Targeted Delivery of Chloroquine to Antigen-Presenting Cells Enhances Inhibition of the Type i Interferon Response

Marilyn E. Allen, Amit Golding, Violeta Rus, Nicholas B. Karabin, Sophia Li, Chamille J. Lescott, Sharan Bobbala, Evan A. Scott, Gregory L. Szeto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid dendritic cells (pDCs) via toll-like receptors (TLRs), contributing to disease pathogenesis by driving the secretion of inflammatory type I interferons (IFNs). Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ∼3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use, resulting in retinopathy. We hypothesized that poly(ethylene glycol)-b-poly(propylene sulfide) filamentous nanocarriers, filomicelles (FMs), could directly deliver CQ to pDCs via passive, morphology-based targeting to concentrate drug delivery to specific immune cells, improve drug activity by increased inhibition of type I IFN, and enhance efficacy per dose. Healthy human peripheral blood mononuclear cells were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN-α ELISA and MX1 gene expression using real-time reverse transcription-quantitative polymerase chain reaction. Our results showed that 50 μg CQ/mg FM decreased MX1 expression and IFN-α production after TLR activation with either synthetic nucleic acid agonists or immune complex-rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs and monocytes in vitro and in tissues frequently damaged in SLE patients (i.e., kidneys), while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.

Original languageEnglish (US)
Pages (from-to)5666-5677
Number of pages12
JournalACS Biomaterials Science and Engineering
Volume7
Issue number12
DOIs
StatePublished - Dec 13 2021

Keywords

  • antimalarial drugs
  • drug delivery
  • monocytes
  • nanocarriers
  • plasmacytoid dendritic cells
  • systemic lupus erythematosus
  • type I interferon

ASJC Scopus subject areas

  • Biomedical Engineering
  • Biomaterials

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