Department of Chemistry, Bharatiya Jain Sanghatana’s Arts, Science and Commerce College, Pune
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by persistent synovial inflammation, progressive joint destruction, and significant disability. Conventional pharmacological interventions, including non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs), provide symptomatic relief and slow disease progression but are often limited by systemic toxicity, poor bioavailability, and non-specific tissue distribution. Targeted drug delivery systems (TDDS) have emerged as a transformative approach to overcome these limitations by enabling site-specific transport of therapeutics. Nanotechnology-based carriers—such as liposomes, micelles, dendrimers, and polymeric nanoparticles—facilitate controlled release, improve solubility of poorly water-soluble drugs, and exploit mechanisms such as receptor-mediated endocytosis and enhanced permeability and retention (EPR) effect. Furthermore, the integration of stimuli-responsive systems allows selective drug release within the inflamed joint microenvironment. These advancements not only enhance therapeutic efficacy but also reduce off-target side effects, thereby improving patient compliance. In addition, TDDS offer promising opportunities in theranostics, integrating diagnostic imaging with therapy, and in gene- and cell-based therapies for RA. Although translational challenges remain, including immunogenicity, large-scale manufacturing, and regulatory hurdles, the continued development of smart drug delivery platforms holds significant potential to redefine the future of RA management
The biological activity of a drug in a patient is governed by its pharmacological properties, which originate from the specific interaction of the drug molecule with its receptor at the site of action. However, the therapeutic efficacy of such drug–receptor interactions remains limited unless the drug can be delivered to the target site at an appropriate concentration and release rate that ensures maximal therapeutic benefit with minimal systemic toxicity.
Targeted drug delivery systems are designed to address this challenge. Their ultimate objective is to achieve spatiotemporal control of drug dosing at defined physiological sites—such as specific cells, tissues, or organs—while minimizing off-target exposure and associated side effects.
Conventional drug delivery relies predominantly on passive targeting mechanisms, such as the enhanced permeability and retention (EPR) effect. To enhance selectivity and therapeutic precision, drug carriers can be functionalized with specific ligands that selectively recognize and bind to overexpressed receptors on diseased cells. This transformation of passive targeting into ligand-mediated active targeting represents a major advancement in drug delivery science.
The primary rationale behind developing ligand-based targeted drug delivery systems is to reduce systemic toxicity, minimize adverse reactions commonly observed with traditional chemotherapy or small-molecule therapies, and thereby improve overall therapeutic efficacy and patient safety.
TARGETED DRUG DELIVERY SYSTEM
Targeted drug delivery, often referred to as a smart drug delivery system, is designed to transport therapeutic agents selectively to diseased sites while minimizing exposure to healthy tissues. Two principal strategies are employed: passive targeting, which exploits physiological phenomena such as the EPR effect, and active targeting, which utilizes ligand–receptor interactions to achieve higher specificity.
An ideal drug delivery system is capable of transporting drugs across biological barriers, including the blood–brain barrier (BBB), thereby enabling treatment of neurological disorders. In recent years, nanomedicine has had a transformative impact on drug delivery owing to advances in nanotechnology. Nanoparticles, by virtue of their ultrafine size, provide multiple advantages: they improve the solubility of hydrophobic drugs, enhance bioavailability, and can reduce hepatic first-pass metabolism.
Figure 1: Drug Targeted System
Furthermore, nanotechnology-enabled drug delivery systems extend the circulation time of therapeutic agents in the bloodstream. This pharmacokinetic modification reduces fluctuations in plasma drug concentration, thereby minimizing systemic toxicity and adverse effects while maintaining sustained therapeutic levels.
Targeted drug delivery systems encompass a wide range of nanotechnological platforms, including polymer–drug conjugates and nanoparticulate systems such as liposomes, quantum dots, and dendrimers. These nanoscale carriers provide enhanced stability, controlled release, and improved pharmacokinetics of therapeutic agents.
In addition to these platforms, advanced strategies involve the conjugation of therapeutic agents with targeting ligands. These ligands are specifically designed to recognize and bind to molecular markers or antigens that are overexpressed on tumor cells, thereby facilitating selective drug accumulation at the diseased site. Such ligand-mediated targeting not only enhances therapeutic efficacy but also reduces systemic toxicity by minimizing drug exposure to healthy tissues.
