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

doi:10.1016/j.omtn.2016.12.010

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

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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 language	English
Pages (from-to)	249-258
Number of pages	10
Journal	Molecular Therapy Nucleic Acids
Volume	6
Early online date	31 Dec 2016
DOIs	https://doi.org/10.1016/j.omtn.2016.12.010
Publication status	Published - 17 Mar 2017

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Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment
Copyright 2017 The Authors This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.86 MBLicence: CC BY

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

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.",

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

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AU - McCrudden, Cian M.

AU - McBride, John W.

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AU - Ali, Ahlam A.

AU - Dunne, Nicholas J.

AU - Kett, Vicky L.

AU - Coulter, Jonathan A.

AU - Robson, Tracy

AU - McCarthy, Helen O.

PY - 2017/3/17

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AB - 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.

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DO - 10.1016/j.omtn.2016.12.010

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JO - Molecular Therapy Nucleic Acids

JF - Molecular Therapy Nucleic Acids

ER -

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

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