Systemic RALA/iNOS nanoparticles: a potent gene therapy for metastatic breast cancer coupled as a biomarker of treatment

Simple item page
dc.contributor.authorMcCrudden, Cian M.
dc.contributor.authorMcBride, John W.
dc.contributor.authorMcCaffrey, Joanne
dc.contributor.authorAli, Ahlam A.
dc.contributor.authorDunne, Nicholas J.
dc.contributor.authorKett, Vicky L.
dc.contributor.authorCoulter, Jonathan A.
dc.contributor.authorRobson, Tracy
dc.contributor.authorMcCarthy, Helen O.
dc.contributor.funderCancer Research UK
dc.date.accessioned2017-09-26T11:39:18Z
dc.date.available2017-09-26T11:39:18Z
dc.date.issued2017
dc.description.abstractThis study aimed to determine the therapeutic benefit of a nanoparticular formulation for the delivery of inducible nitric oxide synthase (iNOS) gene therapy in a model of breast cancer metastasis. Nanoparticles comprising a cationic peptide vector, RALA, and plasmid DNA were formulated and characterized using a range of physiochemical analyses. Nanoparticles complexed using iNOS plasmids and RALA approximated 60 nm in diameter with a charge of 25 mV. A vector neutralization assay, performed to determine the immunogenicity of nanoparticles in immunocompetent C57BL/6 mice, revealed that no vector neutralization was evident. Nanoparticles harboring iNOS plasmids (constitutively active cytomegalovirus [ CMV]driven or transcriptionally regulated human osteocalcin [ hOC]-driven) evoked iNOS protein expression and nitrite accumulation and impaired clonogenicity in the highly aggressive MDA-MB-231 human breast cancer model. Micrometastases of MDA-MB-231-luc-D3H1 cells were established in female BALB/c SCID mice by intracardiac delivery. Nanoparticulate RALA/CMV-iNOS or RALA/hOC-iNOS increased median survival in mice bearing micrometastases by 27% compared with controls and also provoked elevated blood nitrite levels. Additionally, iNOS gene therapy sensitized MDA-MB-231-lucD3H1 tumors to docetaxel treatment. Studies demonstrated that systemically delivered RALA-iNOS nanoparticles have therapeutic potential for the treatment of metastatic breast cancer. Furthermore, detection of nitrite levels in the blood serves as a reliable biomarker of treatment.en
dc.description.sponsorshipCancer Research UK (C17372/A14271, C17372/A18475)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMcCrudden, C. M., McBride, J. W., McCaffrey, J., Ali, A. A., Dunne, N. J., Kett, V. L., Coulter, J. A., Robson, T. and McCarthy, H. O. (2017) 'Systemic RALA/iNOS nanoparticles: a potent gene therapy for metastatic breast cancer coupled as a biomarker of treatment', Molecular Therapy - Nucleic Acids, 6, (10pp). doi: 10.1016/j.omtn.2016.12.010en
dc.identifier.doi10.1016/j.omtn.2016.12.010
dc.identifier.endpage258
dc.identifier.issn2162-2531
dc.identifier.journaltitleMolecular Therapy - Nucleic Acidsen
dc.identifier.startpage249
dc.identifier.urihttps://hdl.handle.net/10468/4780
dc.identifier.volume6
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urihttp://www.sciencedirect.com/science/article/pii/S216225311630378X?via%3Dihub
dc.rights© 2017, the Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNitric oxide synthaseen
dc.subjectProstate canceren
dc.subjectTumor cellsen
dc.subjectMesenchymal transitionen
dc.subjectAmphipathic peptideen
dc.subjectHuman osteocalcinen
dc.subjectCarcinomaen
dc.subjectRadiationen
dc.subjectPromoteren
dc.subjectDeliveryen
dc.titleSystemic RALA/iNOS nanoparticles: a potent gene therapy for metastatic breast cancer coupled as a biomarker of treatmenten
dc.typeArticle (peer-reviewed)en
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
2288_PV.pdf
Size:
1.86 MB
Format:
Adobe Portable Document Format
Description:
Published Version
Download
Collections
Pharmacology and Therapeutics - Journal Articles