Improved antimalarial delivery to inflammatory cells driving lupus pathogenesis using shape-based targeting nanoparticles

• Published in: The Journal of immunology (1950) Vol. 202; no. 1_Supplement; pp. 132 - 132.15
• Main Authors: Allen, Marilyn, Karabin, Nicholas, Golding, Amit, Scott, Evan, Szeto, Gregory
• Format: Journal Article
• Language: English
• Published: 01.05.2019
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.202.Supp.132.15

Abstract Systemic lupus erythematosus (SLE) is a chronic disease that attacks healthy organs via self antigen-autoantibody immune complexes. These complexes activate plasmacytoid dendritic cells (pDCs) via (toll-like receptor) TLR7 and 9, driving inflammatory type I interferon (IFN). Antimalarials, hydroxychloroquine (HCQ) and chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE patients, but require ~3+ months before therapeutic efficacy. Recent work reports 7.5% patients treated with HCQ are at risk of irreversible retinopathy after 5 years, which increases to 1 in 5 patients with duration of therapy. We hypothesized that PEG-b-PPS filomicelles (FMs) will improve drug activity and reduce toxicity by directly delivering HCQ or CQ to pDCs via passive, shape-based targeting. Human peripheral blood mononuclear cells (hPBMCs) were treated with soluble CQ or CQ in FMs, stimulated with CpG-A ODN 2216 and quantified for type I IFN via myxovirus-resistance 1 (MX1) gene expression using real-time RT-PCR. Our results show that 50 μg CQ/mg FM decreased MX1 expression 20 fold to soluble CQ and 10 fold to CpG-A ODN 2216 control, while CQ in control polymer PLGA spheres had no effect. Additionally, cellular-level distribution of FMs in hPBMCs show that FMs accumulate in pDCs more than B and T cells over a 48 hour time course. These results show polymer shape impacts drug delivery, CQ-FMs inhibit SLE-relevant pathways and CQ-FMs may be effective and more targeted than CQ.