One-step assembly of polymeric demethylcantharate prodrug/Akt1 shRNA complexes for enhanced cancer therapy.
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.
School of Chemistry and Chemical Engineering, State Key Laboratory Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
Jia-Liang
JL
Zhang
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Jia-Hui
JH
Gong
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Lei
L
Xing
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Peng-Fei
PF
Cui
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Jian-Bin
JB
Qiao
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Yu-Jing
YJ
He
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Mei
M
Zhang
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Jin-Yuan
JY
Lyu
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Cheng-Qiong
CQ
Luo
School of Chemistry and Chemical Engineering, State Key Laboratory Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
Shun-Ai
SA
Che
School of Pharmacy, Shanghai Jiao Tong University 800 Dongchuan Rd., Shanghai, 200240, China. Electronic address: tjin@sjtu.edu.cn.
Tuo
T
Jin
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China. Electronic address: jianghulin3@163.com.
Hu-Lin
HL
Jiang
D000179:Acrylates / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D002193:Cantharidin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D065546:Drug Liberation; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006868:Hydrolysis; D058105:Polymerization; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D034741:RNA, Small Interfering / Q000737:chemistry
D000179:Acrylates; D000970:Antineoplastic Agents; D011108:Polymers; D011355:Prodrugs; D034741:RNA, Small Interfering; C464435:demethylcantharidin; D049452:Green Fluorescent Proteins; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt; D002193:Cantharidin
Akt1 shRNA; Cancer therapy; Co-delivery; Demethylcantharate; Polymeric prodrug