The Biomedical Applications Of Peptide Based Molecular Hydrogels

Supramolecular hydrogel formed by low-molecular-weight gelators that self-assemble in water through noncovalent interactions have attracted considerable attention because they exhibit several unique advantages,such as ease design and synthetic,readily modified with known functional motifs,good biocompatibility,low immunogenicity and toxicity,inherent biodegradability,fast responses to external stimuli.After nearly 20 years of development,peptide-based supramolecular hydrogels have already been shown great potential in the field of cell culture,cell therapy,drug delivery,disease diagnosis and treatment,immune boosting and regenerative medicine.What's more,some of them have already been commercialized.Although varieties of hydrogelators have been reported,their practical applications especially biomedical application is in its infancy.In this dissertation,we combined supramolecular hydrogel with cancer therapy,to develop efficient novel platform for chemotherapy drugs,new strategy for cell surface engineering,intracellular protein delivery as well as for efficacious protein vaccines.There are four parts in this dissertation which are shown as follows:1.Wehavedeveloped a series of hydrogelators based on Taxol and short peptides/amino acids with simple syntheticstrategies and high yields.The drug content was preciselycontrolled using different amino acid and the length of the peptide.We found that even the conjugates of Taxol and an amino acidwith hydrophilic side chains were efficient molecular hydrogelators which do not compromise the bioactivity of Taxol.We also developed a molecular hydrogel mainlycomposed of Taxol itself,which could be administrated into solidtumors to hinder their growth and prevent their metastasis.Thelow blood concentration of Taxol and high anti-cancer efficacy ofour hydrogels suggested the great potential of the gels forchemotherapy.Our hydrogel of Taxol was only a new administration form of the clinically used Taxol?R injection,which suggested itsbig possibility for the practical application.2.We have developed a novel strategy for intracellular hydrogelation by targeting mitochondrial organelles that control the cell fate.Utilizing the difference of tumor microenvironment,such as overexpression of some enzymes and reductive environment,the designed molecule could diffused into the cells,forming hydrogelation by enzymes or reductant and thus killing the tumor cells but not normal cells.What's more,due to the greater viscosity in the mitochondrial matrix of tumor cells,the critical gelation concentration thus descend which reduced the IC50 of molecular hydrogelator by a tenfold magnitude.3.We have occasionally found that several self-assemblingpeptides containing D-amino acids would bepreferentially enriched in cellular membranes at self-assembledstages while distributed evenly in the cytoplasma of cells atunassembled stages.Self-assembling peptides containing only L-amino acids distributed evenly in cytoplasma of cells at bothself-assembled and unassembled stages.More importantly,by integrating a protein binding peptide with the self-assemblingpeptide containing D-amino acids,protein could also be introduced to the cell surface.The self-assemblingpeptides containing D-amino acids could therefore be appliedfor engineering cell surface with peptides;besides cell surface,we also used the surface of protein that induced self-assembly for detecting and visualizing specific protein-peptide Interactions in both solutionand live bacteria.This novel strategy would have importantmedical applications such as in diagnosing Alzheimer'sand Prion diseases,which are associated with proteinaggregation.4.We have developed a versatile method to prepare co-assembled supramolecular nanofibers of peptides and single or multiple proteins.The room temperature stability of proteins could be greatly enhanced in our co-assembled systems.More importantly,the co-assembled nanofibers could be applied for intracellular protein delivery and increasing the efficiency of tandem enzymatic reaction.On the other hand,we have applied this novel strategy for delivering vaccines(OVA),the results indicated that the co-assembled system of hydrogel can strongly activate both humoral and cellularimmune responses to a balanced level.Further study demonstrated that the strong immune response may due to their capabilityof inducing dendritic cellmaturation,enhancing antigen uptake and presentation,as well as promoting germinalcenter formation.Our strategy opens up the possibility of molecular hydrogel in the applications of intracellular protein delivery,maintaining the stability and function of protein both in vitro and in vivo,as well as an efficient vector that optimize the efficacy of vaccines.