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KMID : 0369820170470020141
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Jorunal of Korean Pharmaceutical Sciences
2017 Volume.47 No. 2 p.141 ~ p.150
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Branched polymeric prodrug/programmed cell death 4 complexes for combinational cancer therapy
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He Yu Jing
Xing Lei
Cui Peng Fei
Zhang Jia Liang
Qiao Jian Bin
Luo Cheng Qiong
Jiang Ge
Jiang Hu Lin
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Abstract
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Here, we demonstrate a co-delivery system constructed by integrating chemotherapeutic molecules into branched polymeric prodrug which can condense nucleic acids. Demethylcantharidate (DCA) was chosen as a model drug and premodified through nucleophilic substitution reaction by its two carboxylic groups with allyl chloride. The synthesized intermediate (DCA-dially) was then used to polymerize with tris (2-aminoethyl) amine (TAEA) through progressively ammonolysis reaction. The obtained poly (DCA-alt-TAEA) (DCAT) was used to pack PDCD4 into spherical-like nanoparticles through electrostatic interaction. Gel retardation assays implied that DCAT could integrate DNA at the weight ratio of 1 and protect it from digestion by nuclease. Acid-base titration experiments showed that DCAT obtained preferable buffering capability which was beneficial for the endosomal escape of DCAT/PDCD4 complexes. Cellular tests involving gene transfection efficiency and cytotoxicity indicated that DCA and PDCD4 co-delivered by the complexes significantly and synergistically suppressed the viability of SMMC-7721 cells. These results suggest that integrating chemotherapeutic molecules into nucleic acid-packing polymeric prodrug as cationic polymer/PDCD4 complexes is a highly efficient way to co-deliver chemotherapeutic drugs and nucleic acids for cancer therapy.
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KEYWORD
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Demethylcantharidate, Prodrug, PDCD4, Co-delivery system
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