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

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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.
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Cell Press
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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.
Nitric oxide synthase , Prostate cancer , Tumor cells , Mesenchymal transition , Amphipathic peptide , Human osteocalcin , Carcinoma , Radiation , Promoter , Delivery
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