The Effect of Polymer Backbone Chemistry on the Induction of the Accelerated Blood Clearance in Polymer Modified Liposomes

Handle URI:
http://hdl.handle.net/10754/558295
Title:
The Effect of Polymer Backbone Chemistry on the Induction of the Accelerated Blood Clearance in Polymer Modified Liposomes
Authors:
Kierstead, Paul H.; Okochi, Hideaki; Venditto, Vincent J.; Chuong, Tracy C.; Kivimae, Saul; Frechet, Jean ( 0000-0001-6419-0163 ) ; Szoka, Francis C.
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)), increase 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 (2.1-2.5 kDa) and incorporated them into 100 nm 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, 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 generate 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 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.
KAUST Department:
Physical Sciences and Engineering (PSE) Division
Citation:
The Effect of Polymer Backbone Chemistry on the Induction of the Accelerated Blood Clearance in Polymer Modified Liposomes 2015 Journal of Controlled Release
Publisher:
Elsevier BV
Journal:
Journal of Controlled Release
Issue Date:
18-Jun-2015
DOI:
10.1016/j.jconrel.2015.06.023
Type:
Article
ISSN:
01683659
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0168365915006306
Appears in Collections:
Articles; Physical Sciences and Engineering (PSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorKierstead, Paul H.en
dc.contributor.authorOkochi, Hideakien
dc.contributor.authorVenditto, Vincent J.en
dc.contributor.authorChuong, Tracy C.en
dc.contributor.authorKivimae, Saulen
dc.contributor.authorFrechet, Jeanen
dc.contributor.authorSzoka, Francis C.en
dc.date.accessioned2015-06-21T09:23:01Zen
dc.date.available2015-06-21T09:23:01Zen
dc.date.issued2015-06-18en
dc.identifier.citationThe Effect of Polymer Backbone Chemistry on the Induction of the Accelerated Blood Clearance in Polymer Modified Liposomes 2015 Journal of Controlled Releaseen
dc.identifier.issn01683659en
dc.identifier.doi10.1016/j.jconrel.2015.06.023en
dc.identifier.urihttp://hdl.handle.net/10754/558295en
dc.description.abstractA 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)), increase 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 (2.1-2.5 kDa) and incorporated them into 100 nm 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, 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 generate 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 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.en
dc.publisherElsevier BVen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0168365915006306en
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in Journal of Controlled Release. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Controlled Release, 18 June 2015. DOI: 10.1016/j.jconrel.2015.06.023en
dc.subjectRAFT polymerizationen
dc.subjectpolymer modified liposomesen
dc.subjectpolyethylene glycolen
dc.subjectpharmacokineticsen
dc.subjectbiodistributionen
dc.subjectanti-polymer IgMen
dc.subjectAccelerated blood clearanceen
dc.titleThe Effect of Polymer Backbone Chemistry on the Induction of the Accelerated Blood Clearance in Polymer Modified Liposomesen
dc.typeArticleen
dc.contributor.departmentPhysical Sciences and Engineering (PSE) Divisionen
dc.identifier.journalJournal of Controlled Releaseen
dc.eprint.versionPost-printen
dc.contributor.institutionDepartment of Chemistry, University of California Berkeley, Berkeley, CA 94720en
dc.contributor.institutionDepartment of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143en
kaust.authorFrechet, Jeanen
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