ADVANTAGES OF TARGETED DRUG DELIVERY
Rational for targeted drug delivery system
Figure 2: Review targeted drug delivery systems for norcantharidin in cancer therapy
Passive targeting
Passive drug targeting is primarily based on the deposition of therapeutic agents in regions surrounding the pathological site, such as tumor tissue. This phenomenon is known as the EPR effect, which exploits the leaky vasculature and poor lymphatic drainage characteristic of many solid tumors. The EPR effect is often observed with nanoscale drug delivery carriers, enabling preferential—but not truly selective—drug accumulation at diseased sites.
However, passive targeting is considered limited because it lacks receptor-specific selectivity. In fact, despite the EPR effect, the majority of systemically administered nanoparticles (up to 95%) tend to accumulate in organs of the reticuloendothelial system (RES), such as the liver, lungs, and spleen, rather than exclusively at the intended site. Consequently, drug distribution largely depends on systemic circulation and vascular permeability rather than precise molecular recognition.
Illustrative applications of passive targeting include the use of nanoparticle formulations of anti-malarial drugs for the management of infectious diseases such as leishmaniasis, candidiasis, and brucellosis, where drug localization occurs due to uptake by macrophages residing in infected tissues.
Active targeting
Ligand–receptor interactions in active drug targeting occur only after the therapeutic carrier has reached the vicinity of the target tissue through systemic circulation and extravasation. Active targeting specifically relies on these molecular recognition events, wherein a ligand conjugated to the carrier binds selectively to its corresponding receptor overexpressed on diseased cells.
Such interactions are feasible only when the ligand and receptor are brought into close spatial proximity, typically within a distance of less than ~0.5 mm. Thus, the effectiveness of active targeting is dependent on the carrier’s ability to first accumulate near the pathological site via blood flow and vascular extravasation.
At present, most drug delivery systems achieve localization at the target site primarily through circulation dynamics and passive accumulation, after which ligand–receptor interactions can enhance specificity and cellular uptake.
Ligand receptor-based interaction
A ligand is a general term used to describe a molecule that specifically interacts with a receptor located on the surface of a cell, tissue, or organ. Ligands constitute a highly diverse class of molecules, including small organic compounds, peptides, proteins, carbohydrates, nucleic acids (aptamers), and antibodies.
In the context of targeted drug delivery, ligands are of particular importance because they enable selective recognition of receptors that are overexpressed in diseased cells. The formation of a ligand–receptor complex is governed by precise molecular interactions that require structural complementarity between the ligand and the receptor’s binding domain. This high specificity provides the basis for active targeting, allowing drug carriers to deliver therapeutic agents directly to pathological sites while sparing healthy tissues.
Receptor used in ligand based drug targeting
1. Antigen: The utilization of tumor-associated antigens (TAAs) for antibody-based targeting represents one of the most extensively investigated strategies in anticancer drug delivery. The underlying principle is that many TAAs are expressed at significantly higher levels in malignant tissues compared to normal tissues, thereby providing a molecular basis for selective targeting.
Several tumor-associated antigens have been identified and characterized for this purpose. For example, the carcinoembryonic antigen (CEA), which is commonly overexpressed in gastrointestinal, lung, and breast cancers, was among the earliest antigens to be recognized and has since been widely exploited as a target in antibody-mediated drug delivery systems.
This approach forms the foundation of antibody–drug conjugates (ADCs) and other immunotherapeutic platforms, which harness the specificity of antibody–antigen recognition to improve drug localization, enhance therapeutic efficacy, and minimize off-target toxicity.
2. Cadharin: Cadherins are a family of glycoproteins that mediate Ca²?-dependent cell–cell adhesion, playing a critical role in maintaining tissue architecture and cellular integrity. Disruption of cadherin function compromises intercellular adhesion, facilitating the detachment and dissemination of tumor cells.
Experimental studies have demonstrated that the aggressive metastasis of undifferentiated epithelial carcinoma cells, which had lost cell–cell adhesion, could be inhibited by transfection with E-cadherin cDNA. This provided strong evidence that E-cadherin functions as a metastasis suppressor.
