) is generated primarily during oxidative phosphorylation(OXPHOS), but can further be produced by oxidative burst of activated phagocytic cells [34]. Polymers with ROS-sensitive thioketal moiety, or selenium (Se), tellurium (Te), B-based linkers in their monomeric backbone can be utilized as building blocks for the synthesis of stimuli- responsive nanoparticles. Hence, ROS can easily be monitored as an intracellular indicator [35] as chronic inflammation induces continuous production of ROS [36]. ROS concentrations in inflammatory tissues ranges 10- to 100- fold higher than normal tissues [36], thus, promising accuracy and specificity to develop the redox stimuli-responsive DDSs.
3.3 Temperature-responsive
Temperature is another crucial factor essential for release of drug [38], as the normal physiological conditions have lower temperatures compared to the inflamed RA microenvironment [39]. Therefore temperature-responsive functionalized NPs can be used to trigger the release of drug at the inflammatory site. They are designed and fabricated to retain their payloads at physiological temperature (37°C), and quick release it when the temperature is increased around 40–45°C, attributing a more efficient targeted SDDS [40]. Phase-transition behavior of the materials that are thermosensitive are used to design NPs, based on the lower critical solution temperature (LCST) of polymers/lipids whose solubility varies with changes in temperature. All excipients in a mixture are totally miscible in all amounts in LCST. In materials with transitional behavior, increased solubility is observed below LCST; and polymeric constituents are prone to swelling due to the hydrogen bonds being formed between the polymer functional groups with water molecules enabling drug loaded molecules. When temperature is raised above the LCST, a hydrophobic-hydrophilic conversion takes place, that leads to a morphological transformation from a random coil-to-globular form. Because of alterations in temperature, the hydrogen bonds breaks causing the network to collapse, and the polymer becomes insoluble, causing shrinkage in the volume and oozing-out of water molecules from inside. This transition initiates release of the entrapped payload of drugs. The application of thermo-responsive SDDS is based on the concept of exploiting the temperature difference between healthy and diseased tissues [40]. Thermal energy can be given directly, or external utilizing heat sources like NIR that may be indirectly applied in RA, that elicits a thermo-responsive behavior based on the thermo-sensitivity of nanomaterials. Typically, the requisite range of temperature fluctuates from 38–43°C [37]. The temperature-stimuli can originate from within the body, or by localized hypothermia, or hyperthermia, may provoke a response based entirely on the thermo-sensitivity of used nanomaterials. Additional advantages of thermo-sensitive NPs may be attributed to reduction in use of toxic organic solvents during fabrication, the capacity to entrap both lipophilic and hydrophilic molecules, controlled and sustained release properties. A plethora of reports using several polymers have been established for the synthesis of temperature-responsive systems, that include derivatives of poly(N-isopropylacrylamide (PNIPAAm), pluronics (poly(ethylene oxide)- poly(propylene oxide) (PEO-PPO)), poly(N vinyl caprolactam), polysaccharide spinoffs, and derivatives of phosphazene [41, 42, 43]. Researchers are making concerted efforts on achieving temperature-responsive NPs stimulated by magnetic action coupled with thermo-responsive effect by light absorption instead of temperature alone.
3.4 Light and magnetic responsive
Light-responsive systems rely on an external stimulus to activate the drug release preferably at the target site using light irradiation. NPs respond to ‘on–off drug’ release, as it may close/open when stimulated using light radiation. Also termed as photodynamic therapy, SDDS based on magnetic stimuli represents another external way to trigger drug release at the target site under programmable exposure of magnetic field [37]. Iron-oxide NPs have excellent potential for smart drug delivery, as it exhibits a significant response to both light and magnetic stimuli, it can be exploited for triggering a burst release of drug at the inflamed sites of RA termed as the magneto-calorific effect and photothermal effects. Thermal properties of magnetic NPs might be conveniently modulated by modifying their own viscosity in the endo-cellular environment. Photodynamic therapy (PDT) and photothermal therapy (PTT) use photosensitizers as therapeutic molecules. Moreover, near infrared(NIR) light can efficiently infiltrate the inflamed RA joints. Cu7.2S4 nanoparticles triggered with NIR irradiation (808 nm, 1 W cm−2) was suggested to accomplish improved bone mineral density (BMD) and bone structure and volume. It further impedes invasion to synovial tissue, erosion of cartilage and bone in vivo.
Huo et al. have prepared optical nanoparticles induced PTT and PDT and documented probable pathways for cell toxicity [44]. During PTT cell necrosis can be induced by NIR laser light irradiation (wavelength:1064 nm), however when given as combination therapies (PTT + PDT), evidence of both necrosis and apoptosis pathways are indicated. Furthermore, PTT-PDT combination given simultaneously, can account for immunogenic cell-death, while fluorophores can be used for optical imaging as a diagnostic tool that can be applied for RA too.
3.5 Enzyme responsive
Specific enzymes like phospholipases, proteases, or glycoside are often overexpressed in different pathological conditions, like inflammation, and can be exploited for enzyme triggered release and accumulation of drugs at the targeted site of interest [37]. Nevertheless, nature of cleavable units, the sensitivity of the delivery system can significantly influence the pharmacokinetics of entrapped payload. Further, it must be ensured that the metabolites or the degraded moieties are non-toxic and biocompatible and are cautiously eliminated from the body. Therefore, in future, enzyme-responsive nanoparticles offer tailor-made therapy according to variations in levels of disease expression. Redox- and enzyme-responsive nanoparticles are coming up as promising therapies in RA treatment.
3.6 Energy upconversion NPs
Nanomaterials with exceptional physico-chemical properties targeting the lesions can be supplemented with precise external stimuli, such as light, microwave, ultrasound, and radiation. Upconversion nanoparticles (UCNPs) synthesized from rare-earth elements that are capable of translating NIR photons that have low-energy to high-energy ultraviolet or visible photons [45]. These extraordinary NIR excitation based optical properties of UCNPs allows penetration to deep tissues with minimum auto-fluorescence background, reinforcing a wide array of diagnostic applications alongwith biomedical imaging system [46, 47]. SDDS can translate the external stimuli and equivalent energy input into beneficial effects or release the payload via an energy-upconversion process [48]. Ultrasound-based, photo-dynamic-based, radiation-based and microwave-based, energy-UPNPs have been widely explored in RA treatment as an alternative therapy (Figure 2). These developing technologies induce death of synovial fibroblasts and other inflammatory cells by generating hyperthermia, cellular ROS, mechanical and photoelectric effects [49]. Synovial cells can be directly targeted by nanoparticles to decrease bone erosion (Table 1)[50].
Figure 2.
Schematic representation of stimuli-responsive polymers for nanotherapeutics of rheumatoid arthritis (RA).
