title: The effect of polymer backbone chemistry on the induction of the accelerated blood clearance in polymer modified liposomes.
abstract: A variety of water-soluble polymers, when attached to a liposome, substantially increase liposome circulation half-life in animals. However, in certain conditions, liposomes modified with the most widely used polymer, polyethylene glycol (PEG), induce an IgM response resulting in an accelerated blood clearance (ABC) of the liposome upon the second injection. Modification of liposomes with other water-soluble polymers: HPMA (poly[N-(2-hydroxypropyl) methacrylamide]), PVP (poly(vinylpyrrolidone)), PMOX (poly(2-methyl-2-oxazoline)), PDMA (poly(N,N-dimethyl acrylamide)), and PAcM (poly(N-acryloyl morpholine)), increases circulation times of liposomes; but a precise comparison of their ability to promote long circulation or induce the ABC effect has not been reported. To obtain a more nuanced understanding of the role of polymer structure/MW to promote long circulation, we synthesized a library of polymer diacyl chain lipids with low polydispersity (1.04-1.09), similar polymer molecular weights (2.1-2.5kDa) and incorporated them into 100nm liposomes of a narrow polydispersity (0.25-1.3) composed of polymer-lipid/hydrogenated soy phosphatidylcholine/cholesterol/diD: 5.0/54.5/40/0.5. We confirm that HPMA, PVP, PMOX, PDMA and PAcM modified liposome have increased circulation times in rodents and that PVP, PDMA, and PAcM do not induce the ABC effect. We demonstrate for the first time, that HPMA does not cause an ABC effect whereas PMOX induces a pronounced ABC effect in rats. We find that a single dose of liposomes coated with PEG and PMOX generates an IgM response in rats towards the respective polymer. Finally, in this homologous polymer series, we observe a positive correlation (R=0.84 in rats, R=0.92 in mice) between the circulation time of polymer-modified liposomes and polymer viscosity; PEG and PMOX, the polymers that can initiate an ABC response were the two most viscous polymers. Our findings suggest that polymers that do not cause an ABC effect such as, HPMA or PVP, deserve further consideration as polymer coatings to improve the circulation of liposomes and other nanoparticles.
authors.affiliation: Department of Chemistry, University of California Berkeley, Berkeley, CA 94720, USA; Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Kierstead
authors.affiliation: Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Okochi
authors.affiliation: Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Venditto
authors.affiliation: Department of Chemistry, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Chuong
authors.affiliation: Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Saul
authors.initials: S
authors.lastname: Kivimae
authors.affiliation: Department of Chemistry, University of California Berkeley, Berkeley, CA 94720, USA; Physical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
authors.forename: Jean M J
authors.initials: JMJ
authors.lastname: Fréchet
authors.affiliation: Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: szoka@cgl.ucsf.edu.
authors.forename: Francis C
authors.initials: FC
authors.lastname: Szoka
mesh_terms: D000818:Animals; D005260:Female; D007075:Immunoglobulin M / Q000276:immunology; D008081:Liposomes / Q000097:blood* / Q000737:chemistry* / Q000276:immunology; D008297:Male; D051379:Mice; D011073:Polyamines / Q000097:blood / Q000737:chemistry / Q000276:immunology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics; D017208:Rats, Wistar
chemical_list: D007075:Immunoglobulin M; D008081:Liposomes; D011073:Polyamines; D011108:Polymers; C117403:poly(2-methyl-2-oxazoline); D011092:Polyethylene Glycols
keywords: Accelerated blood clearance; Anti-polymer IgM; Biodistribution; Pharmacokinetics; Polyethylene glycol; Polymer modified liposomes; RAFT polymerization