Design, Synthesis And Drug Delivery Properites Of Novel Low Molecule Peptide-amphiphiles

As one kind of novel drug carrier materials, peptides have arised highly attention due to its good biological activity, biodegradability and biocompatibility. Furthermore, amphiphilic low molecule peptides can self-assemble into small size micelles in aqueous medium due to its good self-assemble performance. The core-shell structures of peptides nanomicells have been widely applied as carriers of insoluble drugs in the field of biomedical research. Generally, the curative effect of the poor water-soluble anticancer drugs is not obvious. The low molecule peptides with special physiological functions used as drug carriers can not only improve the solubility of drugs, enhance the performance of the controlled release of drugs and drug targeted therapeutic effect, but also reduce the side effects of drugs.This paper is divided into the following chapters:In chapter1, the recent application and advances of peptides and peptide poly materials in drug delivery and other biomedical applications have been reviewed. Systematically, we proved an introduction to the sources and classifications of the peptides, the synthetic principle and mechanism, research progress of the self-assembly, the application and functional physiological of the functional polypeptide. We also described the mechanism and characteristics of some bioactive peptides. Furthermore, the application prospect of peptides in cancer treatments was proposed.In chapter2, three low molecule amphiphilic peptides, VVVVVVKKGRGDS (AP1), C12KKGRGDS (AP2), FAFAFAKKGRGDS(AP3) were designed and prepared by solid-phase synthesis method. The self-assembly behaviors and acid-sensitive properties of these peptides by changing the medium pH value were studied. It was found that three peptides can assemble small size micelles in neutral medium. When changing the medium to acidic pH, the micellar structure of AP1disintegrated and there is no self-assembly structure founded in TEM vision, while the structures of peptides AP2and AP3is still exist but partial aggregation between the nanoparticles of AP2and AP3. CD and FT-IR experimental results showed that the secondary structure of AP1in neutral and acidic medium have changed.Therefore, we deduced that the excellent acid-sensitive properties derived from the change of secondary structure. The self-assembly of peptide AP1is expected to become the ideal environmental stimuli-responsive drug delivery systems for intelligent delivery of anticancer drugs.In chapter3, we conducted a series of characterization experiments focused on DOX-loaded nano-micelles with acid-sensitive peptide AP1as the carrier. The cytotoxicity and endocytosis experiments showed that AP1had not only low toxicity but also can effectively deliver DOX into tumor cells. The release of DOX in vitro at pH7.0is slow, the cumulative release amount of120h is only22%, when changing the release medium to pH5.0, there is a burst release of DOX, the cumulative release of DOX rapidly increases from~20%to85%within4h. All these results strongly demonstrated that the self-assembled micelles of the amphiphilic peptide AP1present a pH responsive drug release behavior, suggesting a potential application of these micelles as anti-tumor drug carriers for cancer therapy.In chapter4, As a plant-derived anticancer drug, curcumin has good anti-cancer properties, but its application is restricted because of its poor water solubility, bioavailability and being easily hydrolyzed. Therefore, we choose amphiphilic peptide AP2as carrier to do a systematic study of the solubilization of curcumin and the release behavior of the packaged curcumin in vitro and the targeting effect of the tumor cells. We found AP2greatly improved the solubility of curcumin with an improvement of295times. Intracellular up take experiments further validated AP2can enhance the therapeutic effect of curcumin on cancer cells, which laid the foundation for cancer treatment to seek new carrier.In chapter5, because the effect of AP2on the solubility of curcumin was not very ideal, we choose AP3as drug carrier to study its effect on the solubilization of curcumin. The experimental results show that the AP3micelle increased the solubility of curcumin about523times which compared with AP2has a greater improvement. Experimental results show that AP3can greatly improve the controlled release of curcumin in cancer treatment and intracellular endocytosis compared with AP2. AP3will be expected to be used as tumor targeting drug carrier.