Stimuli category
Stimulus
Description of the system
Drug
References
Chemical
pH
PLGA-PK3-lipid-polymer hybrid nanoparticles decorated with stearic acid-octa-arginine and folic acid (Sta-R8-FA-PPLPNs/MTX) [PK3, Folate-PEG-PLGA, egg PC, and Sta-R8]
PEGylated hyaluronic acid(P-HA) mineralized nanoparticles having a hydrophilic shell, 5β-cholanic acid as the hydrophobic core and CaP as the pH-responsive mineral
Lipid nanocarriers formed by PEG-PLGA hydrophilic shell, functionalized with folic acid (FA) ligand for targeting FA-receptor, poly (cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) & PLGA as the hydrophobic core. PCADK was used as pH-responsive material
Folate conjugated to PEC 100 monostearate as film-forming material, and methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes (FOL-MTX&CAT-L)
Lipid nanoparticles with PEG coating, composed of triglycerol monostearate (TGMS) and 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG2000) encapsulating Dexamethasone
Presently, the conventional treatments exhibit escalation in dose and systemic toxicity upon administration of drug. Most anti-inflammatory therapeutic drugs are equitoxic to both the normal cells and inflamed cells. SDDS has been well recognized in the past few decades owing to its potential for site-specific and targeted delivery [66]. Encapsulation of anti-inflammatory drugs in nanoparticles can enhance the site-specificity, reduce the dose, curtail the systemic toxicity and improve the biodistribution to targeted disease site [67]. To overcome the disadvantage of conventional delivery of drugs, selective delivery whether passive or active can be used for targeting drug to the site of action as SDDS in RA therapy.
4.1 Passive targeting
Passive targeting can be accomplished by targeting the physiological and anatomical changes in inflamed tissues, that occurred due to RA. For passive targeting, NPs do not require any surface modification, either by conjugation or by attaching a surface ligand. Various studies have shown the enhanced permeability and retention (EPR) mechanism for passive accumulation in inflamed tissues [68]. In the inflammatory RA milieu, there is evidence of angiogenesis but no evidence of displaying an abnormal lymphatic drainage [69]. The long-circulating delivery vehicles have been evidenced to specifically accumulate within the pannus of the inflamed synovium [70]. The hyperplasia in pannus exhibits a leaky vasculature due to high vascular permeability comparable to solid tumors. Consequently, taking advantage of leaky vasculature may for passive targeting is a promising option [71]. EPR allows NPs in size range from 20 to 200 nm to selectively accumulate in pannus and display on the surface of inflamed tissue. In addition to the EPR effect, hypoxic and acidic environment of inflamed joint also favors passive targeting [70]. Arthritic inflamed joint has poor oxygen delivery and increased metabolic rate due to meager perfusion into the diseased synovial joint. Therefore, the two conditions can easily be used as method of passive drug targeting in less oxygen and acidic microenvironment of RA affected inflamed tissue. NPs administrated in blood stream with hydrophobic surface are easily recognized by reticuloendothelial system (RES) such as spleen and liver, and engulfed by macrophages, consequently quickly eliminated from systemic circulation.
4.2 Active targeting
Targeted delivery involves active targeting to specific cells in the microenvironment of arthritic joints. Overexpressed receptors on particular immune cells can be targeted with its complimentary ligand that is decorated on nanoparticle surface. Several receptors are expressed by different cells, we shall be discussing a few including CD44, folate and beta-3 integrins. Targeting angiogenic vascular endothelial cells are also under investigation, with E-selectin as a promising target molecule [72]. Receptor mediated endocytosis is responsible for efficient uptake of the ligand decorated carrier molecule (ligand-receptor interaction) (Figure 3).
Figure 3.
Outline of the targeting strategies for nanoparticulate drug delivery systems used in RA.
4.2.1 Folic acid (FA) based active targeting
Activated macrophages overexpress folate receptor β(FR-β) in the arthritic joints [73]. Owing to post-translational modifications, the folate expressed on neutrophils are incapable of binding to FR-β [74]. Alternatively, a functional FR-β has been identified on the activated macrophages having nanomolar affinity for folate. Hence, the FR-β receptor emerges as a useful target in various diseases including RA, osteoarthritis [75], systemic lupus erythematosus [76], atherosclerosis [77] and Crohn’s disease [78]. Macrophages are key players of RA pathogenesis, as they secrete pro-inflammatory cytokines, metalloproteinases, ROS and prostaglandins. Folate is an attractive option for ease of surface modification, hydrophilicity, and stability in different solvents. Methotrexate (MTX) encapsulated folate-conjugated glycol chitosan (MFGCN) have been targeted to inflamed joint in adjuvant-induced arthritic rat model [79]. Likewise, surface of MTX-loaded liposomes was decorated with folate and were evaluated both in vitro and in vivo (DBA/1 J mice strain) [80, 81], and targeted against the FR-β on activated macrophages. Clinical efficacy of MTX in the DBA/1 J arthritic mice indicated significant expression of CD73. Since, low doses were required, this nanoformulation was economical and cost-effective. MTX loaded dendrimer nanoparticles with folic acid (FA) surface functionalization were reported to reduce progression of disease [82]. Further, authors suggested a ~ 7.5-fold increase in the maximum-tolerated dose of the MTX, when given as the formulation compared to the free MTX.
4.2.2 Hyaluronic acid (HA) based active targeting
CD44 is a glycoprotein, overexpressed on the surface of activated macrophages, present in the inflamed joints of RA. CD44 can be exploited as a prospective target in RA treatment. HA, a biocompatible natural polymer has ben explored as a ligand that effectively binds to CD44 receptor. HA coated hydroxyapatite NPs (HA-NPs) encapsulating methotrexate (MTX) and teriflunomide (TEF) - (HYA-HAMT-NP) were reported for RA treatment [83]. Results suggested that HYA-HAMT-NP could emerge as an effective delivery vehicle to circumvent hepatotoxicity caused by drugs in RA.
4.2.3 Anti-angiogenesis
Hypoxia in a critical factor in inflamed synovium that triggers neo-vascularization from existing vessels termed as angiogenesis [84]. The neo-vascularization preserves the chronic inflammatory state by engaging cells to the inflammatory site, provides nutrition and oxygen to the multiplying cells. Additionally, the enlarged surface of endothelium triggers secretion of adhesion molecules, cytokines and stimulates neutrophil infiltration as well as synovial membrane into the cartilage, causing cartilage destruction and bone erosion [85]. Promising therapies based on angiogenesis are emerging for RA therapy, where VEGF and integrins are the therapeutic targets.
4.2.3.1 Vascular endothelial growth factor (VEGF)
Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor principally secreted by SFs in the pannus. In angiogenesis, VEGF triggers multiplication and migration of endothelial cells. Further, it enhanced blood vascular permeability, stimulates maturation and maintenance of the neo-vessels [86]. TNF-α and IL-1, the pro-inflammatory cytokines induce the SFs and other cells to secrete VEGF, and VEGF is overexpressed at the inflamed joint owing to angiogenesis [87]. Therefore, VEGF and VEGF receptor inhibition can be an attractive strategy for RA treatment as it may effectively decrease inflammation by inhibiting angiogenesis.
