File Download
  Links for fulltext
     (May Require Subscription)

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

TitleCombined prokaryotic–eukaryotic delivery and expression of therapeutic factors through a primed autocatalytic positive-feedback loop
Authors
Issue Date2016
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jconrel
Citation
Journal of Controlled Release, 2016, v. 222, p. 130-140 How to Cite?
AbstractProgress 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 × 106 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.
Persistent Identifierhttp://hdl.handle.net/10722/233560
ISSN
2015 Impact Factor: 7.441
2015 SCImago Journal Rankings: 2.827

 

DC FieldValueLanguage
dc.contributor.authorShi, L-
dc.contributor.authorYu, B-
dc.contributor.authorCai, CH-
dc.contributor.authorHuang, W-
dc.contributor.authorZheng, B-
dc.contributor.authorSmith, DK-
dc.contributor.authorHuang, J-
dc.date.accessioned2016-09-20T05:37:37Z-
dc.date.available2016-09-20T05:37:37Z-
dc.date.issued2016-
dc.identifier.citationJournal of Controlled Release, 2016, v. 222, p. 130-140-
dc.identifier.issn0168-3659-
dc.identifier.urihttp://hdl.handle.net/10722/233560-
dc.description.abstractProgress 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 × 106 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.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jconrel-
dc.relation.ispartofJournal of Controlled Release-
dc.rights© 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleCombined prokaryotic–eukaryotic delivery and expression of therapeutic factors through a primed autocatalytic positive-feedback loop-
dc.typeArticle-
dc.identifier.emailYu, B: ppayubin@hku.hk-
dc.identifier.emailZheng, B: bzheng@hkucc.hku.hk-
dc.identifier.emailSmith, DK: dsmith@hku.hk-
dc.identifier.emailHuang, J: jdhuang@hku.hk-
dc.identifier.authorityHuang, W=rp01335-
dc.identifier.authorityZheng, B=rp00353-
dc.identifier.authorityHuang, J=rp00451-
dc.description.naturepostprint-
dc.identifier.doi10.1016/j.jconrel.2015.12.005-
dc.identifier.hkuros265594-
dc.identifier.volume222-
dc.identifier.spage130-
dc.identifier.epage140-
dc.publisher.placeNetherlands-
dc.customcontrol.immutablesml 161031 - embargo 12 months, pub date: 2016 Jan 28-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats