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)), 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.

A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity

“…Only very little mild and scattered tubular damage was observed in POx/PTX samples (see supplementary information for a more detailed analysis). Overall, our results reinforce the excellent biocompatibility profile of POx reported previously [22–33]. …”

PEGylation as a strategy for improving nanoparticle-based drug and gene delivery

“…They were also able to demonstrate for the first time that HPMA-modification did not cause an ABC effect, whereas PMOX-modified liposomes were rapidly cleared with the second dose in rats. They confirmed that PMOX-modified liposomes induced an IgM response in rats with one dose, similar to PEG-modified liposomes [119]. This work suggests that alternatives such as HPMA or PVP deserve further consideration as polymer coatings to improve the circulation time of liposomes.…”

“…Also to be considered, hyperbranched PG has been observed to slightly increase blood viscosity in vivo , which has been shown to cause a variety of physiological side effects [118]. To compare the potential of several different PEG alternatives as surface modifiers to increase circulation time and reduce the ABC effect, Kiersted and coworkers synthesized a panel of polymer diacyl chain lipids of similar MW and polydispersity to incorporate into liposomes [119]. They evaluated liposomes ~100 nm in size containing lipids modified with PEG, HPMA, poly(vinylpyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOX), poly(N,N-dimethyl acrylamide) (PDMA), and poly(N-acryloyl morpholine) (PAcM), and compared the circulation time in mice and rats.…”

Opsonisation of nanoparticles prepared from poly(β-hydroxybutyrate) and poly(trimethylene carbonate)-b-poly(malic acid) amphiphilic diblock copolymers: Impact on the in vitro cell uptake by primary human macrophages and HepaRG hepatoma cells

“…In addition, the unpredicted clearance times of PEGylated compounds lead to accumulation of high molecular weight compounds in the liver (Dams et al, 2000) with unknown toxicological consequences over a long period of time (Kawai, 2002). Some studies have evaluated other water-soluble polymers in order to overcome the limitations in the use of PEG (Kierstead et al, 2015). For instance, poly[N-(2-hydroxypropyl) methacrylamide] (Lammers and Ulbrich, 2010) and poly(vinylpyrrolidone) (Zelikin et al, 2007;Kierstead et al, 2015) coatings on liposomes also demonstrated the ability to extend circulation times and to avoid accelerated blood clearance although their opsonisation by plasma proteins remains poorly documented.…”