4.2.3.2 Vasoactive intestinal peptide (VIP)
Vasoactive intestinal peptide (VIP) is a neuropeptide of the central and peripheral nervous system that has vasodilatory, anti-proliferative, anti-inflammatory, cell protective agent and broncho-dilatory role. The activity of VIP binds to high affinity VIP receptors, that are overexpressed on T-lymphocytes and several inflammatory cells. VIP inhibits the secretion of pro-inflammatory cytokines to act as anti-inflammatory molecule. It also promotes the secretion of anti-inflammatory molecules by stimulated innate cells [88]. Proliferating synoviocytes and activated macrophages overexpress VIP receptors in inflamed RA. Therefore, VIP receptor specific ligands can be conjugates to nanoparticles to specifically target the diseased site. Therefore, VIP can be exploited as a therapeutic agent for active targeting to RA joint.
4.2.3.3 Integrins
Integrins are the biogenic markers of endothelium undergoing angiogenesis and play a vital effector role in it. Integrin alpha-V-beta 3 (αvβ3 integrin), also referred to as vitronectin receptor are overexpressed on osteoclasts and activated macrophages of the inflamed synovium. Integrin receptor promotes angiogenesis, helps in osteoclast-mediated bone resorption, and induces pathological neo-vascularization [89]. Inhibition of αvβ3 integrin activity stimulates endothelial cell apoptosis, thereby inhibiting angiogenesis [90]. Hence, αvβ3 is considered a reliable maker for targeted delivery to RA patients.
4.2.3.4 E-selectin
E- Selectin is a glycoprotein that is associated with leukocyte rolling and adhesion and is expressed on vascular endothelium of the inflamed synovium, and promotes angiogenesis [91]. The inflammatory cytokines maintain its upregulated expression in the inflamed tissue. Therefore, expression of e-selectin can be a useful molecular target for RA therapy. Therefore, e-selectin serves as yet another attractive strategy for active targeting of the chosen delivery of drug to the diseased RA joint [92].
The assembly of stimuli-sensitive nanoparticles necessities the usage of biocompatible constituents, that can undergo supra-molecular changes in conformation, a hydrolytic cleavage, and precise protonation, etc. Polymers have maximum suitability and has been widely explored class of materials that have incredible potential. Polymers may be of natural or synthetic origin. The flexibility of the polymer sources and its ability for synthesis of various combinations of polymers has facilitated manipulation of the polymer sensitivity to specific stimuli within a narrow range [93]. Nanoparticles could be synthesized by lipid, metals and polymers. NPs decoy pro-inflammatory molecules like cytokines and ROS and sometimes osteoclast differentiation factors. Moreover, surface modification of NPs with target moiety is a extensive application in site specific drug delivery by enhancing the bioavailability of drug and reducing non-target side effects [94].
5.1 Polymer-drug conjugate (PDC)
PDC based DDS has been proposed by Ringsdrof in 1975 [95], in which a low molecular weight drug, targeting moiety and solubilizer are attached to polymeric backbone covalently via bioresponsive linkers. PDC improves drug bioavailability, reduces drug toxicity, and are less toxic in nature, can easily be fabricated in regulated sizes that escape through renal filtration, exhibit increased retention time in blood circulation [96]. PDCs under investigation include N-(2-hydroxypropyl) methacrylamide, poly(vinylpyrrolidone) (PVP), hyaluronic acid (HA) and poly (ethylene glycol) (PEG) [11, 97]. N-(2-hydroxypropyl) methacrylamide (HPMA) shows improved biodegradability, biocompatibility and increased efficacy in treating RA [11, 97]. HPMA-Dex conjugates were administered intravenously into CIA induced RA model, that resulted in accumulation at the inflamed joints [98]. PEG has been used for its hydrophilicity and biocompatible properties. PEG-DEX have been developed via acid-labile hydrazine bond and given to arthritic rats leading to decrease in joint inflammation [99]. Recently, FDA approved two PEGylated proteins for the treatment of RA: Pegloticase (Krystexxa®) and certolizumab pegol (CIMZIA®). Although, PEG attributes stealth properties to the NPs, there are some concerns regarding PEG conjugates that include low biodegradability and the possibility to elicit an anti-PEG IgM antibody [100].
5.2 Nanoparticles
Nanoparticles are solid colloidal particles with unique physico-chemical properties such as ultra-small size, surface charge, large surface area to mass ratio Unlike polymer-drug conjugates, NPs allow encapsulation/absorption/entrapment of drug without modification. The high reactivity, diffusivity, solubility, toxicity, immunogenicity and drug release characteristics can be manipulated to make efficient delivery system. Polymeric, liposomes, micelles and metallic nanoparticles are the most commonly used nanoparticles [101].
5.2.1 Biopolymeric nanoparticles
The biodegradable backbone in biopolymeric NPs protects the drug from in vitro and in vivo degradation. Alginate, Gelatin, Pectin, Chitosan, are natural biopolymers that are highly investigated as they are biocompatible and biodegradable. Chitosan is polycationic in nature, that allows surface modification with ease and is a natural mucoadhesive. Kumar et al. reported Chitosan nanoparticles encapsulating Dexamethasone (DEX) and Methotrexate (MTX) for their in vitro efficacy in RAW264.7 cells and in vivo efficacy in arthritic rat model. Results convincingly indicated reduced toxicity and high efficacy in arthritic model [28]. The main drawback of chitosan is insoluble in alkaline and neutral medium due to absence of free amino group, but due to protonation of free amino group in acidic medium, there is enhanced solubility.
Glycol chitosan has enhanced water solubility and functional groups for further chemical modifications making it better suited as a potent drug carrier [102]. Glycol-chitosan nanoparticles(GCNPs) are biocompatible, pH responsive and biodegradable. Methotrexate (MTX) encapsulated folate-conjugated glycol chitosan (MFGCN) have been reported to target the overexpressed folate receptors β (FR-β) on activated macrophages in the inflamed joint in adjuvant-induced arthritic rat model. Figure 4 gives a pictorial description of MFGCN that reduced the arthritic index, improved the antioxidant response and decreases pro-inflammatory cytokines and suggesting its potential in targeting activated macrophages of synovium [79].
Figure 4.
Pictorial representation of utilization of folate functionalized methotrexate loaded glycol chitosan nanoparticles (MFGCN) in treating CIA rats targeting inflammation and ROS in rat serum post 21 days of treatment (n = 6). [A] MFGCN development and active targeting of M1 macrophages in the inflammatory synovium. [B] LPO and LDH activity [C] panel showing antioxidant potential (activity quantification of GST, GSH, GP and GR) [D] quantification of TNF-α, IL-4, IL-1β, IL-10 and IL-17 [E] Representative H&E staining images of study groups comparing healthy and arthritic control groups with the treatment groups(n = 6). Data was analyzed by one-way ANOVA *p < 0.05, **p < 0.01, ***p < 0.001.
