Synthesis And Self-Assembly Of Polypeptide-Based Copolymers

Macromolecular self-assembly from amphiphilic copolymers has become an attractive research topic in contemporary macromolecular science both for their diversiform morphologies and potential applications. The self-assembled nanostructures have potential applications in fields of drug delivery, coating, nanoreactor, and so on. Polypeptide, which is synthesized by amino acids and their derivates, has been studied widely in fields of protein simulation and biomedical materials. In this paper, polypeptide-based graft copolymers and liner-dendron like polyampholytes were prepared, and their aggregation behaviors in selective solvents were well studied. The influences of molecular architecture, solution condition, etc. on micelle structure were investigated. The drug-loading and release behaviors of the environmental-sensitive micelles were also studied. Additionally, the self-assembly and drug-relesing behaviors were verified by dissipative particle dynamics (DPD) simulations.(1) Polypeptides and their copolymers, such as poly(y-benzyl-L-glutamate) homopolymers (PBLG), poly(ε-benzyloxycarbonyl-L-lysine)(PZLL), poly(propylene oxide)-block-poly(y-benzyl-L-glutamate)-block-poly(ethylene glycol) triblock copolymers (PPO-b-PBLG-b-PEG) were prepared by N-carboxyanhydride (NCA) method. Poly(acrylic acid)(PAA) was obtained by the hydrolysis process of poly(tert-butyl acrylate)(PtBA), prepared by atom transfer radical polymerization (ATRP). Poly(acrylic acid)-graft-poly(γ-benzyl-L-glutamate) graft copolymer (PAA-g-PBLG) was prepared by amide reaction between PBLG and PAA. Poly(ε-benzyloxycarbonyl-L-lysine)-polyamidoamine-poly(y-benzyl-L-glutamate) copolymer (PZLL-b-D2-(PBLG)4) was synthesized by the combination of ring opening polymerization, divergent synthesis procedure and click chemistry. Then, the polyampholyte (PLL-b-D2-(PLGA)4) was obtained by the hydrolysis of protecting benzyl and benzyloxycarbonyl groups of PBLG and PZLL, respectively.(2) Toroids could be self-assembled from the mixture systems containing PAA-g-PBLG graft copolymers and PBLG homopolymers in aqueous solution, while pure PAA-g-PBLG graft copolymers formed rod-like micelles. The added PBLG homopolymers with large molecular weight have great effect on the self-assembly of PAA-g-PBLG graft copolymers. We examined the formation process of toroids. The DPD simulations were also performed to explore the formation mechanism of the toroidal aggregates. The results suggested that the homopolymers determined the overall structure and toroids were formed by the connection of the end-caps of rod-like micelles. This research not only provides a new strategy for toroid formation, but also improves our understanding of the mechanism of toroidal formation. (3)Dual drug delivery system was presented by PPO-b-PBLG-b-PEG tribloek copolymers. One drug (Naproxcn) was physically loaded into PPO-b-PBLG-b-PIXi micelles, while the other drug (Doxorubicin) was chemically conjugated to PBIXi block. The releases of the two drugs were both pH-and temperature-sensitive. Their releasing rates are both faster at lower pH and higher temperature. The releasing behavior of DOX from dual drug delivery system was similar with that from single drug delivery system; but the case of Nap was different, which suggested that the release of DOX from dual drug delivery system affected the release of Nap. It is expected that functional tribloek micelles can be utilized to deliver multiple drugs, which will tend to act on the same cells and then maximize the cytotoxicity. We also performed DPI) simulations to explore the releasing mechanism of this dual drug delivery system.(4) Self-assembly of Iinear-dendron-like polyampholytes (PLL-b-D2-(PLGA)4) was presented. The results show that PLL-b-D2-(PLGA)4) can self-assemble into schizophrenic micelles which can be reversibly produced as a function of pH in pure water. They can self-assemble into large compound micelles or nanorods with PIXiA-core and PIT-shell at acidic pH and vesicles or tubes with PLL-core and PLGA-shell at alkaline pH. We also found that the tubes would hierarchically self-assemble into fractal structures. The hierarchically self-assembly behavior is not common during the sell-assembly of polypeptidcs. The Iinear-dendron-like asymmetrical topological structure is believed to play an important role in the formation of self-assembly nanostructures.