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Lookup NU author(s): Professor Moein MoghimiORCiD
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© 2019 Elsevier B.V. Complement activation plays an important role in pharmacokinetic and performance of intravenously administered nanomedicines. Significant efforts have been directed toward engineering of nanosurfaces with low complement activation, but due to promiscuity of complement factors and redundancy of pathways, it is still a major challenge. Cell membrane-anchored Decay Accelerating Factor (DAF, a.k.a. CD55) is an efficient membrane bound complement regulator that inhibits both classical and alternative C3 convertases by accelerating their spontaneous decay. Here we tested the effect of various short consensus repeats (SCRs, “sushi” domains) of human CD55 on nanoparticle-mediated complement activation in human sera and plasma. Structural modeling suggested that SCR-2, SCR-3 and SCR-4 are critical for binding to the alternative pathway C3bBb convertase, whereas SCR-1 is dispensable. Various domains were expressed in E.coli and purified by an affinity column. SCRs were added to lepirudin plasma or sera from different healthy subjects, to monitor nanoparticle-mediated complement activation as well as C3 opsonization. Using superparamagnetic iron oxide nanoworms (SPIO NWs), we found that SCR-2-3-4 was the most effective inhibitor (IC 50 ~0.24 μM for C3 opsonization in sera), followed by SCR-1-2-3-4 (IC 50 ~0.6 μM), whereas shorter domains (SCR-3, SCR-2-3, SCR-3-4) were ineffective. SCR-2-3-4 also inhibited C5a generation (IC 50 ~0.16 μM in sera). In addition to SPIO NWs, SCR-2-3-4 effectively inhibited C3 opsonisation and C5a production by clinically approved nanoparticles (Feraheme, LipoDox and Onivyde). SCR-2-3-4 inhibited both lectin and alternative pathway activation by nanoparticles. When added to lepirudin-anticoagulated blood from healthy donors, it significantly reduced the uptake of SPIO NWs by neutrophils and monocytes. These results suggest that soluble domains of membrane-bound complement inhibitors are potential candidates for preventing nanomedicine-mediated complement activation in human subjects.
Author(s): Gifford G, Vu VP, Banda NK, Holers VM, Wang G, Groman EV, Backos D, Scheinman R, Moghimi SM, Simberg D
Publication type: Article
Publication status: Published
Journal: Journal of Controlled Release
Year: 2019
Volume: 302
Pages: 181-189
Print publication date: 28/05/2019
Online publication date: 08/04/2019
Acceptance date: 07/04/2019
ISSN (print): 0168-3659
ISSN (electronic): 1873-4995
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.jconrel.2019.04.009
DOI: 10.1016/j.jconrel.2019.04.009
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