5.2.2 Gold nanoparticles(GNPs)
GNPs can be surface functionalized through covalent bonding, by cationic polymers or physical or ionic absorption [103], functional groups like e.g. thiol, amine, and carboxyl groups that are reactive [104]. GNPs were strategically planted in macrophages to target thioredoxin reductase to evaluate its antiangiogenic impact by binding to the vascular endothelial growth factor (VEGF) [105]. Lee et al. suggested MTX encapsulated RGD-attached gold half-shell NP system for RA treatment [106]. On irradiation with near-infrared (NIR), these GNPs delivered MTX to the inflamed joints, maximizing its efficacy with minimal side effects. GNPs were modified physically with Tocilizumab(TCZ) and chemically altered with an end-group thiolated hyaluronate(HA). This complex of HA-GNP-TCZ indicated a synergistic effect for its dual-functional effect on VEGF and IL-6R (receptors for IL-6) in RA treatment [107]. GNPs may block the RANKL induced osteoclast formation which leads to cartilage and bone destruction [108].
5.2.3 Liposomes
Liposomes are bilayered lipids with an aqueous core. Both hydrophobic as well as hydrophilic drugs can be encapsulated within phospholipids and the water phase cavity, making them SDDS [109]. Particle size determines the extent of accumulation at the synovium, with maximum accumulation of liposomes reported with size <100 nm diameter [110]. Therapeutic efficacy is limited due to rapid clearance from circulation via the RES in the liver/spleen. Surface modification by PEG enhances its hydrophilicity, makes them sterically stabilized, circumvent rapid clearance, and enhance the retention time in blood circulation [110]. Corvo et al. reported enhanced circulation and accumulation of PEG-coated SOD entrapped liposomes (mean diameter ~ 0.11 μm) at the arthritic joints [111]. Considering the dynamic microenvironment of the diseased synovium, liposomal surface can be modified with ligands, antibodies/antibody fragments or for site-specific delivery of encapsulated cargo. Recently, dexamethasone encapsulated PEG-liposome treated arthritic rats indicated accumulation of liposomes, down regulation of pro-inflammatory cytokines along with reduced inflammation of the arthritic joints [112]. Liposome tagged with a peptide sequence (CKPFDRALC-called ART-2 ligand) encapsulating DEX significantly inhibited RA progression [113].
5.2.4 Micelles
Micelles can be synthesized in small size with narrow size distribution from amphiphilic molecules that self-assemble into NPs in aqueous solution with a distinct hydrophobic cavity and an exterior hydrophilic surface. This makes them apt for intravenous injection and targeted delivery into the inflamed synovium as a consequence of extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) [114]. Wang et al. reported self-assembled micelles with an amphiphilic copolymer PEG-poly-e-caprolactone (PEG-PCL), which displayed ELVIS in inflamed joints [115], but the non-biodegradable backbone of synthetic polymers caused non-specific accumulation in liver. Bader et al. [116] developed micelles from polysialic acid (PSA)-the hydrophilic polymer and synthesized micelles by altering it with N-decylamine (DA) and PCL, that formed the hydrophobic fragment. Prolonged circulation was observed with these micelles that accumulated passively at the inflamed tissue. PSA-DA micelles exhibited in-vitro cytotoxicity towards a synovial fibroblast cell line, the PSA-PCL micelles displayed negligible in-vivo cytotoxicity [117]. Further modifications were reported to improve the blood kinetic profile of the micelles. Core-cross-linked micelles were developed based on copolymer PEG-b-poly [N-(2-hydroxypropyl) methacrylamide-lactate] for targeted delivery of glucocorticoids to the RA affected joints. Here, dexamethasone was modified by methacrylated linkers via ester bonds, and covalently encapsulated within the polymeric structure, leading to tailorable release of dexamethasone [118]. Targeted delivery of aqueous-synthesized MTX-PEI@HA NPs to mitigate inflammatory arthritis was reported [114]. Li et al. formulated pH-sensitive micelles by conjugating hydrophobic prednisolone to PEG-derivative that confers acid-sensitive sites for attachment by forming hydrazone bonds [119]. Dual-drug loading of nimesulide and MTX in RGD-modified micelles to target αvβ3-integrin validated efficient site-specific delivery, decreased angiogenesis with minimal dose of nimesulide and MTX [120].
Multifactorial pathogenesis is the hallmark in RA causing bone fragility and functional erosion linked disability in extreme conditions. Although, conventional therapeutic formulations alone or in combination may relieve the symptoms, these are associated with complex adverse reactions. Dose-escalation, immunogenicity, systemic toxicity, and non-specific biodistribution in tissues warrant SDDS development. Stimuli-responsive NPs target specific inflammatory intermediaries, thereby suppressing the pathophysiological cascade, that may alleviate RA symptoms and delay joint destruction. Therefore, both the approaches may be exploited for achieving dose reduction coupled with drug accumulation at the targeted inflamed joint.
LB is thankful to UGC, and VS is thankful to ICMR, Govt of India for Senior Research Fellowship. VK is thankful to Individual Fellowship from European Union’s Research and Innovation program, Marie Skłodowska-Curie grant agreement No. 890507.
Writing—original draft preparation, AKV, LB, VS and VK; visualization, AKV; conceptualization, writing—review and editing, supervision and project administration, AKV. All authors have read and agreed to the published version of the manuscript.
1.Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. Jama. 2018 2;320(13):1360-72.
2.Burmester GR, Bijlsma JW, Cutolo M, McInnes IB. Managing rheumatic and musculoskeletal diseases—past, present and future. Nature Reviews Rheumatology.2017;13(7):443.
3.Global RA Network. About Arthritis and RA. https://globalranetwork.org/project/disease-info/
4.Mahdi H, Fisher BA, Källberg H, Plant D, Malmström V, Rönnelid J, Charles P, Ding B, Alfredsson L, Padyukov L, Symmons DP. Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis. Nature genetics. 2009;41(12):1319-24.
5.Koga T, Kawakami A, Tsokos GC. Current insights and future prospects for the pathogenesis and treatment for rheumatoid arthritis. Clinical Immunology. 2021;225:108680.
6.Lühder F, Reichardt HM. Novel drug delivery systems tailored for improved administration of glucocorticoids. International journal of molecular sciences. 2017;18(9):1836.
7.Horton HM, Bernett MJ, Peipp M, Pong E, Karki S, Chu SY, Richards JO, Chen H, Repp R, Desjarlais JR, Zhukovsky EA. Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies. Blood, The Journal of the American Society of Hematology. 2010;116(16):3004-12.
