title: An orthogonal click-chemistry approach to design poly(glycerol monomethacrylate)-based nanomaterials for controlled immunostimulation.
abstract: A versatile approach is proposed for the synthesis of novel immunoactive nanomaterials based on biocompatible poly(glycerol monomethacrylate) (PGMMA). Propargyl-terminated PGMMA is synthesized via atom transfer radical polymerization and then modified through the introduction of dangling acrylate groups, at controlled degree of functionalisation. Acrylates are then able to react quantitatively with thiols, such as immunoactive thiomannose, through Michael-type addition under mild conditions and at a physiologically acceptable pH. The terminal propargyl group can be modified independently with azide end-capping groups and it is utilized to graft the macromolecules to a fluorescent dye. The resulting mannose-linked PGMMAs confirm a safe cytotoxic profile and are able to stimulate cytokine production (TNFα), membrane protein expression (CD40), and cellular uptake in bone marrow derived dendritic cells. Cell stimulation is dependent on the mannose content and enhanced by serum proteins, suggesting a role for mannose-binding receptors and/or complement receptors in the cell membrane.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Lakshminarayanan
authors.initials: L
authors.lastname: Ragupathy
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Millar
authors.forename: Nicola
authors.initials: N
authors.lastname: Tirelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Cellesi
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry / Q000379:methods*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D005990:Glycerol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007114:Immunization; D007700:Kinetics; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D049329:Nanostructures / Q000737:chemistry*; D058105:Polymerization; D011109:Polymethacrylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066244:Proton Magnetic Resonance Spectroscopy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D005456:Fluorescent Dyes; D011109:Polymethacrylic Acids; D014409:Tumor Necrosis Factor-alpha; D005990:Glycerol
keywords: adjuvants; dendritic cells; immunostimulation; mannose; poly(glycerol monomethacrylate)