One-step assembly of polymeric demethylcantharate prodrug/Akt1 shRNA complexes for enhanced cancer therapy

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• 作者：Jia-Liang Zhang^a ; Jia-Hui Gong^b ; Lei Xing^b ; Peng-Fei Cui^b ; Jian-Bin Qiao^b ; Yu-Jing He^b ; Mei Zhang^b ; Jin-Yuan Lyu^b ; Cheng-Qiong Luo^b ; Shun-Ai Che^a ; Tuo Jin^d ; ^{tjin@sjtu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Hu-Lin Jiang^b ; ^c ; ^{jianghulin3@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PEI ; polyethyleneimine ; DCAD ; demethylcantharate diacrylate ; DCA ; demethylcantharate ; poly(EI ; co-DCA) poly(ethylenimine-co-demethylcantharate) ; NCTD ; norcantharidin ; HEA ; 2-hydroxyethyl acrylate ; DMEM ; Dulbeco&rsquo ; s Modified Eagle Medium ; MTT ; 3-(4 5-dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide ; Lipo 2000 ; Lipofectamine® ; 2000 ; FBS ; fetal bovine serum ; scr ; scrambled shRNA encoded plasmid ; ACTD ; acryloyloxyethylnorcantharidin ; DMAP ; 4-(dimethylamino) pyridine ; EDCI ; N-(3-Dimethyla
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：20 November 2016
• 年：2016
• 卷：513
• 期：1-2
• 页码：612-627
• 全文大小：4421 K

文摘

This report demonstrated a one-step assembly for co-delivering chemotherapeutics and therapeutic nucleic acids, constructed by integrating drug molecules into a nucleic acid condensing polymeric prodrug through degradable linkages. Demethylcantharate was selected as the model drug and pre-modified by esterifying its two carboxylic groups with 2-hydroxyethyl acrylate. The synthesized demethylcantharate diacrylate was then used to polymerize with linear polyethyleneimine (PEI 423) through a one-step Michael-addition reaction. The obtained cationic polymeric demethylcantharate prodrug was used to pack Akt1 shRNA into complexes through a one-step assembly. The formed complexes could release the parent drug demethylcantharate and Akt1 shRNA through the hydrolysis of ester bonds. Cellular assays involving cell uptake, cytotoxicity, and cell migration indicated that demethylcantharate and Akt1 shRNA co-delivered in the present form significantly and synergistically suppress the growth and metastasis of three human cancer cells. This work suggests that incorporating drug molecules into a nucleic acid-packing cationic polymer as a polymeric prodrug in a degradable form is a highly convenient and efficient way to co-deliver drugs and nucleic acids for cancer therapy.