Self-assembly Of Small Peptides And Their Applications In Biomedical Field

In recent years, the self-assembly of peptides has been a research focus. Through rational designing the molecular structures of peptides and altering the external environment, peptides can spontaneously or induced self-assemble into specific-shape aggregates via noncovalent forces, such as hydrogen bonding, hydrophobic and π-stacking interactions, etc. Due to well biocompatibility, controlled degradation and chemical versatility, functional materials constructed from the self-assembly of peptides present a great potential in the biomedical fields of drug delivery, tissue engineering scaffold and biomineralization. On the basis of numerous previously published research work, we designed and synthesized a series of peptides and investigated their self-assembly behaviors and applications in the field of tissue engineering in detail.Chapter1presents a detailed review of recent progress in the self-assembly of peptides, including molecular design of peptides, self-assembly mechanisms, morphologies of self-assembled aggregates and applications in material science as well as biomedical field.In chapter2, two types of small peptides with opposite charges were designed and prepared via a standard solid phase peptide (SPPS) technique. When mixing these two oppositely charged peptides in water at a neutral pH, a supramolecular hydrogel with fibroid morphology could be formed via the electrostatic attraction triggered co-assembly. Due to the weak flexibility of peptide chains and steric hindrance of rigid FMOC tails during the initial process of the co-assembly of the oppositely charged peptides, a relatively slow self-assembly was presented and a higher concentration of the oppositely charged peptides was necessary for the hydrogel formation. The strategy demonstrated here can be developed as a convenient approach for different types of functional peptides to co-assemble into multifunctional self-assembled materials.In chapter3, four peptide amphiphiles (PAsl-4) with different hydrophobic alkyl tails were fabricated and their self-assembly behaviors in aqueous medium at different pHs were investigated systematically. It was found that all the peptide amphiphiles can self-assemble at a neutral pH of7to form tightly packed nanofibers with β-sheet conformation. When altering the solution environment to basic medium (pH11), due to the strong hydrophobic interaction of long alkyl tails in PA3and PA4, their self-assembled fibrous nanostructure was not destroyed. However, the nanofibers self-assembled from PA1in which the length of alkyl tail was relatively short converted into loose spherical micelles with a β-sheet conformation. Due to the moderate length of alkyl tail in PA2, both nanofibers and micelles can be formed via the self-assembly of PA2when increasing the pH of the self-assembling system.Positively charged arginine-rich peptides with the unique properties of penetrating cell membrane and delivering DNA can be used as low toxic gene carries to achieve high gene therapy effect. Numerous researches have demonstrated that the chain conformations of the peptide-based gene carriers and the morphologies of the self-assembled aggregates have a significant influence on the effect of gene delivery and expression. In chapter4, a series of arginine-rich peptide amphiphiles were prepared via a standard solid phase peptide (SPPS) technique and their self-assembly behaviors in water and organic phases was systematically investigated. From the data obtained, the arginine-rich peptide amphiphiles with rigid N-fluorenyl-9-methoxycarbony (FMOC) tails can self-assemble into nanofibers in dimethylsulfoxide (DMSO) via the hydrogen bonding interaction among the peptide backbones and π-π interaction of FMOC tails. Whereas, the arginine-rich peptide amphiphiles with flexible aliphatic alkyl tails can self-assemble in water via the hydrogen bonding interaction among the peptide backbones and hydrophobic interaction among the alkyl tails. And the morphology of the self-assembled peptides was significantly affected by solution concentration.In chapter5, a glycine-glycine dipeptide containing a light cleaved pyrenylmethyl ester tail was designed and synthesized. When immersing this dipeptide bound quartz template into the aqueous solution of the dipeptide, chemically bound vertical aligned nanorods (CBVANs) can be formed on the surface of the quartz template via the interface self-assembly of the dipeptide. And the amount of the nanorods was increased if increasing the dipeptide solution concentration. The fluorescence spectroscopy indicated that the interface self-assembly of the dipeptide was built on the π-stacking interaction of pyrenylmethyl ester tails. Under the irradiation of UV light at365nm, due to the photosolvolysis of the pyrenylmethyl ester tail, the vertically aligned nanorods can be cleaved from the surface of the quartz template. This strategy for the formation of light sensitive CBVANs paves the way for the bottom-up construction of morphologically controlled functional material surfaces.Enzymes widely involve various biological reactions