8.Gabay C, Riek M, Scherer A, Finckh A. Effectiveness of biologic DMARDs in monotherapy versus in combination with synthetic DMARDs in rheumatoid arthritis: data from the Swiss Clinical Quality Management Registry. Rheumatology. 2015;54(9):1664-72.
9.Shi J, Ying H, Du J, Shen B. Serum sclerostin levels in patients with ankylosing spondylitis and rheumatoid arthritis: a systematic review and meta-analysis. Biomed Res Int;2017:9295313.
10.Müller-Ladner U, Ospelt C, Gay S, Distler O, Pap T. Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts. Arthritis research & therapy. 2007;9(6):1-0.
11.Gorantla S, Singhvi G, Rapalli VK, Waghule T, Dubey SK, Saha RN. Targeted drug-delivery systems in the treatment of rheumatoid arthritis: recent advancement and clinical status. Therapeutic Delivery. 2020;11(4):269-84.
12.Neumann E, Hasseli R, Ohl S, Lange U, Frommer KW, Müller-Ladner U. Adipokines and Autoimmunity in Inflammatory Arthritis. Cells. 2021 Feb;10(2):216.
13.Bui VL, Brahn E. Cytokine targeting in rheumatoid arthritis. Clinical Immunology (Orlando, Fla.). 2018 3;206:3-8.
14.O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annual review of medicine. 2015;66:311-28.
15.Orr C, Vieira-Sousa E, Boyle DL, Buch MH, Buckley CD, Cañete JD, Catrina AI, Choy EH, Emery P, Fearon U, Filer A. Synovial tissue research: a state-of-the-art review. Nature Reviews Rheumatology. 2017;13(8):463.
16.Lliso-Ribera G, Humby F, Lewis M, Nerviani A, Mauro D, Rivellese F, Kelly S, Hands R, Bene F, Ramamoorthi N, Hackney JA. Synovial tissue signatures enhance clinical classification and prognostic/treatment response algorithms in early inflammatory arthritis and predict requirement for subsequent biological therapy: results from the pathobiology of early arthritis cohort (PEAC). Annals of the rheumatic diseases. 2019;78(12):1642-52.
17.Davis III JM, Crowson CS, Knutson KL, Achenbach SJ, Strausbauch MA, Therneau TM, Matteson EL, Gabriel SE, Wettstein PJ. Longitudinal relationships between rheumatoid factor and cytokine expression by immunostimulated peripheral blood lymphocytes from patients with rheumatoid arthritis: New insights into B-cell activation. Clinical Immunology. 2020;211:108342.
18.Scherer HU, Huizinga TW, Krönke G, Schett G, Toes RE. The B cell response to citrullinated antigens in the development of rheumatoid arthritis. Nature Reviews Rheumatology. 2018;14(3):157.
19.Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Frontiers in immunology. 2014;5:491
20.Xu X, Gao W, Cheng S, Yin D, Li F, Wu Y, Sun D, Zhou S, Wang D, Zhang Y, Jiang R. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. Journal of neuroinflammation. 2017;14(1):1-5.
21.Kotake S, Yago T, Kawamoto M, Nanke Y. Human receptor activator of NF-κB ligand (RANKL) induces osteoclastogenesis of primates in vitro. In Vitro Cellular & Developmental Biology-Animal. 2012;48(9):593-8.
22.Itoh Y. Membrane-type matrix metalloproteinases: Their functions and regulations. Matrix Biology. 2015;44:207-23.
23.Conigliaro P, Triggianese P, De Martino E, Fonti GL, Chimenti MS, Sunzini F, Viola A, Canofari C, Perricone R. Challenges in the treatment of rheumatoid arthritis. Autoimmunity reviews. 2019;18(7):706-13.
24.Konttinen YT, Ainola M, Valleala H, Ma J, Ida H, Mandelin J, Kinne RW, Santavirta S, Sorsa T, López-Otín C, Takagi M. Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis. Annals of the rheumatic diseases. 1999;58(11):691-7.
25.Srivastava S, Singh D, Patel S, Parihar AK, Singh MR. Novel carters and targeted approaches: Way out for rheumatoid arthritis quandrum. Journal of Drug Delivery Science and Technology. 2017 Aug 1;40:125-35.
26.Liu D, Yang F, Xiong F, Gu N. The smart drug delivery system and its clinical potential. Theranostics.2016;6(9):1306.
27.Wu L, Shen S. What potential do magnetic iron oxide nanoparticles have for the treatment of rheumatoid arthritis? Nanomedicine. 2019;14(8):927-30.
28.Kumar V, Leekha A, Tyagi A, Kaul A, Mishra AK, Verma AK. Preparation and evaluation of biopolymeric nanoparticles as drug delivery system in effective treatment of rheumatoid arthritis. Pharmaceutical research. 2017;34(3):654-67.
29.Rajamäki K, Nordström T, Nurmi K, Åkerman KE, Kovanen PT, Öörni K, Eklund KK. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. Journal of Biological Chemistry. 2013;288(19):13410-9.
30.Roiniotis J, Dinh H, Masendycz P, Turner A, Elsegood CL, Scholz GM, Hamilton JA. Hypoxia prolongs monocyte/macrophage survival and enhanced glycolysis is associated with their maturation under aerobic conditions. The Journal of Immunology. 2009;182(12):7974-81.
31.Karimi M, Ghasemi A, Zangabad PS, Rahighi R, Basri SM, Mirshekari H, Amiri M, Pishabad ZS, Aslani A, Bozorgomid M, Ghosh D. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chemical Society Reviews. 2016;45(5):1457-501.
32.Wang L, Zhu B, Huang J, Xiang X, Tang Y, Ma L, Yan F, Cheng C, Qiu L. Ultrasound-targeted microbubble destruction augmented synergistic therapy of rheumatoid arthritis via targeted liposomes. Journal of Materials Chemistry B. 2020;8(24):5245-56.
33.Yang L, Shao Y, Han HK. Improved pH-dependent drug release and oral exposure of telmisartan, a poorly soluble drug through the formation of drug-aminoclay complex. International journal of pharmaceutics. 2014;471(1-2):258-63.
34.Fonseca LJ, Nunes-Souza V, Goulart MO, Rabelo LA. Oxidative stress in rheumatoid arthritis: What the future might hold regarding novel biomarkers and add-on therapies. Oxidative medicine and cellular longevity. 2019;2019.
35.Mortezaee K, Najafi M, Samadian H, Barabadi H, Azarnezhad A, Ahmadi A. Redox interactions and genotoxicity of metal-based nanoparticles: A comprehensive review. Chemico-biological interactions. 2019;312:108814.
36.Kuang M, Zheng G. Nanostructured bifunctional redox electrocatalysts. Small. 2016;12(41):5656-75.
37.De La Rica R, Aili D, Stevens MM. Enzyme-responsive nanoparticles for drug release and diagnostics. Advanced drug delivery reviews. 2012;64(11):967-78.
