Despite recent advances in the treatment of rheumatoid arthritis (RA) attributed to biologic medications, only a minority of patients achieve and maintain disease remission without the need for continuous immunosuppressive therapy.1 Complicating the treatment of RA further is the development of tolerance over time or failure of patients to respond to currently available therapies.1 Thus, the development of new treatment strategies for RA remains a priority.

Nanotherapies for RA have received increasing attention in the past decade because they offer several potential advantages compared with conventional systemic therapies.2 Nanocarriers are submicron transport particles designed to deliver the drug at the site of inflammation — the synovium — thereby maximizing its therapeutic effect and avoiding unwanted systemic adverse effects.1 This targeted drug delivery approach also has the potential to minimize the amount of drug required to control joint inflammation3 and increase local bioavailability by protecting it from degradation in the circulation.1

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In essence, nanotechnology enables the “redesign” of already effective rheumatologic medications into nanoformulations that may confer greater specificity, longer therapeutic effect, and more amenable safety profile.4 Nanoencapsulated nonsteroidal anti-inflammatory drugs (NSAIDs),5 liposomal and polymeric preparations of glucocorticoids,6 and nanosystems that directly inhibit angiogenesis are just several examples of nanotherapies that have been tested in experimental models of inflammatory arthritis.7

Despite the promising findings observed in studies to date, further development and subsequent integration of nanotherapies in the management of RA remains hampered by the lack of efficacy and toxicity studies in humans. In an interview with Rheumatology Advisor, Christine Pham, MD, chief of the Division of Rheumatology at the Washington University School of Medicine in St Louis, discussed the advantages and challenges of applying nanotherapies in RA.

Rheumatology Advisor: How can nanotechnology be applied in the treatment of RA?

Christine Pham, MD: Nanotechnology is a multidisciplinary approach aimed at the delivery of therapeutic agents using submicron nanocarriers. In RA, the vessels at the site of inflammation are leaky, allowing passage of these nanocarriers from the circulation to specific target sites in the joint environment.

Rheumatology Advisor: Which RA drugs are suitable for this approach?

Dr Pham: Many conventional antirheumatic drugs such as methotrexate, glucocorticoids, and NSAIDs have been successfully delivered by nanocarriers to mitigate inflammatory arthritis in experimental models.

Rheumatology Advisor: What are the main advantages of using nanotherapy/nanocarriers, as opposed to systemic therapy, in the treatment of RA?

Dr Pham: The main advantages are selective drug delivery to desired sites of action through passive or active targeting, which can lead to increased local bioavailability and potentially can reduce unwanted off-target side effects. In addition, nanocarriers may increase the solubility of certain drugs and protect therapeutics against degradation in the circulation.

Rheumatology Advisor: How far has the medical community gotten in developing (and testing) nanotherapies for RA? Which nanotherapies have shown the most promise?

Dr Pham: A number of nanotherapeutics have been developed and tested in animal models of RA. Most have shown disease mitigation, however, none has so far made it to the clinic.

Rheumatology Advisor: What needs to happen before nanotherapies can get fully integrated into clinical practice and treatment of patients with RA?

Dr Pham: Insufficient data regarding long-term toxicity and optimal therapeutic efficacy have hampered their integration into clinical practice. Anticytokine biologics have been very successful, so nanotherapeutics need to show clearly that they have higher efficacy and lower toxicity for pharmaceutical companies to invest in their development for the clinic.


Rheumatology Advisor
: Are any other promising treatment strategies for RA currently under investigation?

Dr Pham: RNA interference (RNAi) has recently emerged as a specific way to silence gene expression. The in vivo delivery of small interfering RNA (siRNA), however, remains a significant hurdle, given the short half-life of the molecule in the circulation. We have used a self-assembling peptide-based nanosystem that protects the siRNA from degradation when injected intravenously and which has shown to mitigate experimental RA.8,9 siRNA works by knocking down NFkappaB p65, a subunit of NF-kappa-B transcription complex which plays a central role in inflammation in general and in RA in particular. This platform promises to have real translational potential.

References

1. Pham CTN. Nanotherapeutic approaches for the treatment of rheumatoid arthritis. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2011;3(6):607-619.

2. Dolati S, Sadreddini S, Rostamzadek D, Ahmadi M, Jadidi-Niaragh F, Yousefi M. Utilization of nanoparticle technology in rheumatoid arthritis treatment. Biomed Pharmacother. 2016;80:30-41.

3. Rubinstein I, Weinberg GL. Nanomedicine for chronic non-infectious arthritis: the clinician’s perspective. Nanomedicine. 2012;8(Suppl 1):S77-S82.

4. Henderson CS, Madison AC, Shah A. Size matters – nanotechnology and therapeutics in rheumatology and immunology. Curr Rheumatol Rev. 2014;10(1):11-21.

5. Srinath P, Chary MG, Vyas SP, Diwan PV. Long-circulating liposomes of indomethacin in arthritic rats–a biodisposition study. Pharm Acta Helv. 2000;74:399-404.

6. Metselaar JM, Wauben MH, Wagenaar-Hilbers JP, Boerman OC, Storm G. Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. Arthritis Rheum. 2003;48:2059-2066.

7. Koo OM, Rubinstein I, Önyuksel H. Actively targeted low-dose camptothecin as a safe, long-acting, disease-modifying nanomedicine for rheumatoid arthritis. Pharm Res. 2011;28:776-787.

8. Zhou H-F, Yan H, Pan H, et al. Peptide-siRNA nanocomplexes targeting the NF-kB subunit p65 suppress nascent experimental arthritis. J Clin Invest. 2014;124:4363-4374.

9. Rai MF, Pan H, Yan H, Sandell L, Pham C, Wickline SA. Applications of RNA interference in the treatment of arthritis. Transl Res. 2019;214:1-16.