Journal
JOURNAL OF CONTROLLED RELEASE
Volume 310, Issue -, Pages 74-81Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2019.08.011
Keywords
Amino acid; Liver injury; Hyperammonemia; Ornithine; Self-assembling drug
Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [18H04160]
- Japan Agency for Medical Research and Development (AMED) [17824875]
- Vietnam National Foundation of Science and Technology Developement (NAFOSTED) [108.05-2017.327]
- Grants-in-Aid for Scientific Research [18H04160] Funding Source: KAKEN
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Oligo-peptides, including monomeric amino acids, have received much attention as bioactive molecules and drugs. One of the biggest problems of these compounds, however, is their very short bioavailability due to instant metabolism and rapid excretion. To solve this problem, we newly designed a poly(ethylene glycol) (PEG)-block-polypeptide self-assembling based drug for the treatment of acute liver injury. Here, PEG-block-poly(L-Ornithine) (PEG-b-POrn) was synthesized via a ring opening polymerization, and a nano-sized polyion self-assembling complex (Nano(Orn)) was prepared by simply mixing polycationic PEG-b-P-Orn with polyanionic chondroitin sulfate. The obtained Nano(Orn) was quite stable under high ionic strength and different pH conditions and Nano(Orn) exhibited extremely low toxicity in vitro and in vivo as compared to the original PEG-b-POrn. As compared to monomeric L-ornithine, administration of Nano(Orn) to mice significantly improved bioavailability of liberated ornithine, especially in the liver. Interestingly, Nano(Orn) treatment in acetaminophen (APAP)-induced acute liver injury mice remarkably suppressed blood ammonia levels and liver injury markers, resulting in more effective improvement of liver damage compared to monomeric ornithine via activation of ornithine transcarbomylase. These results show that the self-assembling polypeptide Nano(Orn) may provide a new concept and promising therapeutics as nanomedicines.
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