Synthesis,pH-Responsive Property And Application Of Poly(L-Glutamic Acid-r-L- Leusine)

Polypeptides have the same repeating units of natural a-amino acids as proteins. They are widely used as biomedical materials because of their good biocompatibility and biodegradability. Ring opening polymerization (ROP) of (protected) a-amino acid N-carboxyanhydride (NCA) is the most promising synthetic approach for polypeptides.In this work we first synthesized y-benzyl-L-glutamate (BLG) NCA, L-leusine (Leu) NCA and ε-carbobenzoxy-L-lysine (BLL) NCA by triphosgene method, and sarcosine (Sar) NCA and Nnm-2,4-dinitrophenyl-L-histidine NCA·HC1 by Leuchs method.We synthesized random copolymers of BLG with Leu by ROP of NCA monomers initiated by benzylamine. The composition of copolymers was in good agreement with the feed ratio of two monomers and polydispersity indices (PDIs) of copolymers were narrow. After deprotection of removing benzyl group, we got random copolymers of glutamic acid (Glu) with Leu [poly(Glu-r-Leu)s]. We investigated the relationship between their hydrophilicity-hydrophobicity transitions and the Leu fractions. With the increasing molar ratio of Leu units, both the pH value of cloud point and the micellar size increased. When molar ratio of Leu was 60%, the cloud point of copolypeptide was 5.8 with a transition pH window from 7.0 to 4.3, which was similar with pH change in cellule, and the diameter was ca.44 nm at pH of 7.4. This result had a potential of application in pH-controled release of drug/gene system.We synthesized block copolymers of poly(Glu-r-Leu) and polySar by a consequence addition of NCAs and deprotection. Poly(Glu-7--Leu)-b-polySar self-assembled to nanoparticles in phosphate buffer with a core of amphiphilic poly(Glu-r-Leu) and a shell of hydrophilic polySar. pH-responsive morphology changes were observed from orbicular micelles at high pH of 8.0 to worm-like micelles at low pH of 5.0.We synthesized random copolypeptides of Glu, Leu and histidine [poly(Glu-r-Leu-r-His)s] by ROP of NCA monomers and deprotection. We investigated the pH-dependent hemolysis of poly(Glu-r-Leu)s and poly(Glu-r-Leu-r-His)s. It is confirmed that no hemolysis was observed for both when they performed hydrophilicity-hydrophobicity transitions.We synthesized block copolymer of BLL and Sar with narrow PDI and predicable ratio by a consequence addition of NCA initiated by n-butyl amine. Amine end groups were then capped by azobenzene. After deprotection of BLL units we got azobenzene-end-capped polysarcosine-block-polylysine. This work is a collaboration project with Professor Youxiang Wang’s research group in our university. They used it in gene delivery, and the results were in good agreement with our design.The meaning of our work was to synthesize natural amine acid-based polypeptides which had similar structure of protein by chemical method with potential of industrialization. We adjusted the composition of polymers and research the properties, to set the foundation of application in future.