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en: Ionic Liquids Composed of Lactic Acid and Trometamol Enhance the Oral Absorption of 10 kDa Dextran, as a Model Compound of Mid-Sized Molecules

en: Oral administration is the preferred route for drug administration owing to a high level of patient compliance and suitability for long-term treatment. However, drugs with a molecular weight of >1000 Da such as peptide-based therapeutics generally exhibit poor absorption from the gastrointestinal tract. In this study, we evaluated the potential of ionic liquids to enhance the oral absorption of mid-sized molecules such as dextran, which has a size of 10 kDa. In this study, the ionic liquids we tested enhanced the oral absorption of 10 kDa mid-sized dextran. Among the ionic liquids we tested, d/l-Lactic acid-trometamol ([Lac][Tris])-based ionic liquids consistently yielded higher values for maximum concentration (Cmax; 153.9 ± 11.0 nmol/L) of dextran as well as for the area under the curve representing 0-2 h (AUC0-2 h; 228.9 ± 54.1 nmol × h/L) compared with that of the other ionic liquids tested. The [Lac][Tris] = 5 : 1 ionic liquid achieved relatively higher values for both Cmax and AUC0-2 h. Interestingly, the observed oral absorption enhancement effect by the [Lac][Tris] = 5 : 1 ionic liquid for mid-sized molecules depended on the concentration of dextran (10 kDa). These results show that ionic liquid formulations can overcome the intestinal barrier and lead to systemic absorption of mid-sized molecules with molecular weights. Although further optimizations aimed at translating ionic liquid technology to the oral delivery of peptide drugs must be required, our results could expand the utility and possibility of ionic liquids as an oral absorption enhancer for mid-sized molecules such as peptides.

en: Biological & Pharmaceutical Bulletin

ja: Biological & Pharmaceutical Bulletin


en: Impact of pre-existing anti-polyethylene glycol (PEG) IgM on biodistribution and humoral response of intramuscularly administered PEGylated mRNA loaded lipid nanoparticle

en: With the approval of mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), lipid nanoparticles (LNP) have emerged as a powerful tool for nucleic acid delivery. Modification of LNP with polyethylene glycol (PEG)-lipids contributes to their in vitro and in vivo stability by reducing aggregation of the particles. Despite the general acknowledgement of the low immunogenicity of PEG, there are numerous reports of the occurrence of anti-PEG antibodies in the blood of healthy individuals. Furthermore, there are reports that pre-existing anti-PEG IgM antibodies attenuated the efficacy of PEG-modified drugs administered systemically. Skeletal muscles, the administration site for mRNA vaccines, are highly vascularized by a network of blood vessels to provide them with nutrients and oxygen. Since skeletal muscles can contain circulating anti-PEG antibodies or the administered mRNA-LNP extravasate into bloodstream, the purpose of this study was to evaluate the effects of pre-existing anti-PEG IgM on the protein translation, biodistribution, and humoral responses to mRNA-loaded LNP (mRNA-LNP) administered intramuscularly (i.m.) in mice. We found that the presence of anti-PEG IgM in blood has only a minor effect on the translation and distribution of mRNA-LNP in the localized muscle area where the mRNA-LNP were administered. Circulating anti-PEG IgM did not increase the total accumulation of mRNA-LNP in the liver, but did markedly diminish its protein translation because the mRNA-LNP were delivered primarily to Kupffer cells rather than to hepatocytes. Binding of anti-PEG IgM to mRNA-LNP, and subsequent complement activation, suppressed mRNA translation loaded in LNP in the liver. Repeated intramuscular injections of SARS-CoV-2 Spike protein mRNA-LNP elicited a robust immune response. Our results indicate that the presence of circulating anti-PEG IgM does not interfere with the efficiency of mRNA vaccines administered i.m. in mice. We can speculate that non-specific translation of mRNA vaccines in somatic cells may be inhibited in vivo by circulating anti-PEG IgM, reducing adverse effects such as hepatitis and myocarditis that are caused by immune responses against translated antigen proteins.

en: Journal of Controlled Release

ja: Journal of Controlled Release