Subsequent investigations further supported this concept, showing that the loss of adhesion in human gastric, prostatic, and lung cancer cells was associated with mutations in genes encoding proteins essential for cadherin function. These findings underscore the pivotal role of cadherins in tumor suppression and highlight their importance as potential biomarkers and therapeutic targets in oncology.
3. Selectins: Selectins are a distinct class of cell adhesion molecules (CAMs) that facilitate carbohydrate-mediated binding during cell–cell interactions. They mediate adhesion by specifically recognizing carbohydrate ligands displayed on the surfaces of target cells.
Importantly, cell adhesion mediated by selectins is not attributed to a single ligand–receptor interaction but rather to the cumulative effect of multiple simultaneous interactions among carbohydrate moieties, a phenomenon referred to as polyvalency or the cluster effect. This multivalent binding significantly enhances both affinity and selectivity.
Two well-characterized examples of such interactions involve the tetrasaccharide glycolipids sialyl Lewis X (sLe?) and sialyl Lewis A (sLe?). These glycoconjugates are critical in regulating biological processes such as inflammation, ischemia–reperfusion injury, and tumor metastasis, where selectin–carbohydrate interactions contribute to leukocyte trafficking and cancer cell dissemination.
4. Integrins: The integrin family has emerged as a promising target for the development of receptor-specific cancer therapies. Integrins are heterodimeric transmembrane glycoproteins composed of non-covalently associated α (alpha) and β (beta) subunits, which combine in different pairings to generate functional receptors with diverse biological roles.
To date, 18 α-subunits and 8 β-subunits have been identified in humans, forming 24 distinct integrin heterodimers. These receptors regulate critical processes such as cell adhesion, migration, proliferation, survival, and angiogenesis. Importantly, aberrant integrin expression is closely associated with tumor progression, metastasis, and resistance to therapy, making them attractive molecular targets for ligand-mediated drug delivery and anticancer therapeutics.
5. Vitamin: Vitamins are indispensable for normal cellular metabolism, growth, and homeostasis. Under pathological conditions, vitamins and their transport pathways often play crucial roles in disease progression. Owing to their natural uptake mechanisms, cell surface vitamin receptors have been widely investigated as potential targets for drug delivery.
Most vitamins are internalized via receptor-mediated endocytosis, making them attractive candidates for ligand-directed targeting strategies. Several vitamins—including folic acid, riboflavin, biotin, and vitamin B6—have been evaluated as ligands for the selective delivery of therapeutic agents to diseased cells. Among these, folic acid has been particularly well-studied due to the frequent overexpression of folate receptors in various cancers, enabling efficient tumor-targeted delivery with minimal toxicity to normal tissues.
6. Transferin: Transferrin is a serum glycoprotein that plays a pivotal role in iron homeostasis by binding ferric ions (Fe³?) and transporting them into cells. Cellular uptake occurs through a highly specific receptor-mediated endocytosis pathway via the transferrin receptor (TfR).
While transferrin receptors are expressed on the surface of both proliferating and non-proliferating normal cells, their expression is markedly upregulated in tumor cells to meet the elevated iron demand required for rapid growth and DNA synthesis. Clinically, this is reflected in reduced circulating transferrin levels in cancer patients due to enhanced receptor-mediated uptake by malignant tissues.
Owing to this differential expression, transferrin has been extensively investigated as a targeting ligand for site-specific drug delivery. Conjugation of therapeutic agents or nanoparticles with transferrin enables selective accumulation in tumor cells, thereby improving therapeutic efficacy and reducing systemic toxicity.
7. Hormone: The overexpression of hormone receptors in hormone-sensitive cancers provides a valuable opportunity for the development of hormone-targeted drug delivery systems. This strategy exploits the natural affinity of hormones for their receptors to achieve selective delivery of therapeutic agents to malignant tissues.
Such an approach is particularly relevant in ovarian, endometrial, and breast cancers, where tumor initiation and progression are closely associated with increased expression of receptors for estrogen, progesterone, and other hormones. By coupling conventional chemotherapeutic drugs with hormone ligands or hormone analogs, drug delivery systems can be engineered to preferentially accumulate in hormone receptor–positive tumors, thereby enhancing therapeutic efficacy while reducing systemic toxicity.