38.Goyal AK, Rath G, Faujdar C, Malik B. Application and perspective of pH-responsive nano drug delivery systems. In Applications of Targeted Nano Drugs and Delivery Systems. 2019;15-33.
39.Karimi M, Sahandi Zangabad P, Ghasemi A, Amiri M, Bahrami M, Malekzad H, Ghahramanzadeh Asl H, Mahdieh Z, Bozorgomid M, Ghasemi A, Rahmani Taji Boyuk MR. Temperature-responsive smart nanocarriers for delivery of therapeutic agents: applications and recent advances. ACS applied materials & interfaces. 2016;8(33):21107-33.
40.Singh A, Amiji MM, editors. Stimuli-responsive Drug Delivery Systems. Royal Society of Chemistry; 2018.
41.Behrens MA, Lopez M, Kjøniksen AL, Zhu K, Nyström B, Pedersen JS. The effect of cationic and anionic blocks on temperature-induced micelle formation. Journal of Applied Crystallography. 2014;1;47(1):22-8.
42.Chen YC, Xie R, Chu LY. Stimuli-responsive gating membranes responding to temperature, pH, salt concentration and anion species. Journal of membrane science. 2013;442:206-15.
43.Zhang X, Hou Y, Xiao X, Chen X, Hu M, Geng X, Wang Z, Zhao J. Recent development of the transition metal complexes showing strong absorption of visible light and long-lived triplet excited state: From molecular structure design to photophysical properties and applications. Coordination Chemistry Reviews. 2020;417:213371.
44.Huo, Y; Yang, X; Liu, R; Zhao,D; Guo, C; Zhu, A; Wen, M; Liu, Z, Qu, G; Meng, H; “Pathological Mechanism of Photodynamic Therapy and Photothermal Therapy Based on Nanoparticles”International Journal of Nanomedicine. 2020:15 6827-6838
45.Chen G, Qiu H, Prasad PN, Chen X. Upconversion nanoparticles: design, nanochemistry, and applications in theranostics. Chemical reviews. 2014;114(10):5161-214.
46.Xu J, Xu L, Wang C, Yang R, Zhuang Q , Han X, Dong Z, Zhu W, Peng R, Liu Z. Near-infrared-triggered photodynamic therapy with multitasking upconversion nanoparticles in combination with checkpoint blockade for immunotherapy of colorectal cancer. ACS nano. 2017;11(5):4463-74.
47.Kwon OS, Song HS, Conde J, Kim HI, Artzi N, Kim JH. Dual-color emissive upconversion nanocapsules for differential cancer bioimaging in vivo. ACS nano. 2016;10(1):1512-21.
48.Xiang H, Chen Y. Energy-converting nanomedicine. Small. 2019;15(13):1805339.
49.Chen X, Zhu X, Ma L, Lin A, Gong Y, Yuan G, Liu J. A core–shell structure QRu-PLGA-RES-DS NP nanocomposite with photothermal response-induced M2-macrophage polarization for rheumatoid arthritis therapy. Nanoscale. 2019;11(39):18209-23.
50.Tang Q , Cui J, Tian Z, Sun J, Wang Z, Chang S, Zhu S. Oxygen and indocyanine green loaded phase-transition nanoparticle-mediated photo-sonodynamic cytotoxic effects on rheumatoid arthritis fibroblast-like synoviocytes. International journal of nanomedicine. 2017;12:381.
51.Zhao J, Zhang X, Sun X, Zhao M, Yu C, Lee RJ, Sun F, Zhou Y, Li Y, Teng L. Dual-functional lipid polymeric hybrid pH-responsive nanoparticles decorated with cell penetrating peptide and folate for therapy against rheumatoid arthritis. European Journal of Pharmaceutics and Biopharmaceutics. 2018;130:39-47.
52.Yu C, Li X, Hou Y, Meng X, Wang D, Liu J, Sun F, Li Y. Hyaluronic acid coated acid-sensitive nanoparticles for targeted therapy of adjuvant-induced arthritis in rats. Molecules. 2019;24(1):146.
53.Alam MM, Han HS, Sung S, Kang JH, Sa KH, Al Faruque H, Hong J, Nam EJ, San Kim I, Park JH, Kang YM. Endogenous inspired biomineral-installed hyaluronan nanoparticles as pH-responsive carrier of methotrexate for rheumatoid arthritis. Journal of Controlled Release. 2017;252:62-72.
54.Zhao J, Zhao M, Yu C, Zhang X, Liu J, Cheng X, Lee RJ, Sun F, Teng L, Li Y. Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis. International journal of nanomedicine. 2017;12:6735.
55.Moon SJ, You DG, Li Y, Um W, Jung JM, Kim CH, Oh BH, Park JH, Lee DS. pH-Sensitive Polymeric Micelles as the Methotrexate Carrier for Targeting Rheumatoid Arthritis. Macromolecular Research. 2020;28(2):99-102.
56.Xu Y, Mu J, Xu Z, Zhong H, Chen Z, Ni Q , Liang XJ, Guo S. Modular acid-activatable acetone-based ketal-linked nanomedicine by dexamethasone prodrugs for enhanced anti-rheumatoid arthritis with low side effects. Nano letters. 2020;20(4):2558-68.
57.Chen M, Daddy JC KA, Su Z, Guissi NE, Xiao Y, Zong L, Ping Q . Folate receptor-targeting and reactive oxygen species-responsive liposomal formulation of methotrexate for treatment of rheumatoid arthritis. Pharmaceutics. 2019;11(11):582.
58.Lee SM, Kim HJ, Ha YJ, Park YN, Lee SK, Park YB, Yoo KH. Targeted chemo-photothermal treatments of rheumatoid arthritis using gold half-shell multifunctional nanoparticles. ACS nano. 2013, 22;7(1):50-7.
59.Lu Y, Li L, Lin Z, Wang L, Lin L, Li M, Zhang Y, Yin Q , Li Q , Xia H. A new treatment modality for rheumatoid arthritis: combined photothermal and photodynamic therapy using Cu7. 2S4 nanoparticles. Advanced healthcare materials. 2018;7(14):1800013.
60.Wu, K; Su, D; Liu J, Saha R and Wang, J.P. Magnetic nanoparticles in nanomedicine: a review of recent advances; 2019 Nanotechnology30 502003.
61.Kim HJ, Lee SM, Park KH, Mun CH, Park YB, Yoo KH. Drug-loaded gold/iron/gold plasmonic nanoparticles for magnetic targeted chemo-photothermal treatment of rheumatoid arthritis. Biomaterials. 2015;61:95-102.
62.He L, Fan D, Liang W, Wang Q , Fang J. Matrix Metalloproteinase-Responsive PEGylated Lipid Nanoparticles for Controlled Drug Delivery in the Treatment of Rheumatoid Arthritis. ACS Applied Bio Materials. 2020;3(5):3276-84.
