Construction Of Gene/drug Co-deliveried Polyethyleneimine/hyaluronic Acid Polyion Complexes For Cancer Therapy

The co-delivery of gene and drug shows synergistic efficacy and it has become a promising strategy for cancer therapy.In this study,polyethyleneimine(PEI)and hyaluronic acid(HA)were modified with histidine(His)to obtain PEI-His(PH)and HA-His(HH)conjugates.PH and HH could form complexes via electrostatic interactions and hydrophilic/hydrophobic interactions with gene/drug loading inside.This thesis consists three main parts as follows:(1)Preparation of PH/pDNA complexes(PD)and the study of their transfections.By varying the ratio(w/w)of His and PEI,four kinds of PH conjugates with different substitution degrees were obtained.The chemical structure of PHs was identified by 1H NMR,their degrees of substitution(DS)were 3.2%(PH1),5.4%(PH2),6.0%(PH3)and 7.3%(PH4),respectively.PH conjugates and DNA could form stable complexes(PD)via electrostatic interactions.Moreover,the particle size of these spherical PD complexes was uniform.The results showed that the DNA could be encapsulated completely at the PH/DNA weight ratio of 2:1,which induced the highest transfection efficiency among all the samples with various weight ratios.As compared with that of PEI25 K,the transfection efficiency induced by PDs were 3.6-,2.9-,2.4-,0.46-fold,respectively.Furthermore,the PH showed favorite biocompatibility.(2)Preparation HH/PH/pDNA ternary complexes(HPD)for gene therapyBy varying the ratio of His and HA,three kinds of HH conjugates with different DS of His were synthesized.The 1H NMR identified the chemical structure of HHs,and their DS of His was 6.2%(HH1),3.4%(HH2)and 2.0%(HH3),respectively.HH could coat on the surface of PD binary complexes via electrostatic interactions to form HPD ternary complexes,which possessed adjustable surface property.The results showed that three kinds of HPDs could induce efficient transfection efficiency of p53 gene at the weight ratio(w/w/w)of 7:2:1.The tumor(B16)cells were selectively inhibited by three HPDs,the cell viability was 27.7%(HPD1),35.1%(HPD2)and 47.8%(HPD3),respectively.(3)Construction of gene/drug co-delivery complexes for cancer therapyDoxorubicin(DOX)was encapsulated in HPD via hydrophilic/hydrophobic interactions.The formed DOX@HPD co-delivery complexes showed pH-sensitive drug release behavior.The cumulative drug release rate was higher than 65.0% at acidic condition.The DOX@HPD could inhibit the growth of B16 cells,the cell viability was 18.3%(DOX@HPD1),20.9%(DOX@HPD2)and 28.7%(DOX@HPD3).In summary,this study fabricated a series of pH-sensitive polyelectrolyte complexes for co-delivery of gene and therapeutic drug.The complexes could achieve targeted and efficient tumor cell inhibition.Combined with their good biocompatibility,these complexes were promising in cancer therapy.