Combined prokaryotic-eukaryotic delivery and expression of therapeutic factors through a primed autocatalytic positive-feedback loop

Shi, Lei1,2; Yu, Bin1,2,3; Cai, Chun-Hui4,5; Huang, Wei6; Zheng, Bo-Jian7; Smith, David Keith8; Huang, Jian-Dong1,2,9

2016-01-28

10.1016/j.jconrel.2015.12.005

JOURNAL OF CONTROLLED RELEASE   影响因子和分区

0168-3659

1873-4995

Progress in bacterial therapy for cancer and infectious diseases is hampered by the absence of safe and efficient vectors. Sustained delivery and high gene expression levels are critical for the therapeutic efficacy. Here we developed a Salmonella typhimrium strain to maintain and safely deliver a plasmid vector to target tissues. This vector is designed to allow dual transcription of therapeutic factors, such as cytotoxic proteins, short hairpin RNAs or combinations, in the nucleus or cytoplasm of eukaryotic cells, with this expression sustained by an autocatalytic positive-feedback loop. Mechanisms to prime the system and maintain the plasmid in the bacterium are also provided. Synergistic effects of attenuated Salmonella and our inter-kingdom system allow the precise expression of Diphtheria toxin A chain (DTA) gene in tumor microenvironment and eradicate large established tumors in immunocompetent animals. In the experiments reported here, 26% of mice (n= 5/19) with aggressive tumors were cured and the others all survived until the end of the experiment. We also demonstrated that ST4 packaged with shRNA-encoding plasmids has sustained knockdown effects in nude mice bearing human MDA-MB-231 xenografts. Three weeks after injection of 5 x 10(6) ST4/pIKT-shPlk, PLK1 transcript levels in tumors were 62.5 +/- 18.6% lower than the vector control group (P = 0.015). The presence of PLK1 5' RACE-PCR cleavage products confirmed a sustained RNAi-mediated mechanism of action. This innovative technology provides an effective and versatile vehicle for efficient inter-kingdom gene delivery that can be applied to cancer therapy and other purposes. (C) 2015 Published by Elsevier B.V.

Bacterial therapy Tumor-targeting Salmonella Inter-kingdom delivery and dual expression (IKDE) Positive-feedback loop Metastasis

SCI ; EI

英语

其他

National Science Foundation of China (NSFC)[31200639]

Chemistry ; Pharmacology & Pharmacy

Chemistry, Multidisciplinary ; Pharmacology & Pharmacy

WOS:000368105300003

ELSEVIER SCIENCE BV

20155201731402

Cytology ; Disease control ; Diseases ; DNA ; Enzyme inhibition ; Gene therapy ; Gene transfer ; Mammals ; Salmonella ; Transcription ; Tumors ; Vector control (Electric machinery) ; Vectors

Bioengineering and Biology:461 ; Control Systems:731.1 ; Control System Applications:731.2 ; Algebra:921.1

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Univ Hong Kong, Sch Biomed Sci, Pokfulam 999077, Hong Kong, Peoples R China
2.Univ Hong Kong, Shenzhen Inst Res & Innovat, Pokfulam 999077, Hong Kong, Peoples R China
3.Shenzhen Univ, Coll Optoelect Engn, Key Lab Optoelect Devices & Syst, Minist Educ & Guangdong Prov, Shenzhen 518060, Peoples R China
4.Univ Hong Kong, Dept Obstet & Gynaecol, Pokfulam 999077, Hong Kong, Peoples R China
5.Tongji Univ, Sch Med, Adv Inst Translat Med, Shanghai 200092, Peoples R China
6.South Univ Sci & Technol China, Fac Biol, Shenzhen 518055, Peoples R China
7.Univ Hong Kong, Dept Microbiol, Pokfulam 999077, Hong Kong, Peoples R China
8.Univ Hong Kong, Sch Publ Hlth, Pokfulam 999077, Hong Kong, Peoples R China
9.Shenzhen Inst Adv Technol, Ctr Synthet Biol Engn Res, Shenzhen 518055, Peoples R China

Shi, Lei,Yu, Bin,Cai, Chun-Hui,et al. Combined prokaryotic-eukaryotic delivery and expression of therapeutic factors through a primed autocatalytic positive-feedback loop[J]. JOURNAL OF CONTROLLED RELEASE,2016,222:130-140.

Shi, Lei.,Yu, Bin.,Cai, Chun-Hui.,Huang, Wei.,Zheng, Bo-Jian.,...&Huang, Jian-Dong.(2016).Combined prokaryotic-eukaryotic delivery and expression of therapeutic factors through a primed autocatalytic positive-feedback loop.JOURNAL OF CONTROLLED RELEASE,222,130-140.

Shi, Lei,et al."Combined prokaryotic-eukaryotic delivery and expression of therapeutic factors through a primed autocatalytic positive-feedback loop".JOURNAL OF CONTROLLED RELEASE 222(2016):130-140.