Tao Liu,Xidong Wu,Shaohua Chen,Peina Wu,Hong Han,Hongbin Zhang,Junzheng Li,Guanxue Li,Siyi Zhang
To obtain a high-efficiency drug and gene co-delivery system to HNE-1 tumor therapy, a polymeric prodrug (PAAs-MTX) with chemotherapeutic sensibilization was synthesized consisting of a GSH-response hyperbranched poly(amido amine) (PAAs) and an antitumor drug of methotrexate (MTX). Then, the targeting molecule to HNE-1 cells, transferrin (Tf), was conjugated to form the Tf-PAAs-MTX. This polymeric prodrug could deliver MMP-9 shRNA plasmid (pMMP-9) again to form the drug and gene co-delivery system of Tf-PAAs-MTX/pMMP-9. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency to HNE-1 cells. Besides that, Tf-PAAs-MTX also showed the chemotherapeutic sensibilization effect, the formulation containing PAAs segments showed much higher cytotoxicity than that of free MTX. Benefiting from the sensibilization effect and MTX/pMMP-9 co-delivery strategy, this Tf-PAAs-MTX/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. Moreover, its biocompatibility, especially the blood compatibility was analyzed. This polymeric prodrug provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization and targeting into one single platform, which showed a promising application in nasopharyngeal carcinoma therapy.
Tao Liu,Shaohua Chen,Siyi Zhang,Xidong Wu,Peina Wu,Beiping Miao,Xiang Cai
Transferrin-functionalized chitosan-graft-poly(L-lysine) dendrons (CS–PLLD–Tf) were synthesized in this work and then used to deliver the MMP-9 shRNA plasmid to HNE-1 cells for gene therapy. The obtained CS–PLLD–Tf displayed excellent gene transfection in vitro, verifying the strategy of constructing a high-efficiency gene carrier by conjugating the multiple low generation PLLDs to one molecule of CS to form a copolymer. Particularly, CS–PLLD–Tf showed much higher gene transfection efficiency than PEI-25k and CS–PLLD in the presence of serum, and more than 40% HNE-1 cells were transfected. This result led to an obvious decrease in MMP-9 protein expression and the apoptosis of HNE-1 cells as well as inhibition of the growth and invasion of HNE-1 tumors. The in vivo anti-tumor assay showed that CS–PLLD–Tf delivered the MMP-9 plasmid effectively and the tumor volume decreased more than 77% compared with the PBS control group. Moreover, CS–PLLD–Tf displayed higher bioavailability and good biocompatibility such as lower cytotoxicity, excellent blood compatibility and non-toxicity to organs, suggesting a potential application in gene therapy of tumors.
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