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Biochem Biophys Res Commun ; 555: 32-39, 2021 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-33812056

RESUMEN

Protein-protein (e.g., antibody-antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.


Asunto(s)
Antídotos/farmacología , Meliteno/toxicidad , Nanopartículas Multifuncionales/química , Polietilenglicoles/química , Animales , Antídotos/química , Antídotos/farmacocinética , Bovinos , Línea Celular , Hemólisis/efectos de los fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Lípidos/química , Masculino , Meliteno/sangre , Meliteno/metabolismo , Meliteno/farmacocinética , Ratones Endogámicos BALB C , Nanopartículas Multifuncionales/administración & dosificación , Nanopartículas Multifuncionales/metabolismo , Distribución Tisular
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