Combining nanotechnology with monoclonal antibody drugs for rheumatoid arthritis treatments

Abstract

Rheumatoid arthritis (RA) is a systemic immune disease characterized by synovial inflammation. Patients with RA commonly experience significant damage to their hand and foot joints, which can lead to joint deformities and even disability. Traditional treatments have several clinical drawbacks, including unclear pharmacological mechanisms and serious side effects. However, the emergence of antibody drugs offers a promising approach to overcome these limitations by specifically targeting interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and other cytokines that are closely related to the onset of RA. This approach reduces the incidence of adverse effects and contributes to significant therapeutic outcomes. Furthermore, combining these antibody drugs with drug delivery nanosystems (DDSs) can improve their tissue accumulation and bioavailability.Herein, we provide a summary of the pathogenesis of RA, the available antibody drugs and DDSs that improve the efficacy of these drugs. However, several challenges need to be addressed in their clinical applications, including patient compliance, stability, immunogenicity, immunosupression, target and synergistic effects. We propose strategies to overcome these limitations. In summary, we are optimistic about the prospects of treating RA with antibody drugs, given their specific targeting mechanisms and the potential benefits of combining them with DDSs.

Keywords: Antibody drugs; Drug delivery nanosystem; Rheumatoid arthritis.

Fig. 1

Pathogenesis of rheumatoid arthritis. The occurrence of rheumatoid arthritis (RA) is attributed to the activation of immune cells such as T cells, B cells, macrophages, and dendritic cells. B cells release rheumatoid factor (RF), and dendritic cells differentiate into osteoclasts, leading to bone erosion. T cells secrete receptor activator for nuclear factor-κ B ligand (RANKL) and activate osteoclasts, resulting in cartilage destruction. The overproduction of matrix metalloproteinases (MMPs) by fibroblast-like synoviocytes (FLSs) is also a critical factor in cartilage damage. Excessive immune complex activates the complement system and mediates the invasion process of inflammation. Additionally, interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) not only cause the accumulation of inflammation at joints but also systemic inflammation. Abbreviation:TNF: tumor necrosis factor; IL-1: interleukin 1; IL-6: interleukin 6; FLSs: fibroblast-like synoviocytes; MMPS: matrix metalloproteinases; RF: rheumatoid factor; RANKL: receptor activator for nuclear factor-κ B ligand;M-CSF:macrophage-stimulating factor;ACPA:Anti-citrullinated peptide antibodies

Fig. 2

Current drugs used to treat rheumatoid arthritis. There are several treatment strategies available for rheumatoid arthritis, including non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs), and antibody drugs. While NSAIDs can effectively reduce pain in patients, they have no influence on the progress of the disease and do not reduce cartilage damage. Glucocorticoids can rapidly reduce pain, but their usage is limited due to serious side effects, particularly in elderly and pediatric patients. Antibody drugs have clear targets and can reduce inflammation at the lesion, reducing bone and joint injury, and clearing immune complexes and cytokines. However, long-term usage may cause drug tolerance problems. Abbreviation: NASIDS: Non-steroidal anti-inflammatory drugs; GCs: Glucocorticoids; DMARDs: Disease-modifying anti-rheumatic drugs

Fig. 3

Nanocarriers applied to load drugs. Some nanocarriers can be utilized to overcome the limitations of antibody drugs and enhance their therapeutic efficacy. For instance, micelles are easily to functionalize, which can improve drug targeting. Dendrimers have a large specific surface area, which enhances drug loading capacity and promotes effective drug distribution. Gold nanoparticles are capable of tunable size, photothermal conversion and high biocompatibility, making them useful in combination therapy. Nanogels have revolutionized the way of administration of conventional antibody drugs, since they can be applied directly to the skin surface, thereby improving patient compliance. Albumin, an endonegous protein, dispalys high safety and compatibility. Loading antibody drugs with it can enhance their affinity and reduce adverse reactions

Fig. 4

HA-GNP-TCZ targets both VEGF and IL-6R [104].Reprinted from Lee H, Lee MY, Bhang SH, et al. Hyaluronate-gold nanoparticle/tocilizumab complex for the treatment of rheumatoid arthritis. The dual-targeted HA-GNP-TCZ complex was developed to simul-taneously bind VEGF and IL-6R to treat RA. The combination between AuNP and VEGF demonstrated brilliant antiangiogenic effect on RA. TCZ, an immunosuppressive drug, interferes with IL-6 during the pathogenesis of RA. Hyaluronic acid is widely used for cartilage protection and lubrication. This compound alleviates the immune disorder at the joint, and ultimately achieves the therapeutic response of reduced excessive cytokines and repaired cartilage. Abbreviation:TCZ: Tocilizumab ; VEGF:vascular endothelial growth factor; AuNPs:Gold nanoparticles; IL-6:interleukin 6.ACS Nano. 2014;8(5):4790–4798. https://creativecommons.org/licenses/by/4.0/0.44.

Fig. 5

After MNs arrive at the body, etanercept blocks the TNF-α-to-TNF receptor [80]. The microneedle system is applied to the skin on the back of mice, and etanercept (EN) is released from the system and absorbed by the capillaries in the surrounding tissue. In arthritic tissue, EN combines with TNF-α receptors and blocks TNF-α-mediated pathway to exhibit therapeutic potential. Reprinted from Cao J, Zhang N, Wang Z, et al. Microneedle-Assisted Transdermal Delivery of Etanercept for Rheumatoid Arthritis Treatment. Pharmaceutics. 2019;11(5):235.https://creativecommons.org/licenses/by/4.0/0.44.