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Cancer-Specific Transgene Expression Mediated by Systemic Injection of Nanoparticles

¹ Centre for Molecular Oncology, Queen Mary's School of Medicine and Dentistry; ² Department ENT, Barts and The London NHS Trust; ³ Cancer Proteomics Laboratory, EGA Institute for Women's Health, University College London; ⁴ Cancer Research United Kingdom, Nuclear Medicine Group, St. Bartholomew's Hospital; ⁵ The School of Pharmacy, University of London, London, United Kingdom; ⁶ Centro de Investigación Biomédica de Aragón/Instituto Aragonés de Ciencias de la Salud, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain; ⁷ Institut National de la Santé et de la Recherche Médicale (INSERM) U915; ⁸ Institut du Thorax, Université de Nantes; ⁹ INSERM U948, Université de Nantes, CHU Hôtel Dieu; ¹⁰ Institut des Maladies de l'Appareil Digestif, CHU Hôtel Dieu, Nantes, France; and ¹¹ CBMN, UMR-CNRS 5248, Université Bordeaux, ENITAB, IECB, Talence, France

Requests for reprints: Georges Vassaux, Institut National de la Santé et de la Recherche Médicale U948, Laboratoire de Biothérapie, 4ème étage HNB Nord, CHU Hotel Dieu, 1 place Alexis Ricordeau, 44035 Nantes Cedex 1, France. Phone: 33-240-08-74-88; Fax: 33-240-08-75-06; E-mail: georges.vassaux{at}nantes.inserm.fr.

Key Words: Synthetic vector • gene transfer • molecular imaging • hNIS • colloidal stability of nanoparticles

The lack of safe and efficient systemic gene delivery vectors has largely reduced the potential of gene therapy in the clinic. Previously, we have reported that polypropylenimine dendrimer PPIG3/DNA nanoparticles are capable of tumor transfection upon systemic administration in tumor-bearing mice. To be safely applicable in the clinic, it is crucial to investigate the colloidal stability of nanoparticles and to monitor the exact biodistribution of gene transfer in the whole body of the live subject. Our biophysical characterization shows that dendrimers, when complexed with DNA, are capable of forming spontaneously in solution a supramolecular assembly that possesses all the features required to diffuse in experimental tumors through the enhanced permeability and retention effect. We show that these nanoparticles are of sizes ranging from 33 to 286 nm depending on the DNA concentration, with a colloidal stable and well-organized fingerprint-like structure in which DNA molecules are condensed with an even periodicity of 2.8 nm. Whole-body nuclear imaging using small-animal nano-single-photon emission computed tomography/computer tomography scanner and the human Na/I symporter (NIS) as reporter gene shows unique and highly specific tumor targeting with no detection of gene transfer in any of the other tissues of tumor-bearing mice. Tumor-selective transgene expression was confirmed by quantitative reverse transcription-PCR at autopsy of scanned animals, whereas genomic PCR showed that the tumor sites are the predominant sites of nanoparticle accumulation. Considering that NIS imaging of transgene expression has been recently validated in humans, our data highlight the potential of these nanoparticles as a new formulation for cancer gene therapy. [Cancer Res 2009;69(6):2655–62]

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