Abstract
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.
Highlights
To be efficient against cancer, the ideal antitumoral agent would have to target malignant cells throughout the body while sparing normal tissues
At higher DNA concentrations, the complex precipitated. These results show that the size of PPIG3/DNA nanoparticles was directly dependent on the DNA loaded and led, as shown in the gallery of Fig. 2, to the formation of compact, concentric, and homogeneous structures with a fingerprint-like aspect
We show for the first time tumor-specific gene transfer on systemic injection of nanoparticles of dendrimers in tumor-bearing animal
Summary
To be efficient against cancer, the ideal antitumoral agent would have to target malignant cells throughout the body while sparing normal tissues. Cancer gene therapy has far been limited by the lack of systemically active, cancer-specific delivery vectors [1], especially in the field of nonviral, synthetic gene delivery vectors [2,3,4] In this context, we have recently described that nanoparticles composed of the polypropylenimine dendrimers of third generation (PPIG3), when complexed with DNA, are capable of efficient gene transfer to tumor deposits, upon systemic injection. Key to the furthering clinical development of this technology and its safe application in patients is the ability to monitor gene transfer in the live subject, using a minimally invasive method. This is of particular importance considering the toxic nature of the therapeutic transgenes required for cancer gene therapy. This imaging method has very recently been validated in humans [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
