Drug Delivery Nanosystems Based On PH (Low) Insertion Peptide For Preliminary Biomedical Application

Cancer is one of the diseases that threaten human life and health。At present,Chemotherapy is an important cancer treatment, but many anticancer drugs havemany shortcomings, for example, poor targeting of tumor cells and side effects onhealthy tissues. Meanwhile, chemotherapy is easy to reduce the human immunesystem and damage to our normal body. Targeted nanodrug delivery systems canresolve these problems. Targeted nanodrug delivery systems directly targets tumor,which not only can improve the efficiency of tumor targeting, but also reduce thedrug’s toxic effects on normal tissues.One significant difference between tumors and normal tissues is that the formerexhibits an acidic extracellular environment. The acidic extracellular environmentmay serve as a general biomarker for targeting cancer. The discovery of pH (Low)Insertion Peptides offers completely new design ideals and platforms for targetingtumor acidic microenvironment. pHLIPssare water-soluble, moderately hydrophobicpolypeptides originally derived from the bacteriorhodopsin C helix, which can formhelical structures embedded in the cell membrane in acidic conditions. Therefore, wehave been developing two targeting drug delivery nanosystems for cancer treatment,based on pH-sensitive peptides targeting tumor acidic microenvironment.In chapter2, we have used gold nanorod and Chlorin e6to develop a drugdelivery nanosystem. This system with extracellular pH (pHe)-driven tumor targetingability has been successfully developed for bimodal photodynamic and photothermaltherapy. pHLIPsscan form helical structures embedded in the cell membrane andtranslocate the drug delivery nanosystem into the cell under acidic extracellularenvironment. When this occurs, Ce6separates from the AuNRs as a result ofdisulfide bond cleavage caused by intracellular glutathione (GSH), and singletoxygen is produced for PDT upon light irradiation, gold nanorods can convert thelight to heat for PTT after light irradiation, a combination of both to achievedual-mode treatment.In chapter3, we use mesoporous silica nanoparticles and pHLIPss to construct acontrolled-release drug delivery system for drug delivery. This system can achieve acontrolled release of the drug. Since mesoporous silica particles having a pore rule,easy modification of the inner and outer surfaces, a stable frame and non-toxic physiological characteristics, its use as a nanocarrier of anticancer drugdoxorubicin(Dox). In our design, pHLIPss is modified on mesoporous silicananoparticles surface, blocking the pore to prevent leakage of drugs. Once exposedto an acidic extracellular environment, pHLIPss will rapidly insert into membraneand then translocate MSNs into cells cytoplasm, where the disulfide bonds inpHLIPss will be cleaved and pHLIP will leave from the surface of MSNs, leading todrug release and cell death, due to the presence of reduced glutathione (GSH).In chapter4，we designed a series of C-rich DNA nucleotide sequences, andstudied the binding of the DNA and tumors cells under different pH. Theconformational change from the cytosine (C)-rich single-stranded DNA to i-motiftakes place at slightly acidic pH, and it may be combined with the tumor cells whilei-motif structure is formed. This work provides a basic research for the diagnosis andtreatment of tumor cells and cell imaging.