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 (2.1-2.5 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, 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.
|Number of pages||9|
|Journal||Journal of Controlled Release|
|State||Published - Jul 7 2015|
Bibliographical noteFunding Information:
We thank Dr. Charles Noble and Dr. Mark Hayes for their guidance with the production of liposomes. We would also like to thank Dr. Aditya Kohli for his help on the measurement of liposomes in plasma and tissue samples. This work was supported by R01 GM061851 (FCS) and R01 EB002047 (FCS) . VJ Venditto was funded by Ruth L. Kirschstein National Research Service Award from the National Institutes of Allergy and Infectious Diseases of the National Institutes of Health under Award Number F32AI095062 .
© 2015 Elsevier B.V.
- Accelerated blood clearance
- Anti-polymer IgM
- Polyethylene glycol
- Polymer modified liposomes
- RAFT polymerization
ASJC Scopus subject areas
- Pharmaceutical Science