title: Influence of architecture of high molecular weight linear and branched polyglycerols on their biocompatibility and biodistribution.
abstract: The availability of long circulating, multifunctional polymers is critical to the development of drug delivery systems and bioconjugates. The ease of synthesis and functionalization make linear polymers attractive but their rapid clearance from circulation compared to their branched or cyclic counterparts, and their high solution viscosities restrict their applications in certain settings. Herein, we report the unusual compact nature of high molecular weight (HMW) linear polyglycerols (LPGs) (LPG - 100; M(n) - 104 kg mol(-1), M(w)/M(n) - 1.15) in aqueous solutions and its impact on its solution properties, blood compatibility, cell compatibility, in vivo circulation, biodistribution and renal clearance. The properties of LPG have been compared with hyperbranched polyglycerol (HPG) (HPG-100), linear polyethylene glycol (PEG) with similar MWs. The hydrodynamic size and the intrinsic viscosity of LPG-100 in water were considerably lower compared to PEG. The Mark-Houwink parameter of LPG was almost 10-fold lower than that of PEG. LPG and HPG demonstrated excellent blood and cell compatibilities. Unlike LPG and HPG, HMW PEG showed dose dependent activation of blood coagulation, platelets and complement system, severe red blood cell aggregation and hemolysis, and cell toxicity. The long blood circulation of LPG-100 (t(1/2β,) 31.8 ± 4 h) was demonstrated in mice; however, it was shorter compared to HPG-100 (t(1/2β,) 39.2 ± 8 h). The shorter circulation half life of LPG-100 was correlated with its higher renal clearance and deformability. Relatively lower organ accumulation was observed for LPG-100 and HPG-100 with some influence of on the architecture of the polymers. Since LPG showed better biocompatibility profiles, longer in vivo circulation time compared to PEG and other linear drug carrier polymers, and has multiple functionalities for conjugation, makes it a potential candidate for developing long circulating multifunctional drug delivery systems similar to HPG.
authors.affiliation: Centre for Blood Research, Department of Pathology and Laboratory Medicine, The University of British Columbia, Life Sciences Centre, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Imran ul-haq
authors.forename: Benjamin F L
authors.initials: BF
authors.lastname: Lai
authors.forename: Rafi
authors.initials: R
authors.lastname: Chapanian
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D005260:Female; D005990:Glycerol / Q000737:chemistry* / Q000493:pharmacokinetics*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D057446:Hydrodynamics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008422:Materials Testing / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D011108:Polymers; C043941:polyglycerol; D011092:Polyethylene Glycols; D005990:Glycerol