title: Engineering complement activation on polypropylene sulfide vaccine nanoparticles.
abstract: The complement system is an important regulator of both adaptive and innate immunity, implicating complement as a potential target for immunotherapeutics. We have recently presented lymph node-targeting, complement-activating nanoparticles (NPs) as a vaccine platform. Here we explore modulation of surface chemistry as a means to control complement deposition, in active or inactive forms, on polypropylene sulfide core, block copolymer Pluronic corona NPs. We found that nucleophile-containing NP surfaces activated complement and became functionalized in situ with C3 upon serum exposure via the alternative pathway. Carboxylated NPs displayed a higher degree of C3b deposition and retention relative to hydroxylated NPs, upon which deposited C3b was more substantially inactivated to iC3b. This in situ functionalization correlated with in vivo antigen-specific immune responses, including antibody production as well as T cell proliferation and IFN-γ cytokine production upon antigen restimulation. Interestingly, inactivation of C3b to iC3b on the NP surface did not correlate with NP affinity to factor H, a cofactor for protease factor I that degrades C3b into iC3b, indicating that control of complement protein C3 stability depends on architectural details in addition to factor H affinity. These data show that design of NP surface chemistry can be used to control biomaterials-associated complement activation for immunotherapeutic materials.
authors.affiliation: Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Station 15, Lausanne CH 1015, Switzerland.
authors.forename: Susan N
authors.initials: SN
authors.lastname: Thomas
authors.forename: André J
authors.initials: AJ
authors.lastname: van der Vlies
authors.forename: Conlin P
authors.initials: CP
authors.lastname: O'Neil
authors.forename: Sai T
authors.initials: ST
authors.lastname: Reddy
authors.forename: Shann S
authors.initials: SS
authors.lastname: Yu
authors.forename: Todd D
authors.initials: TD
authors.lastname: Giorgio
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology; D003170:Complement Pathway, Alternative / Q000276:immunology; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D011126:Polypropylenes / Q000737:chemistry* / Q000276:immunology; D013440:Sulfides / Q000737:chemistry* / Q000276:immunology; D020349:Surface Plasmon Resonance; D013499:Surface Properties; D014612:Vaccines / Q000737:chemistry / Q000276:immunology*
chemical_list: D001672:Biocompatible Materials; D003176:Complement C3; D011126:Polypropylenes; D013440:Sulfides; D014612:Vaccines