63.Wardwell PR, Forstner MB, Bader RA. Investigation of the cytokine response to NF-κB decoy oligonucleotide-coated polysaccharide based nanoparticles in rheumatoid arthritis:in vitro models. Arthritis research & therapy. 2015(1):1-1.
64.Lima SA, Reis S. Temperature-responsive polymeric nanospheres containing methotrexate and gold nanoparticles: a multi-drug system for theranostic in rheumatoid arthritis. Colloids and Surfaces B: Biointerfaces. 2015;133:378-87.
65.He L, Qin X, Fan D, Feng C, Wang Q , & Fang J. Dual-Stimuli Responsive Polymeric Micelles for the Effective Treatment of Rheumatoid Arthritis. ACS Appl Mater Interfaces 2021;13(18):21076-21086.
66.Yang M, Feng X, Ding J, Chang F, Chen X. Nanotherapeutics relieve rheumatoid arthritis. Journal of Controlled Release. 2017;252:108-24.
67.Prasad LK, O’Mary H, Cui Z. Nanomedicine delivers promising treatments for rheumatoid arthritis. Nanomedicine. 2015;10(13):2063-74.
68.Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 2001;41:189-207
69.Walsh DA. Angiogenesis and arthritis. Rheumatology (Oxford, England).999;38(2):103-12.
70.Girdhar V, Patil S, Banerjee S, Singhvi G. Nanocarriers for drug delivery: mini review. Current Nanomedicine (Formerly: Recent Patents on Nanomedicine). 2018;8(2):88-99.
71.Xu H, Edwards J, Banerji S, Prevo R, Jackson DG, Athanasou NA. Distribution of lymphatic vessels in normal and arthritic human synovial tissues. Annals of the rheumatic diseases. 2003;62(12):1227-9.
72.Gao C, Huang Q , Liu C, Kwong CH, Yue L, Wan JB, Lee SM, Wang R. Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines. Nature communications.2020;11(1):1-4.
73.Nakashima-Matsushita N, Homma T, Yu S, Matsuda T, Sunahara N, Nakamura T, Tsukano M, Ratnam M, Matsuyama T. Selective expression of folate receptor β and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1999;42(8):1609-16.
74.Hao H, Qi H, Ratnam M. Modulation of the folate receptor type β gene by coordinate actions of retinoic acid receptors at activator Sp1/ets and repressor AP-1 sites. Blood. 2003;101(11):4551-60.
75.Tsuneyoshi Y, Tanaka M, Nagai T, Sunahara N, Matsuda T, Sonoda T, Ijiri K, Komiya S, Matsuyama T. Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles. Scandinavian journal of rheumatology. 2012;41(2):132-40.
76.Varghese B, Haase N, Low PS. Depletion of folate-receptor-positive macrophages leads to alleviation of symptoms and prolonged survival in two murine models of systemic lupus erythematosus. Molecular pharmaceutics. 2007;4(5):679-85.
77.Ayala-López W, Xia W, Varghese B, Low PS. Imaging of atherosclerosis in apoliprotein e knockout mice: targeting of a folate-conjugated radiopharmaceutical to activated macrophages. Journal of Nuclear Medicine. 2010;51(5):768-74.
78.Low PS, Antony AC. Folate receptor-targeted drugs for cancer and inflammatory diseases. Advanced drug delivery reviews. 2004;56(8).
79.Kumar V, Leekha A, Kaul A, Mishra AK, Verma AK. Role of folate-conjugated glycol-chitosan nanoparticles in modulating the activated macrophages to ameliorate inflammatory arthritis: in vitro and in vivo activities. Drug delivery and translational research. 2020;10(4):1057-75.
80.Nogueira E, Lager F, Le Roux D, Nogueira P, Freitas J, Charvet C, Renault G, Loureiro A, Almeida CR, Ohradanova-Repic A, Machacek C. Enhancing methotrexate tolerance with folate tagged liposomes in arthritic mice. Journal of biomedical nanotechnology. 2015;11(12):2243-52.
81.Thomas TP, Goonewardena SN, Majoros IJ, Kotlyar A, Cao Z, Leroueil PR, Baker Jr JR. Folate-targeted nanoparticles show efficacy in the treatment of inflammatory arthritis. Arthritis & Rheumatism. 2011;63(9):2671-80.
82.Pandey P.K. ; Maheshwari, R; Raval, N; Raval P; Kalia, G. K.; Tekade, R.K.; Nanogold-core multifunctional dendrimer for pulsatile chemo-, photothermal- and photodynamic- therapy of rheumatoid arthritis; 2019; 544, 15, 61-77.
83.Pandey S, Rai N, Mahtab A, Mittal D, Ahmad FJ, Sandal N, Neupane YR, Verma AK, Talegaonkar S. Hyaluronate-functionalized hydroxyapatite nanoparticles laden with methotrexate and teriflunomide for the treatment of rheumatoid arthritis. International Journal of Biological Macromolecules. 2021;28;171:502-13.
84.Szekanecz Z, Koch AE. Mechanisms of disease: angiogenesis in inflammatory diseases. Nature clinical practice Rheumatology. 2007; 3(11):635-43.
85.Marrelli A, Cipriani P, Liakouli V, Carubbi F, Perricone C, Perricone R, Giacomelli R. Angiogenesis in rheumatoid arthritis: a disease specific process or a common response to chronic inflammation? Autoimmunity reviews. 2011;10(10):595-8.
86.Shibuya M. Vascular endothelial growth factor-dependent and-independent regulation of angiogenesis. BMB reports. 2008;41(4):278-86.
87.Szekanecz Z, Koch AE. VEGF as an activity marker in rheumatoid arthritis. International Journal of Clinical Rheumatology. 2010;5(3):287.
88.Ganea D, Hooper KM, Kong W. The neuropeptide vasoactive intestinal peptide: direct effects on immune cells and involvement in inflammatory and autoimmune diseases. Acta Physiologica. 2015;213(2):442-52.
89.Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504-8.
90.Wilder RL. Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Annals of the rheumatic diseases. 2002;61(suppl 2):ii,96-9.
91.Jamar F, Chapman PT, Harrison AA, Binns RM, Haskard DO, Peters AM. Inflammatory arthritis: imaging of endothelial cell activation with an indium-111-labeled F (ab') 2 fragment of anti-E-selectin monoclonal antibody. Radiology. 1995;194(3):843-50.
92.Jubeli E, Moine L, Vergnaud-Gauduchon J, Barratt G. E-selectin as a target for drug delivery and molecular imaging. Journal of controlled release. 2012;158(2):194-206.
93.James HP, John R, Alex A, Anoop K. Smart polymers for the controlled delivery of drugs–a concise overview. Acta Pharmaceutica Sinica B. 2014;4(2):120-7.
