Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA

Koppu, Swati; Oh, Yew Jinn; Edrada-Ebel, RuAngelie; Blatchford, David R.; Tetley, Laurence; Tate, Rothwelle J.; Dufès, Christine

doi:10.1016/j.jconrel.2009.11.015

Cited by 84 publications

(56 citation statements)

References 19 publications

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“…Therefore, although extensive safety testing must be done before eventual clinical translation, our tumoractivatable MC system should be considered relatively safe. Because safety issues are primarily a concern when normal tissues are transfected, it should be noted that our system can be modified to use emerging delivery vehicles, such as more tumor-specific polymeric transfection agents that limit normal tissue transfection (29,43), and/or delivery vehicles targeted to a protein expressed at high levels by cancer cells (44). These newer delivery agents also may yield benefits in the sensitivity and specificity of tumor detection.…”

Section: Discussionmentioning

confidence: 99%

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Ronald

Chuang

Dragulescu-Andrasi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Earlier detection of cancers can dramatically improve the efficacy of available treatment strategies. However, despite decades of effort on blood-based biomarker cancer detection, many promising endogenous biomarkers have failed clinically because of intractable problems such as highly variable background expression from nonmalignant tissues and tumor heterogeneity. In this work we present a tumor-detection strategy based on systemic administration of tumor-activatable minicircles that use the pan-tumorspecific Survivin promoter to drive expression of a secretable reporter that is detectable in the blood nearly exclusively in tumor-bearing subjects. After systemic administration we demonstrate a robust ability to differentiate mice bearing human melanoma metastases from tumor-free subjects for up to 2 wk simply by measuring blood reporter levels. Cumulative change in reporter levels also identified tumor-bearing subjects, and a receiver operator-characteristic curve analysis highlighted this test's performance with an area of 0.918 ± 0.084. Lung tumor burden additionally correlated (r 2 = 0.714; P < 0.05) with cumulative reporter levels, indicating that determination of disease extent was possible. Continued development of our system could improve tumor detectability dramatically because of the temporally controlled, high reporter expression in tumors and nearly zero background from healthy tissues. Our strategy's highly modular nature also allows it to be iteratively optimized over time to improve the test's sensitivity and specificity. We envision this system could be used first in patients at high risk for tumor recurrence, followed by screening high-risk populations before tumor diagnosis, and, if proven safe and effective, eventually may have potential as a powerful cancer-screening tool for the general population.cancer | minicircles | tumor-specific promoter | reporter gene | blood test

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Section: Discussionmentioning

confidence: 99%

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Ronald

Chuang

Dragulescu-Andrasi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Generation 3-diaminobutyric polypropylenimine dendrimer (DAB, 24 mg) was conjugated to transferrin (Tf, 6 mg) by cross-linking with dimethylsuberimidate (DMSI, 12 mg) in triethanolamine HCl buffer (pH 7.4, 2 mL), as previously described [4,10]. The conjugation reaction took place at 25 o C for 2 h whilst stirring.…”

Section: Preparation Of Transferrin-bearing Polypropylenimine Dendrimermentioning

confidence: 99%

“…The conjugation reaction took place at 25 o C for 2 h whilst stirring. DAB-Tf dendrimer was then purified by size exclusion chromatography using a Sephadex G75 column, freeze-dried, before having its identity confirmed by 1 H NMR spectroscopy, using a Jeol Oxford NMR AS 400 spectrometer [4].…”

Section: Preparation Of Transferrin-bearing Polypropylenimine Dendrimermentioning

confidence: 99%

“…to 100 µg/mL. After 72 hours incubation with the treatment, antiproliferative activity was assessed by using a standard MTT assay [4] Bioluminescence imaging using an IVIS Spectrum (Caliper Life Sciences, Hopkinton, MA) was also used to monitor the therapeutic efficacy of the treatments. To this end, mice bearing subcutaneous PC-3M-luc-C6 tumors were intravenously injected with treatments as described above.…”

Section: In Vitro Transfectionmentioning

confidence: 99%

“…In order to overcome this problem, we recently demonstrated that the conjugation of transferrin (whose receptors are abundantly expressed on cancer cells) to generation 3-diaminobutyric polypropylenimine (DAB) dendrimer led to gene expression principally in the tumors following intravenous administration [4]. As a result, the intravenous administration of DAB-Tf dendrimer complexed to the Tumor Necrosis Factor (TNF±) expression plasmid led to tumor suppression for 90% of the A431 epidermoid carcinoma tumors, with long-term survival of the mice.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Efficacy of Intravenously Administered Transferrin-Conjugated Dendriplexes on Prostate Carcinomas

et al. 2014

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This version is available at https://strathprints.strath.ac.uk/42676/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. would be an attractive anti-cancer treatment strategy, however the lack of suitable carrier systems able to selectively deliver therapeutic genes to tumors has so far limited this investigation. Given that transferrin receptors are overexpressed on prostate cancer cells, the purpose of this study is to determine whether transferrinbearing dendriplex encoding TNF±, TRAIL and IL-12 would suppress the growth of prostate cancer cell lines in vitro and in vivo. TITLE Materials & Methods:Transferrin-bearing dendriplexes encoding TNF±, TRAIL and IL-12 were intravenously administered to mice bearing subcutaneous PC-3 and DU145 tumors. Results:The administration of the DAB-Tf dendriplex encoding TNF± resulted in tumor suppression for 60% of PC-3 and 50% of DU145 prostate tumors. Conclusions:These dendriplexes hold great potential as a novel approach for prostate cancer therapy. KEYWORDS 4 MATERIALS & METHODS Cell lines and reagents Preparation of transferrin-bearing polypropylenimine dendrimerGeneration 3-diaminobutyric polypropylenimine dendrimer (DAB, 24 mg) was conjugated to transferrin (Tf, 6 mg) by cross-linking with dimethylsuberimidate (DMSI, 12 mg) in triethanolamine HCl buffer (pH 7.4, 2 mL), as previously described 8 Statistical AnalysisResults were expressed as means ± standard error of the mean (S.E.M). Statistical significance was assessed by one-way analysis of variance (ANOVA) and Bonferroni multiple comparison post-test (GraphPad Prism software). P values lower than 0.05 were considered statistically different. 9 RESULTS Cellular uptake of DNAConfocal microscopy experiments confirmed that Cy3-labelled DNA was taken up by PC-3, DU145 and LNCaP cells (Figure 1). The fluorescently-labeled DNA was found to be disseminated in the cytoplasm following treatment with DAB-Tf and DAB dendriplexes in the three teste...

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Dendrimer‐Based Gene Delivery Systems: Administration Routes andIn VivoEvaluation

Santander-Ortega¹,

Uchegbu²,

Schätzlein³

2012

Dendrimer‐Based Drug Delivery Systems

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Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA

Cited by 84 publications

References 19 publications

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Therapeutic Efficacy of Intravenously Administered Transferrin-Conjugated Dendriplexes on Prostate Carcinomas

Dendrimer‐Based Gene Delivery Systems: Administration Routes andIn VivoEvaluation

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