in organism and the biological glycolysis of glucose has been demonstrated to be a complicated metabolic pathway with the aid of various kinds of enzymes. In chapter6, we constructed a biological glucose metabolism by using glucose oxidase (GOx) and investigated its influence on the peptide self-assembly. Herein, two types of small peptides respectively containing acidic aspartic acid (Asp) and basic lysine (Lys) residues were designed and prepared. Because the metabolic product of GOx mediated glucose metabolism was acidic gluconic acid, the self-assembly of the small peptide containing acidic Asp residue can be triggered by the GOx mediated glucose metabolism with the appearance of a phase transition from solution to gelation (Sol-Gel). In case of the small peptide containing basic Lys residue, its self-assembly can be disturbed by GOx mediated glucose metabolism, resulting in a phase transition from gelation to solution (Gel-Sol).Shape-specific aggregates can be formed via the self-assembly of peptides. Because of the presence of numerous functional groups in the molecular structures of peptides, a variety of chemical reactions can be performed on the surface of the self-assembled aggregates of peptides to achieve the post-self-assembly modification. In chapter7, a facile strategy to perform the boron coordination reaction on a template of nanofiber was developed. Three types of small peptides with phenylboronic acid tails (peptidyl boronic acids) were designed and prepared as building blocks that can self-assemble into nanofibers. After the addition of vicinal diol structural motifs (vancomycin and glucose) to the self-assembling system, the surface boron coordination reaction occurred on the template of nanofibers resulted in the increase of the width and roughness of the nanofibers. Because the surface bound vicinal diol structural motifs had an ability to form hydrogen bonds with the peptide segments on the nanofibers, which restrained and disturbed the hydrogen bonding interaction among the nanofibers, the network structure formed based on the entanglement of nanofibers via hydrogen bonding interaction was destroyed, leading to a gel-sol transition.Glaucoma is an eye disease that can cause vision loss or blindness. The main clinical symptom of glaucoma is the increased intraocular pressure (IOP), which can put pressure on the optical disk and result in injuring the optic nerve. Currently, filtration surgery is a standard therapy for glaucoma. However, the success rate of glaucoma filtration surgery is generally limited by the formation of postoperative scarring. In clinical practice, antiproliferative drugs such as5-fluorouracil (5-Fu) is usually frequently injected to prevent postoperative scarring formation. However, the toxicity to the intraocular tissues can not be ignored due to the direct exposure to5-Fu injections. In chapter8, a biocompatible hydrogel self-assembled from a designed small peptide was prepared to load antiproliferative drug of5-Fu. After administrating this5-Fu loaded hydrogel in the filtration surgery of rabbit eyes, because of the sustained release of5-Fu from the hydrogel to inhibit the scleral flap fibrosis efficiently, the filtration fistula formed after filtration surgery was patent without postoperative scarring formation, resulting in the significantly low IOP of the rabbit eyes within postoperative28days. In comparison with the conventional5-Fu injections, the strategy demonstrated here presented several advantages including providing convenience and preventing the toxicity of5-Fu to the intraocular tissues efficiently.In order to inhibit scarring formation after glaucoma filtration surgery, antiproliferative drugs such as5-fluorouracil (5-Fu) or mitomycin C (MMC) was clinically administrated. The applications of these antiproliferative drugs generally induce toxicity to intraocular tissues such as leading to the leakage of conjunctival incision or bleb and exhibiting damage to corneal epithelium. In chapter9, a biocompatible glycopeptide containing therapeutic glucosamine moiety was designed and synthesized. When dissolving this therapeutic glycopeptide in PBS solution (pH7.4), a supramolecular hydrogel can be formed via the self-assembly of the glycopeptide. After the administration of this therapeutic glycopeptide hydrogel in the filtration surgery of the rabbit eyes, due to the glucosamine moieties of the hydrogel inhibiting the proliferation of fibroblasts mediated fibrosis, the filtration fistula formed after the filtration surgery were patent without postoperative scarring formation, resulting in the significantly low intraocular pressure (IOP) of the rabbit eyes within postoperative21day. In comparison with the traditional antiproliferative drug injections, the intraoperative administration of this glycopeptide hydrogel can achieve an equivalent therapeutic effect. Importantly, the intraoperative administration of this therapeutic glycopeptide hydrogel has the advantages including providing convenience and preventing the toxicity of antiproliferative drugs to the ocular tissues, presenting a significant potential alternative for the treatment of glaucoma.