94.Ulbrich W, Lamprecht A. Targeted drug-delivery approaches by nanoparticulate carriers in the therapy of inflammatory diseases. Journal of The Royal Society Interface. 2010;7(suppl_1):S55-66.
95.Bader RA. The development of targeted drug delivery systems for rheumatoid arthritis treatment. Rheumatoid Arthritis–Treatment. Rijeka and Shanghai: InTech. 2012;18:111-32.
96.Syed A, Devi VK. Potential of targeted drug delivery systems in treatment of rheumatoid arthritis. Journal of Drug Delivery Science and Technology. 2019;1;53:101217.
97.Wang Q , Sun X. Recent advances in nanomedicines for the treatment of rheumatoid arthritis. Biomaterials science. 2017;5(8):1407-20.
98.Wang D, Miller SC, Liu XM, Anderson B, Wang XS, Goldring SR. Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis. Arthritis research & therapy. 2007;9(1):1-9.
99.Liu XM, Quan LD, Tian J, Laquer FC, Ciborowski P,Wang D. Syntheses of click PEG−dexamethasone conjugates for the treatment of rheumatoid arthritis. Biomacromolecules. 2010;11(10):2621-2628.
100.Li Q , Cao J, Li Z, Chu X. Cubic liquid crystalline gels based on glycerol monooleate for intra-articular injection. AAPS PharmSciTech. 2018;19(2):858-65.
101.Junkai Zhao, Xuan Chen, Kwun-Hei Ho, Chao Cai, Cheuk-Wing Li, Mo Yang, Changqing Yi. Nanotechnology for diagnosis and therapy of rheumatoid arthritis: Evolution towards theranostic approaches. Chinese Chemical Letters, 2021;32(1): 66-86.
102.Yang H, Tang C, Yin C. Estrone-modified pH-sensitive glycol chitosan nanoparticles for drug delivery in breast cancer. Acta biomaterialia. 2018;73:400-11.
103.Vigderman L, Zubarev ER. Therapeutic platforms based on gold nanoparticles and their covalent conjugates with drug molecules. Advanced drug delivery reviews. 2013;65(5):663-76.
104.Jeong EH, Jung G, Am Hong C, Lee H. Gold nanoparticle (AuNP)-based drug delivery and molecular imaging for biomedical applications. Archives of pharmacal research. 2014;37(1):53-9.
105.James LR, Xu ZQ , Sluyter R, Hawksworth EL, Kelso C, Lai B, Paterson DJ, de Jonge MD, Dixon NE, Beck JL, Ralph SF. An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase. Journal of inorganic biochemistry. 2015 1;142:28-38.
106.Lee SM, Kim HJ, Ha YJ, Park YN, Lee SK, Park YB, Yoo KH. Targeted chemo-photothermal treatments of rheumatoid arthritis using gold half-shell multifunctional nanoparticles. ACS nano. 2013; 22;7(1):50-7.
107.Lee H, Lee MY, Bhang SH, Kim BS, Kim YS, Ju JH, Kim KS, Hahn SK. Hyaluronate-gold nanoparticle/ tocilizumab complex for the treatment of rheumatoid arthritis. ACS Nano. 2014;8(5):4790-8.
108.Pirmardvand CS, Varshosaz J, & Taymouri S. Recent approaches for targeted drug delivery in rheumatoid arthritis diagnosis and treatment. Artificial cells, nanomedicine, and biotechnology. 2018;46(sup2):502-514.
109.Wang WX, Feng SS, Zheng CH. A comparison between conventional liposome and drug-cyclodextrin complex in liposome system. International journal of pharmaceutics. 2016;513(1-2):387-92.
110.Mastrotto F, Brazzale C, Bellato F, De Martin S, Grange G, Mahmoudzadeh M, Magarkar A, Bunker A, Salmaso S, Caliceti P. In vitro and in vivo behavior of liposomes decorated with PEGs with different chemical features. Molecular pharmaceutics. 2019;17(2):472-87.
111.Corvo ML, Boerman OC, Oyen WJG, et al. Intravenous administration of superoxide dismutase entrapped in long circulating liposomes II. In vivo fate in a rat model of adjuvant arthritis. BBA Membranes. 1999;1419:325-334
112.Wang Q , He L, Fan D, Liang W, Fang J. Improving the anti-inflammatory efficacy of dexamethasone in the treatment of rheumatoid arthritis with polymerized stealth liposomes as a delivery vehicle. Journal of Materials Chemistry B. 2020;8(9):1841-51.
113.Meka RR, Venkatesha SH, Acharya B, Moudgil KD. Peptide-targeted liposomal delivery of dexamethasone for arthritis therapy. Nanomedicine. 2019;14(11):1455-69.
114.Zhong, S.; Liu, P.; Ding, J.; Zhou, W. Hyaluronic Acid-Coated MTX-PEI Nanoparticles for Targeted Rheumatoid Arthritis Therapy. Crystals. 2021;11:321.
115.Wang Q , Jiang J, Chen W, Jiang H, Zhang Z, Sun X. Targeted delivery of low-dose dexamethasone using PCL–PEG micelles for effective treatment of rheumatoid arthritis. Journal of Controlled Release. 2016;230:64-72.
116.Bader RA, Silvers AL, Zhang N. Polysialic acid-based micelles for encapsulation of hydrophobic drugs. Biomacromolecules. 2011;12(2):314-20.
117.Wilson DR, Zhang N, Silvers AL, Forstner MB, Bader RA. Synthesis and evaluation of cyclosporine A-loaded polysialic acid–polycaprolactone micelles for rheumatoid arthritis. European Journal of Pharmaceutical Sciences. 2014;51:146-56.
118.Crielaard BJ, Rijcken CJ, Quan L, Van Der Wal S, Altintas I, Van Der Pot M, Kruijtzer JA, Liskamp RM, Schiffelers RM, Van Nostrum CF, Hennink WE. Glucocorticoid-loaded core-cross-linked polymeric micelles with tailorable release kinetics for targeted therapy of rheumatoid arthritis. Angewandte Chemie. 2012;124(29):7366-70.
119.Li C, Li H, Wang Q , Zhou M, Li M, Gong T, Zhang Z, Sun X. pH-sensitive polymeric micelles for targeted delivery to inflamed joints. Journal of Controlled Release. 2017;246:133-41
120.Wang Y, Liu Z, Li T, Chen L, Lyu J, Li C, Lin Y, Hao N, Zhou M, Zhong Z. Enhanced therapeutic effect of RGD-modified polymeric micelles loaded with low-dose methotrexate and nimesulide on rheumatoid arthritis. Theranostics. 2019;9(3):708.
Written By
Largee Biswas, Vikas Shukla, Vijay Kumar and Anita Kamra Verma
Submitted: 17 May 2021Reviewed: 24 July 2021Published: 31 August 2021
Open access peer-reviewed chapter
