Preparation Of PH Sensitive HA/PEI Polyion Complexes And Their Applications In Drug And Gene Delivery

Polyion complexes(PICs) with special size and structure have been widely used in antitumor chemotherapy drugs and gene delivery as nanocarriers. Herein, hyaluronic acid(HA) and polyethylenimine(PEI) were conjugated with His to prepare HA-His conjugates(HH) and PEI-His conjugates(PH), respectively, and then they were applied to form p H sensitive HH/PH PICs by electronic interactions and hydrophilic/hydrophobic interactions. The HH/PH PICs were further used for the encapsulation and delivery of model hydrophobic antitumor drug and gene.(1) Preparation and characterization of p H-sensitive HH/PH PICs.First, the chemical structures of HH and PH were identified by 1H NMR and their degrees of substitution(DS) were calculated to be 18% and 16%, respectively. HH and PH could self assemble in aqueous solution to form HH/PH PICs. The size of HH/PH PICs was able to adjust ranging from 98.5 nm to 410.5 nm by changing the weight ratios of HH/PH, and the electronic properties were also detected. HH/PH PICs of the weight ratio at 4:1 had the mean size of 192.8 nm and the ζ-potential of-32.1 m V. These HH/PH PICs showed an increased average size with the decrease of p H value and were used for further study.(2) Application of HH/PH PICs in drug delivery.HH/PH PICs were used for encapsulation and delivery of model hydrophobic antitumor drug doxorubicin(DOX). DOX was first encapsulated to form PH/DOX complexes by PH through hydrophilic/hydrophobic interactions, where the encapsulation efficiency and loading efficiency of DOX were 57.6% and 13.6%. The PH/DOX complexes were further coated by HH via electronic interaction to obtain DOX-loaded HH/PH PICs. They were of good dispersity and stability in the solution containing serum. In vitro drug release assay demonstrated that the DOX release rate were higher at low p H, the accumulated drug release amount was 70.2% at p H 5.5 in 100 h. Cytotoxicity and cellular uptake experiments showed that DOX-loaded HH/PH PICs could targetedly deliver DOX to B16F10 tumor cells through CD44 receptor-mediating, showing improved antitumor activity.(3) Application of HH/PH PICs in gene delivery.PH could combine with DNA to form PH/DNA complexes(PD complexes) through electronic interaction. The DNA could be entirely packed inside the PD complexes by regulating the weight ratio of PH and DNA. The obtained HH/PH/DNA complexes(HPD complexes) had negatively charged surface and the mean size of 142 nm. They had stable structure and could protect DNA from degrading by DNase I, showing good stability in the solution with serum. Neither charge property nor size distribution was interacted by serum. Cytotoxicity assay showed the HPD complexes have lower toxicity than PEI/DNA complexes. HPD complexes could induce gene transfection with the efficiency of 2.88%.The results suggested that the drug and gene carriers based on HA and PEI have favorable biocompatibility. HH/PH PICs with tumor targeting and p H sensibility showed great potential as the drug and gene carrier in tumor therapy.