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  • Review Article
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Trojan horses and guided missiles: targeted therapies in the war on arthritis

Nature Reviews Rheumatology volume 11, pages 328–337 (2015)Cite this article

Subjects

Key Points

  • Systemic drug administration often results in off-site, on-target activity as well as amplification of off-target effects, with increased risk of adverse events

  • Active targeting to deliver therapeutic agents to disease-affected tissues is being developed as a modality to promote in situ drug activity and decrease systemic toxicity

  • Drug encapsulation within nanoparticles is a useful approach to provide protection from degradation and activation in the circulation and to reduce systemic activity

  • Antibodies are powerful targeting agents as both stand-alone therapeutics or as delivery methods to specifically direct drug conjugates to sites of active disease

  • The development of novel drugs with targeting and multi-specific properties will improve therapeutic indexes and could represent the next generation of RA therapeutics

Abstract

Despite major advances in the treatment of rheumatoid arthritis (RA) led by the success of biologic therapies, the lack of response to therapy in a proportion of patients, as well as therapy discontinuation owing to systemic toxicity, are still unsolved issues. Unchecked RA might develop into progressive structural joint damage, loss of function and long-term disability, disorders which are associated with a considerable health–economic burden. Therefore, new strategies are required to actively target and deliver therapeutic agents to disease sites in order to promote in situ activity and decrease systemic toxicity. Polymer–drug conjugates can improve the pharmacokinetics of therapeutic agents, conferring desirable properties such as increased solubility and tissue penetration at sites of active disease. Additionally, nanotechnology is an exciting modality in which drugs are encapsulated to protect them from degradation or early activation in the circulation, as well as to reduce systemic toxicity. Together with the targeting capacity of antibodies and site-specific peptides, these approaches will facilitate selective accumulation of therapeutic agents in the inflamed synovium, potentially improving drug efficacy at disease sites without affecting healthy tissues. This Review aims to summarize key developments in the past 5 years in polymer conjugation, nanoparticulate drug delivery and antibody or peptide-based targeting—strategies that might constitute the platform for the next generation of RA therapeutics.

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Figure 1: History of technological advances leading to the development of targeted NPs, PDCs and targeted biologic agents.
Figure 2: 'Trojan horse' approaches for drug delivery.
Figure 3: 'Guided missile' approaches for drug delivery.

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Acknowledgements

The authors would like to acknowledge The Nuffield Foundation (Oliver Bird PhD Studentship to M.F.) and Arthritis Research UK (Project Grant 20062).

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  1. Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, John Vane Building, Charterhouse Square, London, EC1M 6BQ, UK

    Mathieu Ferrari, Shimobi C. Onuoha & Costantino Pitzalis

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Contributions

M.F. and S.C.O. contributed equally to the research of data for the article; all authors contributed substantially to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Costantino Pitzalis.

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Competing interests

C.P. is the inventor in a patent regarding single-chain variable fragment A7, and an inventor in a patent regarding the synovium-targeting peptide 3.1. The other authors declare no competing interests.

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Ferrari, M., Onuoha, S. & Pitzalis, C. Trojan horses and guided missiles: targeted therapies in the war on arthritis. Nat Rev Rheumatol 11, 328–337 (2015). https://doi.org/10.1038/nrrheum.2015.17

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