Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle

Koide, Hiroyuki; Yoshimatsu, Keiichi; Hoshino, Yu; Ariizumi, Saki; Okishima, Anna; Ide, Takafumi; Egami, Hiromichi; Hamashima, Yoshitaka; Nishimura, Y.; Kanazawa, Hiroaki; Miura, Yoshiko; Asai, Tomohiro; Oku, Naoto; Shea, Kenneth J.

doi:10.1016/j.jconrel.2018.12.033

Cited by 30 publications

(30 citation statements)

References 42 publications

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“…Therefore, intercepting and clearing histones in the bloodstream as rapidly as possible is important for an effective sepsis therapy. Most previous studies of poly(N-isopropylacrylamide) (pNIPAm)-based therapeutic HNPs found that they are rapidly cleared from the bloodstream shortly after intravenous injection 23,31 . Many of these applications were for the immediate removal of a toxin, circulation time was not a factor 23,36 .…”

Section: Resultsmentioning

confidence: 99%

“…Although the physiochemical properties of hydrogel nanoparticles can be altered to achieve both a nity and selectivity 47 , these properties alone are insu cient for therapeutic e cacy; circulation time is also an important factor. Unfortunately, prior studies with HNPs have shown an inherently short circulation time 23,31 . Since a nity and selectivity depend on HNP chemical composition, a traditional method of enhancing circulation time by incorporating Peg chains presents a unique challenge.…”

Section: Discussionmentioning

confidence: 99%

“…The HNPs have a high capacity for target peptides compared with antibodies by sequestering them not only on their surface, but also within the HNPs themselves 23 . These features notwithstanding, a current challenge in HNP-based therapy has been their short circulation time in the blood 23,31 . One attempt to improve these involved conjugating histonecapturing synthetic linear copolymers to a lipid NP (a highly biocompatible drug delivery agent), improving the bloodstream circulation time following intravenous injection 32 .…”

Section: Read Full License Introductionmentioning

confidence: 99%

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Synthetic hydrogel nanoparticles for sepsis therapy

Shea

Koide

Okishima

et al. 2021

Preprint

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Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protected mice against a lethal dose of histones through the inhibition of platelet migration into the lungs. In vivo administration in murine sepsis model mice resulted in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Read Full License Introductionmentioning

confidence: 99%

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Synthetic hydrogel nanoparticles for sepsis therapy

Shea

Koide

Okishima

et al. 2021

Preprint

Self Cite

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“…34) Then, phosphorylation of VEGFR-2 and cell growth enhancement are induced. 35) Because anti-VEGF NPs bind to the heparinbinding domain of VEGF, binding of NPs to VEGF does not guarantee that NPs inhibit the VEGF-VEGFR-2 interaction. To demonstrate whether NPs inhibit the VEGF and VEGFR-2 interaction or not, human umbilical vein endothelial cells (HUVECs) were incubated with the NPs and VEGF.…”

Section: Biographymentioning

confidence: 99%

Design of Functional Nanoparticles for Intractable Disease Therapy

Koide

2021

Biological & Pharmaceutical Bulletin

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“…[ 4c,9 ] In addition, we have previously reported that the inclusion of hydrophobic and multiple sulfated monomers in polymer nanoparticle allowed them to bind to the vascular endothelial growth factor [ 9e ] (VEGF) and inhibited the VEGF‐dependent tumor growth. [ 10 ] Although these synthetic polymers have attracted considerable attention as a novel protein affinity reagent alternative to antibodies, their performance in living animals still remains a remarkable challenge. For example, multiple injections of these undegradable synthetic polymer nanomaterials induce unexpected side effects such as inflammations in living animals.…”

Section: Introductionmentioning

confidence: 99%

Engineering of Lipid Nanoparticles by the Multifunctionalization of the Surface with Amino Acid Derivatives for the Neutralization of a Target Toxic Peptide

Koide

Hirano

Ide

et al. 2020

Adv Funct Materials

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Protein affinity reagents (e.g., antibodies) are often used for basic research, diagnostics, separations, and disease therapy. Although a lot of "synthetic" protein affinity reagents have been developed as a cost-effective alternative to antibodies, their low biocompatibility is a considerable problem for clinical application. Lipid nanoparticles (LNP) represent a highly biocompatible drug delivery agent. However, little has been reported that LNP itself works as a protein affinity reagent in living animals. Here, LNP is engineered for binding to and neutralizing a target toxic peptide in living animals by multifunctionalization with amino acid derivatives. Multifunctionalized LNP (MF-LNP) is prepared using amino acid derivative-conjugated lipids. Optimized MF-LNP exhibits nanomolar affinity to the target toxic peptide and inhibits toxic peptide-dependent hemolysis and cytotoxicity. In addition, MF-LNP captures and neutralizes the toxic peptide after intravenous injection in the bloodstream; in addition, MF-LNP does not release the toxic peptide in the accumulated organ. These results reveal the potential of using LNP as a highly biocompatible protein affinity reagent such as an antidote.

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Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle

Cited by 30 publications

References 42 publications

Synthetic hydrogel nanoparticles for sepsis therapy

Synthetic hydrogel nanoparticles for sepsis therapy

Design of Functional Nanoparticles for Intractable Disease Therapy

Engineering of Lipid Nanoparticles by the Multifunctionalization of the Surface with Amino Acid Derivatives for the Neutralization of a Target Toxic Peptide

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