APPLICATION OF LIGAND BASED DRUG TARGETING SYSTEM
Hepatocellular carcinoma: Hepatocellular carcinoma (HCC) represents the most prevalent primary liver malignancy and is associated with high morbidity and mortality worldwide. Conventional chemotherapeutic regimens exhibit limited efficacy due to multidrug resistance (MDR), rapid clearance, nonspecific biodistribution, severe systemic toxicities, and suboptimal intracellular drug accumulation. To overcome these limitations, nanoparticle-based targeted drug delivery systems (NTDDSs) have emerged as promising therapeutic platforms, capitalizing on enhanced permeability and retention (EPR) effects, as well as ligand-mediated active targeting strategies.
Active targeting in HCC is mediated by surface-functionalized ligands that specifically recognize and internalize into hepatocellular carcinoma cells through receptor-mediated endocytosis. Such systems improve cellular uptake, enhance drug accumulation at the tumor site, and minimize off-target effects. Tumor vasculature and intra-tumoral angiogenesis provide overexpressed molecular targets, including glycoproteins, polysaccharides, peptides, antibodies, aptamers, transferrin, vitamins, and growth factors, which have been successfully exploited to decorate nanocarriers and achieve precision therapy.
Once administered, nanoparticles can disperse into tumor tissue via feeding arteries and subsequently accumulate in the tumor interstitial fluid through vascular fenestrations by the EPR effect. However, specific ligand–receptor interactions are crucial for efficient endocytosis and intracellular drug release, thereby potentiating tumoricidal effects.
Among various ligands, vitamin-based targeting has gained significant attention, as tumor cells exhibit increased metabolic demands and consequently upregulate vitamin receptors on their surfaces. Folate (vitamin B9), biotin (vitamin B7), retinoic acid (RA), and dehydroascorbic acid (DHAA) are among the most studied ligands. Folate receptor–mediated endocytosis, in particular, is a high-affinity mechanism extensively utilized in nanomedicine, given the inability of mammalian cells to synthesize folates de novo.
Figure 3: Ligand based targeting
Functionalized Protocells and Ligand-Based Targeting Approaches: A functionalized protocell represents a modular nanocarrier design in which a tumor-targeting ligand, such as an antibody fragment (e.g., single-chain variable fragment, scFv) or peptide, is conjugated onto a supported lipid bilayer encapsulating a mesoporous silica core loaded with therapeutic agents. This architecture allows simultaneous structural stability, drug protection, and selective tumor recognition. Importantly, such protocells can be customized for a specific cancer subtype or therapeutic regimen by varying either the targeting ligand or the therapeutic payload. Moreover, their adaptability permits integration of both diagnostic and therapeutic functionalities, creating theranostic platforms.
Peptide-based targeting has also shown considerable promise. For example, tumor-homing peptides derived from luteinizing hormone/chorionic gonadotropin (LH/CG) have been conjugated with membrane-disrupting lytic peptides to achieve effective inhibition of tumor growth and metastasis in breast and prostate cancer xenograft models. Such ligand–drug conjugates exploit receptor-mediated endocytosis and selective tumor receptor overexpression for enhanced efficacy and minimized systemic toxicity.
Beyond peptides and antibodies, aptamers—short, single-stranded RNA or DNA oligonucleotides—have been developed as highly specific targeting ligands. Aptamers possess unique three-dimensional folding patterns that confer high affinity and specificity toward their target receptors.
Folate and Transferrin Receptor-Mediated Targeting in Cancer Therapy: The folate receptor (FR, pteroylmonoglutamate receptor) is a well-characterized tumor biomarker that binds folic acid and folate–drug conjugates with high affinity, subsequently internalizing these molecules into cells via receptor-mediated endocytosis. Clinical and histopathological investigations have reported FR expression in approximately 53% of head and neck primary and malignant tumor tissues, whereas normal tissues such as bone marrow exhibit negligible or no expression. This tumor-selective overexpression has been exploited for targeted chemotherapy.
