Systemic RALA/iNOS nanoparticles: a potent gene therapy for metastatic breast cancer coupled as a biomarker of treatment
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Published Version
Date
2017
Authors
McCrudden, Cian M.
McBride, John W.
McCaffrey, Joanne
Ali, Ahlam A.
Dunne, Nicholas J.
Kett, Vicky L.
Coulter, Jonathan A.
Robson, Tracy
McCarthy, Helen O.
Journal Title
Journal ISSN
Volume Title
Publisher
Cell Press
Published Version
Abstract
This 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.
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Keywords
Nitric oxide synthase , Prostate cancer , Tumor cells , Mesenchymal transition , Amphipathic peptide , Human osteocalcin , Carcinoma , Radiation , Promoter , Delivery
Citation
McCrudden, 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.2016.12.010