PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: Faster PEG shedding attenuates anti-PEG IgM production

Suzuki, Takuya; Suzuki, Yuta; Hihara, Taro; Kubara, Kenji; Kondo, Kazunori; Hyôdô, Kenji; Yamazaki, Kazuto; Ishida, Tatsuhiro; Ishiguro, Hiroshi

doi:10.1016/j.ijpharm.2020.119792

Cited by 77 publications

(87 citation statements)

References 41 publications

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“…Probably, the shield effect of PEG 2000, with medium chain length, is situated between PEG 750 and PEG 5000 [57], and therefore results in a slightly higher and prolonged accumulation in the spleen, as compared to conventional liposomes. Furthermore, recent studies on PEGylated lipid nanoparticles imply a PEG-shedding effect with subsequent increase in phagocytosis rate of Kupffer-cells [59,60], or via immune complex formation, which is complement and/or IgM mediated. Long acyl-chains in the PEG used in this study yield a higher potential to associate with complement or be the object of IgM opsonization, possibly explaining the increased recovery of PS PEG and PG PEG liposomes in organs rich of the MPS, namely, liver and spleen.…”

Section: Discussionmentioning

confidence: 99%

Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

et al. 2021

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The anionic phospholipids (PLs) phosphatidylserine (PS) and phosphatidylglycerol (PG) are endogenous phospholipids with anti-inflammatory and immunomodulatory activity. A potential clinical use requires well-defined systems and for several applications, a long circulation time is desirable. Therefore, we aimed the development of long circulating liposomes with intrinsic anti-inflammatory activity. Hence, PS- and PG-enriched liposomes were produced, whilst phosphatidylcholine (PC) liposomes served as control. Liposomes were either formulated as conventional or PEGylated formulations. They had diameters below 150 nm, narrow size distributions and composition-dependent surface charges. Pharmacokinetics were assessed non-invasively via in vivo fluorescence imaging (FI) and ex vivo in excised organs over 2 days. PC liposomes, conventionally formulated, were rapidly cleared from the circulation, while PEGylation resulted in prolongation of liposome circulation robustly distributing among most organs. In contrast, PS and PG liposomes, both as conventional or PEGylated formulations, were rapidly cleared. Non-PEGylated PS and PG liposomes did accumulate almost exclusively in the liver. In contrast, PEGylated PS and PG liposomes were observed mainly in liver and spleen. In summary, PEGylation of PS and PG liposomes was not effective to prolong the circulation time but caused a higher uptake in the spleen.

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Section: Discussionmentioning

confidence: 99%

Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

et al. 2021

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“…The PEG-shedding is necessary to prevent the potential induction of PEG-specific antibodies that cause rapid systemic clearance of subsequent doses of PEGylated nanomaterials via accelerated blood clearance (ABC) phenomenon [ 224 ]. The severity of ABC may also be suppressed by adjusting the PEG-lipid structure, affecting the kinetics of shedding and the recognition of the chains [ 224 , 225 ]. These findings indicate that the structure and the amount of PEG-lipid must be adjusted carefully to preserve the “stealth” effect.…”

Section: Materials For Mrna Deliverymentioning

confidence: 99%

Self-assembled mRNA vaccines

Kim

Eygeris

Gupta

et al. 2021

Advanced Drug Delivery Reviews

276

358

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“…While structural lipids allow the maintenance of the particle structure, cholesterol enhances particle stability, thereby most likely affecting LNP morphology and mRNA delivery [ 57 , 58 ]. Stealth coating lipids such as polyethylene glycol (PEG)-lipid or polysarcosine (pSar) enable the control of physicochemical characteristics of the LNP-mRNA (e.g., particle size and the structure) and influence the circulation half-life of the particle [ 56 , 59 , 60 ].…”

Section: Lnp Induced Immune Activationmentioning

confidence: 99%

“…In addition, PEG-lipids-shielding has impact against undesired aggregation and accumulation in filtering organs that might be caused by protein corona [ 148 ]. However, PEG-shielding may also lower the recognition of apolipoprotein E (ApoE), and it can cause the formation of anti-PEG ADAs that lead to lowering the efficiency of the LNP [ 60 , 150 ]. Thus, the level of PEG-shielding must be optimized to obtain a compromise between efficacy and safety.…”

Section: Boosting the Efficacy And Safety Of Lnp-mrna Applicationsmentioning

confidence: 99%

“…Thus, the level of PEG-shielding must be optimized to obtain a compromise between efficacy and safety. With regard to anti-PEG ADAs formation, a recent study by Suzuki et al examined PEG-containing LNP-siRNA in mice and found that LNPs with a fast-shedding PEG-lipid (short acyl chain) induced less anti-PEG IgM compared with those with long acyl chain LNPs [ 60 ]. The usage of the fast-shedding PEG-lipid allowed more hepatocyte targeting compared with Kupffer cells, the liver macrophages, thus improving the effectivity of LNP-siRNA drug [ 60 ].…”

Section: Boosting the Efficacy And Safety Of Lnp-mrna Applicationsmentioning

confidence: 99%

See 1 more Smart Citation

Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety

Vlatkovic

2021

Biomedicines

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Lipid nanoparticle (LNP) formulated messenger RNA-based (LNP-mRNA) vaccines came into the spotlight as the first vaccines against SARS-CoV-2 virus to be applied worldwide. Long-known benefits of mRNA-based technologies consisting of relatively simple and fast engineering of mRNA encoding for antigens and proteins of interest, no genomic integration, and fast and efficient manufacturing process compared with other biologics have been verified, thus establishing a basis for a broad range of applications. The intrinsic immunogenicity of LNP formulated in vitro transcribed (IVT) mRNA is beneficial to the LNP-mRNA vaccines. However, avoiding immune activation is critical for therapeutic applications of LNP-mRNA for protein replacement where targeted mRNA expression and repetitive administration of high doses for a lifetime are required. This review summarizes our current understanding of immune activation induced by mRNA, IVT byproducts, and LNP. It gives a comprehensive overview of the present status of preclinical and clinical studies in which LNP-mRNA is used for protein replacement and treatment of rare diseases with an emphasis on safety. Moreover, the review outlines innovations and strategies to advance pharmacology and safety of LNP-mRNA for non-immunotherapy applications.

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PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: Faster PEG shedding attenuates anti-PEG IgM production

Cited by 77 publications

References 41 publications

Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

Self-assembled mRNA vaccines

Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety

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