title: Exploring deformable particles in vascular-targeted drug delivery: Softer is only sometimes better.
abstract: The ability of vascular-targeted drug carriers (VTCs) to localize and bind to a targeted, diseased endothelium determines their overall clinical utility. Here, we investigate how particle modulus and size determine adhesion of VTCs to the vascular wall under physiological blood flow conditions. In general, deformable microparticles (MPs) outperformed nanoparticles (NPs) in all experimental conditions tested. Our results indicate that MP modulus enhances particle adhesion in a shear-dependent manner. In low shear human blood flow profiles in vitro, low modulus particles showed favorable adhesion, while at high shear, rigid particles showed superior adhesion. This was confirmed in vivo by studying particle adhesion under venous shear profiles in a mouse model of mesenteric inflammation, where MP adhesion was 127% greater (p < 0.0001) for low modulus particles compared to more rigid ones. Mechanistically, we establish that particle collisions with leukocytes drive these trends, rather than differences in particle deformation, localization, or detachment. Overall, this work demonstrates the importance of VTC modulus as a design parameter for enhanced VTC interaction with vascular walls, and thus, contributes important knowledge for development of successful clinical theranostics with applications for many diseases.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Margaret B
authors.initials: MB
authors.lastname: Fish
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Fromen
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Genesis
authors.initials: G
authors.lastname: Lopez-Cazares
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Golinski
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Macromolecular Science and Engineering Program, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Scott
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Reheman
authors.initials: R
authors.lastname: Adili
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, United States; Department of Cardiovascular Medicine, Samuel and Jean Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Holinstat
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Macromolecular Science and Engineering Program, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: lolaa@umich.edu.
authors.forename: Omolola
authors.initials: O
authors.lastname: Eniola-Adefeso
mesh_terms: D000268:Adhesiveness; D000327:Adsorption; D000818:Animals; D001769:Blood; D001774:Blood Chemical Analysis; D002214:Capsules / Q000008:administration & dosage / Q000737:chemistry*; D019245:Compressive Strength; D055119:Elastic Modulus; D004730:Endothelium, Vascular / Q000737:chemistry*; D006244:Hardness; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry*; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D033081:Shear Strength; D013314:Stress, Mechanical
chemical_list: D002214:Capsules; D020100:Hydrogels; D053769:Nanocapsules
keywords: Deformability; Hemodynamics; Hydrogel; Modulus; Shear force; Vascular-targeted carrier