title: Tailoring Nanostructure Morphology for Enhanced Targeting of Dendritic Cells in Atherosclerosis.
abstract: Atherosclerosis, a leading cause of heart disease, results from chronic vascular inflammation that is driven by diverse immune cell populations. Nanomaterials may function as powerful platforms for diagnostic imaging and controlled delivery of therapeutics to inflammatory cells in atherosclerosis, but efficacy is limited by nonspecific uptake by cells of the mononuclear phagocytes system (MPS). MPS cells located in the liver, spleen, blood, lymph nodes, and kidney remove from circulation the vast majority of intravenously administered nanomaterials regardless of surface functionalization or conjugation of targeting ligands. Here, we report that nanostructure morphology alone can be engineered for selective uptake by dendritic cells (DCs), which are critical mediators of atherosclerotic inflammation. Employing near-infrared fluorescence imaging and flow cytometry as a multimodal approach, we compared organ and cellular level biodistributions of micelles, vesicles (i.e., polymersomes), and filomicelles, all assembled from poly(ethylene glycol)-bl-poly(propylene sulfide) (PEG-bl-PPS) block copolymers with identical surface chemistries. While micelles and filomicelles were respectively found to associate with liver macrophages and blood-resident phagocytes, polymersomes were exceptionally efficient at targeting splenic DCs (up to 85% of plasmacytoid DCs) and demonstrated significantly lower uptake by other cells of the MPS. In a mouse model of atherosclerosis, polymersomes demonstrated superior specificity for DCs (p < 0.005) in atherosclerotic lesions. Furthermore, significant differences in polymersome cellular biodistributions were observed in atherosclerotic compared to naïve mice, including impaired targeting of phagocytes in lymph nodes. These results present avenues for immunotherapies in cardiovascular disease and demonstrate that nanostructure morphology can be tailored to enhance targeting specificity.
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Sijia
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Sean David
authors.initials: SD
authors.lastname: Allen
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Yu-Gang
authors.initials: YG
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Brian Zhou
authors.initials: BZ
authors.lastname: Ouyang
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Xiaomo
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Punn
authors.identifier: 0000-0001-8602-5433
authors.initials: P
authors.lastname: Augsornworawat
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Edward Benjamin
authors.initials: EB
authors.lastname: Thorp
authors.affiliation: Department of Biomedical Engineering, ‡Chemistry of Life Processes Institute, §Interdisciplinary Biological Sciences Program, and ∥Master of Biotechnology Program, Northwestern University , Evanston, Illinois 60208, United States.|Department of Pathology and #Simpson Querrey Institute, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
authors.forename: Evan Alexander
authors.identifier: 0000-0002-8945-2892
authors.initials: EA
authors.lastname: Scott
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000628:therapy*; D003713:Dendritic Cells; D007249:Inflammation; D008024:Ligands; D051379:Mice; D008823:Micelles; D049329:Nanostructures; D011108:Polymers
chemical_list: D008024:Ligands; D008823:Micelles; D011108:Polymers
keywords: atherosclerosis; biodistribution; dendritic cells; flow cytometry; near-infrared fluorescence imaging; polymersome; targeted delivery