Studies On Drug Carriers Based On Poly(Amino Acid) Hybrid Copolymers

It is the goal of numerous scientists in biomedicine to develop safe and effective drug cariers. Various drug carriers have been reported over the decades. During these carriers, stimulus-responsive polymeric nanoparticles have attracted extensive attention due to their unique merits. The polymeric nanoparticles could undergo conformation switch in response to environmental stimuli, which offer the possibility of controlling the release of entrapped drugs. For in-vivo delivery, the polymeric materials should be biocompatible and biodegradable. Poly(amino acid) have the advantage of biodegradability and biocompatibility due to their component and structure analogy with natural proteins, which are excellent candidate biomaterials. They can be engineered into nanoparticles composed of highly organized structures owing to their unique secondary structure. To date, there are many reports about the smart nanocarriers based on the poly(amino acid). The applications of poly(amino acid) in controlled drug release have attracted more and more attentions in recent years. In this thesis, we designed and synthesized a series of novel polymeric micelles based on poly(amino acid) hybrid copolymers, and investigated their properties on the following issues.In chapter1, the classification of stimulus-responsive polymeric materials and their developments and applications in controlled drug release was summarized. The recent research progress of poly(amino acid), including synthesis approach, synthesis mechanism and the applications in controlled drug release, was reviewed.In Chapter2, we prepared a novel amphiphilic four-armed hybrid copolymer, PzLL2-PEG-PzLL2. The cytotoxicity study shows that the copolymer has good biocompatibility with no obvious inhibition effect on cell growth. The amphiphilic copolymers could self-assemble to form vesicles in aqueous solution. DOX. HCl, as a hydrophilic drug, can be loaded into the vesicles, and then successfully internalized by human breast cancer MCF-7cells. The DOX-loaded vesicles show a greatly improved drug release behavior with a zero-order release at the initial stage, suggesting a great potential as the carrier of hydrophilic drugs for controlled drug delivery. In Chapter2, we prepared novel drug carriers based on PEG-polypeptide copolymers, four-armed PLys(Ad)2-b-PEG-b-PLys(Ad)2). The copolymers were synthesized via the ring-opening polymerization of amino acid N-carboxyanhydrides. The copolymers could spontaneously form core-shell micelles in aqueous solutions. The morphology and size distribution were characterized by TEM and DLS. It has been found that these micelles undergo conformation switch in response to an additional β-CD. The in-vitro drug release in response to β-CD was studied and the release of the entrapped drug DOX from the micelles could be accelerated by the addition of β-CD. Their cytotoxicity and cell internalization behavior were also investigated in detail. These micelles are expected to have great potential in controlled drug release applications.In Chapter3, novel PEG-polypeptide hybrid triblock copolymers, PEG-PCys-PPhe, were prepared via the ring-opening polymerization of amino acid N-carboxyanhydrides. The copolymers can self-assemble to form core-shell-corona micelles in aqueous solutions. The shell of the micelles has the ability of self-cross-linking (SCL) by the oxidation of thiol groups in the PCys segments. The morphology and stability of SCL micelles were characterized by TEM, DLS and SEM. The results showed the SCL micelles could hold the physical structure of micelles in severe environment. The in vitro drug release in response to GSH was also studied. It was found that the cross-linked shell could be helpful to reduce the drug loss at extracellular environment. Under a reductive environment, the micelles would undergo the destruction of cross-linked shell due to the cleavage of disulfide bond, followed by the accelerated drug release from the micelles. The glutathione-responsive SCL micelles could be easily uptaken by HeLa cells, suggesting these micelles might have great potential in intracellular drug delivery.In Chapter4, novel disulfide-containing triblock copolymers, PEG-SS-PLys-PLeu, were prepared. In aqueous solution, the copolymers can self-assemble to form core-shell-corona micelles with disulfide-linked detachable PEG corona. The PLys middle shells with primary amine groups were cross-linked by a disulfide-containing cross-linker. The morphology and stability of the micelles were thoroughly characterized by TEM, DLS and SEM. Upon the intracellular environment, the micelles undergo the destruction of cross-linked shell and the detachment of PEG corona due to the cleavage of disulfide bond, followed by the collapse of the micelles. The in-vitro drug release in response to GSH was studied. Interestingly, it showed the micelles not only reduced the drug loss at extracellular environments but also accelerated the drug release at the cytoplasmic GSH level, resulting to enhanced growth inhibition to HeLa cells,.These glutathione-responsive micelles might have great potential applications in intracellular drug delivery.