A notable example is the development of a folate receptor–targeted nanoparticle formulation of paclitaxel using heparin as a carrier, termed heparin–folate–Taxol (HFT). Preclinical evaluation in nude mouse xenograft models demonstrated that HFT nanoparticles exhibited significantly greater antitumor efficacy compared to binary heparin–Taxol conjugates or free paclitaxel. Furthermore, HFT was effective even against paclitaxel-resistant KB tumor derivatives, underscoring the therapeutic potential of folate receptor–mediated targeting in overcoming drug resistance.
Figure 4: folate receptor-mediated transporters in cancer therapy
Similarly, the transferrin receptor (TfR) has been extensively investigated as a target for selective drug delivery. Transferrin, a serum glycoprotein responsible for iron transport, binds to TfR and undergoes clathrin-mediated endocytosis. Importantly, TfR is markedly overexpressed in various tumor tissues relative to normal tissues, making it a valuable ligand for tumor-specific drug targeting.
For instance, transferrin-conjugated paclitaxel-loaded nanoparticles formulated with poly(lactic-co-glycolic acid) (PLGA) displayed superior inhibition of cancer cell proliferation compared to free paclitaxel in both MCF-7 breast cancer cells and their drug-resistant variant (MCF-7/Adr). In another application, transferrin-functionalized liposomes were engineered to deliver the tumor suppressor gene p53, significantly enhancing gene transfection efficiency and sensitizing tumor xenografts to ionizing radiation therapy.
Collectively, folate and transferrin receptor–mediated targeting exemplifies robust strategies for achieving tumor-selective delivery, overcoming multidrug resistance, and potentiating the effects of conventional chemotherapy and radiotherapy.
INTERNALIZATION OF NANOPARTICLE VIA RECEPTOR MEDIATED ENDOCYTOSIS
Arthritis and Rheumatoid Arthritis (RA)
Arthritis is broadly defined as an inflammatory disorder of the joints, clinically manifested by pain, swelling, stiffness, and reduced mobility. The spectrum of arthritic diseases encompasses several subtypes that may be classified as inflammatory, metabolic, degenerative, or infectious in origin. These pathological conditions not only affect the joints but also extend to surrounding connective tissues, including bone, cartilage, muscle, and skin, thereby compromising structural and functional integrity.
Among these, rheumatoid arthritis (RA) is the most prevalent form of chronic inflammatory arthritis. RA is characterized by persistent synovial inflammation, leading to synovial hyperplasia driven by the infiltration of activated immune cells (e.g., T cells, B cells, macrophages, and dendritic cells). The sustained inflammatory milieu subsequently results in the progressive degradation of articular cartilage and bone, ultimately causing joint deformity, disability, and systemic complications.
Nanocarrier-Based and Polymer-Drug Conjugate Strategies for Rheumatoid Arthritis Therapy
Polymer backbones serve as versatile scaffolds for the attachment of therapeutic agents, solubilizers, and targeting moieties. Among nanocarrier systems, liposomes, micelles, metallic nanoparticles, and polymeric nanoparticles represent the most extensively utilized platforms for drug delivery. The cellular internalization of therapeutic payloads from such carriers typically occurs via fluid-phase endocytosis, adsorptive endocytosis, or receptor-mediated endocytosis.
An ideal nanocarrier system is designed to selectively respond to microenvironmental cues unique to diseased tissues, such as elevated enzyme activity, acidic pH, or oxidative stress. This has led to the development of stimuli-responsive drug delivery systems, which are currently being investigated for the treatment of rheumatoid arthritis (RA).
Several polymer–drug conjugates have been engineered to improve the therapeutic efficacy of conventional disease-modifying antirheumatic drugs (DMARDs) and biologics. Interestingly, many of these conjugates were originally developed for oncology and have since been repurposed for RA management. Methotrexate, for example, has been widely investigated in polymer-conjugated formulations for enhanced stability and targeted delivery.
Liposome-based systems have demonstrated promising results in both preclinical and clinical contexts. For instance, technetium-labeled liposomes exhibited selective accumulation within synovial tissue following intravenous administration in RA patients. Similarly, phosphatidylcholine- and cholesterol-based liposomes in arthritic rat models facilitated efficient drug encapsulation. Encapsulation of clodronate, a bisphosphonate with anti-inflammatory properties that reduces bone resorption, effectively halted disease progression and reversed inflammation.
