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Innovative approaches to the use of polyamines for DNA nanoparticle preparation for gene therapy

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Abstract

Advances in genomic technologies, such as next generation sequencing and disease specific gene targeting through anti-sense, anti-gene, siRNA and microRNA approaches require the transport of nucleic acid drugs through the cell membrane. Membrane transport of DNA/RNA drugs is an inefficient process, and the mechanism(s) by which this process occurs is not clear. A pre-requisite for effective transport of DNA and RNA in cells is their condensation to nanoparticles of ~100 nm size. Although viral vectors are effective in gene therapy, the immune response elicited by viral proteins poses a major challenge. Multivalent cations, such as natural polyamines are excellent promoters of DNA/RNA condensation to nanoparticles. During the past 20 years, our laboratory has synthesized and tested several analogs of the natural polyamine, spermine, for their efficacy to provoke DNA condensation to nanoparticles. We determined the thermodynamics of polyamine-mediated DNA condensation, measured the structural specificity effects of polyamine analogs in facilitating the cellular uptake of oligonucleotides, and evaluated the gene silencing activity of DNA nanoparticles in breast cancer cells. Polyamine-complexed oligonucleotides showed a synergistic effect on target gene inhibition at the mRNA level compared to the use of polyamines and oligonucleotides as single agents. Ionic and structural specificity effects were evident in DNA condensation and cellular transportation effects of polyamines. In condensed DNA structures, correlation exists between the attractive and repulsive forces with structurally different polyamines and cobalt hexamine, indicating the existence of a common force in stabilizing the condensed structures. Future studies aimed at defining the mechanism(s) of DNA compaction and structural features of DNA nanoparticles might aid in the development of novel gene delivery vehicles.

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Acknowledgments

This work was partially supported by Italian MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca), by Istituto Superiore di Sanità “Project Italy-USA”, by funds MIUR-PRIN (Cofin) and by Istituto Pasteur -Fondazione Cenci Bolognetti (EA), and by a grant from the Foundation of the University of Medicine and Dentistry of New Jersey (PC28-11).

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The authors declare that they have no conflict of interest.

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  1. Veena Vijayanathan

    Present address: Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Ave, Bronx, NY, 10461, USA

  2. Thresia Thomas

    Present address: , 40 Caldwell Drive, Princeton, NJ, 08540, USA

Authors and Affiliations

  1. Departments of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA

    Veena Vijayanathan, Thresia Thomas & T. J. Thomas

  2. Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biochemical Sciences “A. Rossi Fanelli”, SAPIENZA University of Rome and CNR, Institute of Biology and Molecular Pathology, P.le Aldo Moro 5, 00185, Rome, Italy

    Enzo Agostinelli

  3. Environmental and Community Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA

    Thresia Thomas

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Vijayanathan, V., Agostinelli, E., Thomas, T. et al. Innovative approaches to the use of polyamines for DNA nanoparticle preparation for gene therapy. Amino Acids 46, 499–509 (2014). https://doi.org/10.1007/s00726-013-1549-2

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