Immunosuppressive drugs such as cyclosporine A (CsA) are used for the treatment of various rheumatic diseases, including systemic lupus erythematosus (SLE), but their use is hampered by high non-response rates and adverse effects. Targeted delivery of immunosuppressant drugs could help overcome these issues, as shown in a new study published in Science Advances.
“Because CsA strongly inhibits T cell activation and proliferation, and the aetiology of SLE involves abnormal T cell and B cell hyperactivity, there has been a long and ongoing interest in using CsA as a treatment for SLE,” explains corresponding author Ravi Kumar. “However, current oral dosage forms of CsA are limited by two major drawbacks: poor bioavailability that necessitates elevated doses and severe nephrotoxicity that arises from the increased dosage.”
To address this issue, his group developed a drug delivery system composed of polyester nanoparticles conjugated to gambogic acid. “We showed that gambogic acid-conjugated nanoparticles are more than six times more likely to bind to T cells than unconjugated nanoparticles,” reports Kumar. “As T cells are the primary targets of CsA, having nanoparticles with high affinity for T cells might provide additional drug specificity and disposition to this cell type.”
In a mouse model of SLE, Kumar and colleagues tested the effects of nanoparticle-mediated delivery of CsA against treatment with a generic formulation of CsA. “We were entirely surprised to note that almost every inflammatory cytokine marker tested had been normalized by this nanoparticle–CsA formulation, leading to mice that had near wild-type physiological and anatomical characteristics,” says Kumar. By contrast, the generic formulation had negligible effects compared with no treatment, in line with current consensus for using CsA as a glucocorticoid-sparing therapy, rather than as a standalone treatment, in SLE.
“Immunosuppressive drugs … are … hampered by high non-response rates and adverse effects”
Kumar and his group would like to test this delivery system in other animal models, including elucidating the most effective dose and uncovering any associated toxicities, with the long-term aim of translating these findings to human efficacy studies.
Ganugula, R. et al. A highly potent lymphatic system–targeting nanoparticle cyclosporine prevents glomerulonephritis in mouse model of lupus. Sci. Adv. 6, eabb3900 (2020)
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McHugh, J. Targeted delivery of immunosuppressant in SLE. Nat Rev Rheumatol 16, 410 (2020). https://doi.org/10.1038/s41584-020-0462-9