title: Size and rigidity of cylindrical polymer brushes dictate long circulating properties in vivo.
abstract: Studies of spherical nanoengineered drug delivery systems have suggested that particle size and mechanical properties are key determinants of in vivo behavior; however, for more complex structures, detailed analysis of correlations between in vitro characterization and in vivo disposition is lacking. Anisotropic materials in particular bear unknowns in terms of size tolerances for in vivo clearance and the impact of shape and rigidity. Herein, we employed cylindrical polymer brushes (CPBs) to answer questions related to the impact of size, length and rigidity on the in vivo behavior of PEGylated anisotropic structures, in particular their pharmacokinetics and biodistribution. The modular grafting assembly of CPBs allowed for the systematic tailoring of parameters such as aspect ratio or rigidity while keeping the overall chemical composition the same. CPBs with altered length were produced from polyinitiator backbones with different degrees of polymerization. The side chain grafts consisted of a random copolymer of poly[(ethylene glycol) methyl ether methacrylate] (PEGMA) and poly(glycidyl methacrylate) (PGMA), and rendered the CPBs water-soluble. The epoxy groups of PGMA were subsequently reacted with propargylamine to introduce alkyne groups, which in turn were used to attach radiolabels via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Radiolabeling allowed the pharmacokinetics of intravenously injected CPBs to be followed as well as their deposition into major organs post dosing to rats. To alter the rigidity of the CPBs, core-shell-structured CPBs with polycaprolactone (PCL) as a water-insoluble and crystalline core and PEGMA-co-PGMA as the hydrophilic shell were synthesized. This modular buildup of CPBs allowed their shape and rigidity to be altered, which in turn could be used to influence the in vivo circulation behavior of these anisotropic polymer particles. Increasing the aspect ratio or altering the rigidity of the CPBs led to reduced exposure, higher clearance rates, and increased mononuclear phagocytic system (MPS) organ deposition.
authors: Department of Chemical and Biomolecular Engineering, The University of Melbourne , Parkville, Victoria 3010, Australia.
authors: Markus
authors: M
authors: Müllner
authors: Sarah J
authors: SJ
authors: Dodds
authors: Tri-Hung
authors: TH
authors: Nguyen
authors: Danielle
authors: D
authors: Senyschyn
authors: Christopher J H
authors: CJ
authors: Porter
authors: Ben J
authors: BJ
authors: Boyd
authors: Frank
authors: F
authors: Caruso
mesh_terms: D000818:Animals; D016880:Anisotropy; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010316:Particle Size; D010586:Phagocytes / Q000378:metabolism; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D000067996:RAW 264.7 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D008689:Methacrylates; C524499:polyethylene glycol methacrylate; D014867:Water; D011092:Polyethylene Glycols
keywords: PEGylation; anisotropic polymer particles; biodistribution; grafting-from; long circulation; macrophages; pharmacokinetics