title: Modulation of complement activation and amplification on nanoparticle surfaces by glycopolymer conformation and chemistry.
abstract: The complement system plays an integral part of a host's innate immunity, and its activation is highly dependent on the chemistry and structure of a "foreign" target surface. We determined that the conformational state of glycopolymer chains, defined by the grafting density (chains/nm(2)), on the nanoparticle (NP) surface acts as a "molecular switch" for complement activation and amplification, and the protein corona on the NP surface dictates this process. A grafting density threshold was determined, below which minimal complement activation was observed and above which substantial complement activation was detected. The glycopolymer-grafted NPs activated complement via the alternative pathway. The chemical structure of pendent sugar units on the grafted polymer was also an important determinant for complement activation. NPs grafted with glucose-containing polymer activated complement at a lower grafting density compared to NPs grafted with galactose-containing polymer. Analysis of complement activation products C3a and SC5b-9 followed a similar pattern. Complement activation on the NP surface was independent of particle size or concentration for a given conformational state of grafted polymer. To gain insight into a putative surface-dependent mechanism of complement activation, we determined the nature of adsorbed protein corona on various NPs through quantitative mass spectrometry. Elevated levels of two pro-complement proteins, factors B and C3, present on the NP surface grafted with glycopolymer chains at high grafting density compared to low grafting density surface, may be responsible for its complement activity. Galactose polymer modified NPs adsorbed more of the negative regulator of complement, factor H, than the glucose surface, providing an explanation for its lower level of complement activation.
authors.affiliation: Centre for Blood Research and Department of Pathology & Laboratory Medicine and ‡Department of Chemistry, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Benjamin F L
authors.initials: BF
authors.lastname: Lai
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Foley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krisinger
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
mesh_terms: D000818:Animals; D002241:Carbohydrates / Q000737:chemistry* / Q000494:pharmacology*; D003167:Complement Activation / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011817:Rabbits; D012756:Sheep; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D002241:Carbohydrates