Repurposing anticancer agents for RA has also shown promise. Camptothecin, initially developed as a chemotherapeutic, has been investigated as a novel therapeutic approach for inhibiting pannus formation and preventing cartilage degradation. To address solubility and stability limitations, PEG–phospholipid micelles were employed for camptothecin encapsulation. These camptothecin-loaded micelles displayed superior anti-inflammatory effects compared to free camptothecin in arthritic mouse models.
Similarly, cyclosporine A, a potent immunosuppressant indicated for multiple autoimmune conditions, has been extensively studied using micelle-based delivery systems to enhance solubility and therapeutic index.
The versatility of nanocarriers also enables multifunctional platforms, capable of simultaneous delivery of multiple therapeutics or integration of theranostic functionalities (combined drug delivery and diagnostic imaging).
Beyond small-molecule drugs, gene therapy approaches are being explored in RA treatment. Here, nucleic acids are introduced into target cells to silence pathogenic genes (e.g., pro-inflammatory cytokines) or upregulate protective genes, representing a promising alternative to conventional pharmacotherapy.
Figure 5: Ringsdorf’s model of polymer-drug conjugate
Figure 6: Various polymer articutectures
Figure 7: Various nanoparticulate carrier systems
TOLL-LIKE RECEPTORS IN RHEUMATOID ARTHRITIS PATHOGENESIS
An increasing body of evidence implicates the innate immune system as a central contributor to the pathogenesis of rheumatoid arthritis (RA). Among its components, Toll-like receptors (TLRs) have emerged as critical mediators. These pattern recognition receptors are expressed by multiple cell types within the inflamed synovium of RA patients and are activated not only by microbial pathogens but also by a variety of endogenous ligands.
Upon exposure to immunogenic stimuli, TLRs initiate the inflammatory cascade by activating innate immune cells such as monocytes, macrophages, and dendritic cells. Several studies have identified potential endogenous TLR ligands within RA synovial tissue, including fibrinogen, heat shock proteins (HSP60, HSP70), and the extra domain A (EDA) of fibronectin. These molecules are released as a consequence of ongoing inflammation in early RA and may sustain the cycle of synovial hyperplasia and tissue destruction.
In genetically susceptible individuals, particularly those carrying the shared epitope HLA-DR alleles, the initial immunological insult may be triggered by immune complexes containing anti-cyclic citrullinated peptide (anti-CCP) antibodies. These pathogenic immune complexes, in concert with endogenous danger-associated molecular patterns (DAMPs) such as gp96, amplify TLR activation and propagate a self-perpetuating inflammatory loop.
This persistent stimulation drives the release of pro-inflammatory cytokines, notably tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are central to RA pathophysiology. In addition, non-apoptotic Fas–FasL signaling may reduce the threshold for macrophage and fibroblast activation, further sensitizing them to TLR-mediated signals. The presence of low-level interferon-γ (IFN-γ) can potentiate this sensitization, creating a local synovial microenvironment conducive to sustained inflammation.
Collectively, these mechanisms establish a “perfect storm” of chronic inflammation in RA, characterized by persistent macrophage activation, cytokine overproduction, and progressive joint destruction.
DRUGS USED IN RA
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Rheumatoid Arthritis Management
NSAIDs are commonly employed in the early stages of RA to alleviate pain and reduce inflammation, thereby helping to preserve joint function. The pharmacological mechanism of NSAIDs involves the inhibition of cyclooxygenase isoenzymes (COX-1 and COX-2), which catalyze the conversion of arachidonic acid into prostaglandins (PGs). Since prostaglandins play a pivotal role in mediating pain, vasodilation, and inflammatory responses, their suppression accounts for the symptomatic relief provided by NSAIDs.
However, despite their efficacy in pain reduction, NSAIDs do not modify disease progression or prevent long-term articular destruction. Consequently, they are generally prescribed as adjunctive agents alongside disease-modifying antirheumatic drugs (DMARDs), which target the underlying immunopathology of RA.
NSAID therapy is associated with a range of adverse effects. Gastrointestinal (GI) complications—including dyspepsia, peptic ulceration, and GI bleeding—arise from COX-1 inhibition and reduced prostaglandin-mediated mucosal protection. NSAIDs may also induce renal dysfunction, impairing glomerular filtration and electrolyte balance. Furthermore, chronic NSAID use has been linked to increased cardiovascular risk, partly through mechanisms involving altered prostacyclin–thromboxane balance and effects on blood pressure regulation.
