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

Cian M. McCrudden, John W. McBride, Joanne McCaffrey, Ahlam A. Ali, Nicholas J. Dunne, Vicky L. Kett, Jonathan A. Coulter, Tracy Robson, Helen O. McCarthy

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
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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 were established in female BALB/c SCID mice by intracardiac delivery. Nanoparticulate RALA/CMV-iNOS or RALA/hOC-iNOS increased mean survival in mice bearing micrometastases by 27% compared to controls, and also provoked elevated blood nitrite levels. Additionally iNOS gene therapy sensitized MDA-MB-231-luc-D3H1 tumors to docetaxel treatment. Studies demonstrated that systemically delivered RALA-iNOS nanoparticles has therapeutic potential for the treatment of metastatic breast cancer. Furthermore, detection of nitrite levels in the blood serves as a reliable biomarker of treatment.
Original languageEnglish
Pages (from-to)249-258
Number of pages10
JournalMolecular Therapy: Nucleic Acids
Volume6
Early online date31 Dec 2016
DOIs
Publication statusPublished - 17 Mar 2017

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