Study On Tumor-targeting Peptide Nanofibers Of D-amino Acids As Carriers Of10-hydroxycamptothecin

Self-assembled nano-drug carriers have been intensitively applied in controlled drug release and targeting drug delivery. In addition to chemical composition, size, surface potential and other factors, recent researches have confirmed that the shape of the nanocarriers plays an important role in vivo metabolism. For some types of carriers, nanofibers have less uptake by the reticuloendothelial system (RES) and stronger tumor tissue selectivity than nanospheres. Peptide based nanomaterials have been widely used because of their good biocompatibility, easy modification by functional groups and design flexibility according to the needs through a "bottom-up" approach. Self-assembling peptide nanofiber has great application prospects in the field of drug delivery.Composed of natural amino acid (L amino acid) nanofiber in the body is easy to be a variety of protease catalytic degradation, and has the faults of poor stability and short half-life. This may cause the premature release of load drugs, and to a certain extent, restrict its applications as drug carrier in the body. D configuration amino acid introduced to the natural peptide sequence can reduce the body recognition and degradation of various of protease elimination, and show a higher stability of the configuration than L amino acids. The tripeptide motif, arginine-glycine-aspartic acid (RGD) is the binding motif of integrin αvβ3, which is overexpressed on the angiogenic endothelium in malignant tumors and is vital for the adhesion, signaling, migration and survival of integrin αvβ3overexpressed cancer cells. It has been widely used for tumor diagnosis and targeting therapy. Therefore, we designed RGD containing and L-/D-amino acid based self-assembling peptides, Nap-GFFYGRGD and Nap-GDFDFDYGRGD (L-peptide and D-peptide, respectively), as nanofiber carriers for the delivery of10-hydroxycamptothecin (HCPT) for tumor treatment research in vivo and in vitro. The experimental results show that L-peptide and D-peptide after heating boiling and natural cooling can self-assemble to form a diameter of10-20nm nanofiber (expressed by L-fiber and D-fiber). Compared with L-fiber, D-fiber has better resistance to protease K degradation ability, which shows that the introduction of D amino acids can improve the stability of polypeptide nanofibers, and laid a foundation for its application in vivo; After125I radioactive isotope labeling of peptides in vivo distribution by chloramine-T method, results show that the D-fiber and L-fiber have different metabolic regularity. L-fiber is mainly distributed in the stomach, while D-fiber is mainly distributed in the liver, and both in the tumor site has obvious accumulation; L-peptide and D-peptide can assembly form injectable drug loaded nanofibers through the hydrophobic effect with HCPT (with L-fiber-HCPT and D-fiber-HCPT); L-fiber and D-fiber as the carriers can increase HCPT solubility in the physiological environment about51times and46times, and the cell level in vitro and in vivo increased HCPT antitumor effect; Studies have shown that D-fiber-HCPT has better stability in vitro and is also better in vivo tumor treatment effect than L-fiber-HCPT.Through this thesis we completed a research of D configuration peptide nanofiber as a hydrophobic anticancer drug HCPT carrier, which can increase solubilization of HCPT, improve its anti-tumor effect in vivo and in vitro, and reduce the side effects. The design of D configuration peptide provides a new idea and method at the tumor targeting therapy and peptide drug carrier.