For these reasons, NSAIDs are typically administered at the lowest effective dose for the shortest possible duration, with careful clinical monitoring of gastrointestinal, renal, and cardiovascular parameters to minimize toxicity.
Glucocorticoids in Rheumatoid Arthritis Therapy
Glucocorticoids (GCs), such as dexamethasone and prednisolone, are potent anti-inflammatory and immunoregulatory agents that can provide rapid relief of joint inflammation in rheumatoid arthritis (RA). Due to their strong efficacy, they are often employed as first-line therapeutic agents, particularly in cases of acute disease exacerbation.
However, the systemic administration of glucocorticoids is limited by their substantial adverse effect profile, especially with long-term or repeated use. Chronic glucocorticoid therapy is associated with metabolic disturbances (insulin resistance, obesity), dermatological complications (skin thinning, impaired wound healing), and skeletal effects (osteoporosis). Additionally, glucocorticoids can contribute to hypertension and increased cardiovascular risk. Despite these limitations, epidemiological data indicate that approximately 44–75% of RA patients continue to use glucocorticoids during the course of their disease.
Interestingly, evidence from multiple clinical studies suggests that low-dose glucocorticoid therapy may exert disease-modifying effects in RA, beyond symptomatic relief. For example, low-dose prednisolone, when combined with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, has been shown to significantly attenuate disease progression, reducing both synovial inflammation and structural joint damage.
Thus, while glucocorticoids remain a cornerstone of RA management due to their rapid onset of action, their use requires a risk–benefit balance, with preference for short-term administration and the lowest effective dose to minimize toxicity while leveraging potential disease-modifying benefits.
Disease-Modifying Antirheumatic Drugs (DMARDs)
The term DMARDs was first introduced in the late 1980s to describe therapeutic agents with specific antirheumatic activity. Because their clinical benefits typically appear only after 1–6 months of continuous treatment, they are also referred to as “slow-acting antirheumatic drugs.”
Unlike NSAIDs and glucocorticoids, which primarily relieve pain and inflammation without altering disease progression, DMARDs directly modify the course of rheumatoid arthritis (RA) by reducing or preventing joint destruction. However, they do not provide immediate pain relief or strong anti-inflammatory effects, and are therefore often used in combination with NSAIDs or glucocorticoids in the early stages of RA.
Response to DMARD therapy is heterogeneous: while approximately two-thirds of patients achieve favorable clinical outcomes, the remaining one-third require alternative treatment strategies.
Among available agents, methotrexate (MTX) is the most widely prescribed and considered the first-line DMARD for more than two decades. Its popularity stems from its:
The exact mechanism underlying methotrexate’s antirheumatic activity remains incompletely understood. Traditionally, it has been attributed to antimetabolic effects via inhibition of purine synthesis, leading to reduced lymphocyte proliferation. More recently, the extracellular release of adenosine, a potent endogenous anti-inflammatory mediator, has been proposed as a major mechanism of methotrexate’s efficacy in RA.
CONCLUSION
Targeted drug delivery represents a transformative strategy in the management of rheumatoid arthritis. By enabling site-specific delivery of therapeutics, these systems minimize systemic exposure, reduce toxic side effects, and enhance therapeutic efficacy. While NSAIDs, glucocorticoids, and conventional DMARDs remain mainstays of RA treatment, their use is limited by non-specific organ toxicity and treatment discontinuation in some patients.
The integration of nanotechnology-based carriers and stimuli-responsive systems has provided innovative solutions that not only improve drug selectivity but also open new avenues for diagnostic imaging, gene therapy, and personalized medicine. Although challenges remain, the continued advancement of targeted drug delivery strategies offers the potential to redefine RA therapy, ensuring better disease control and improved quality of life for patients worldwide.
REFERENCES
Dr. Veerendra Yadav, Ligand–Receptor Guided Drug Delivery for Chronic and Inflammatory Diseases, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 9, 1882-1895. https://doi.org/10.5281/zenodo.17141669
10.5281/zenodo.17141669
