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    Tunable Delivery of siRNA from a Biodegradable Scaffold for Regenerative Medicine

    Nelson, Christopher Edward
    : https://etd.library.vanderbilt.edu/etd-03242014-182641
    http://hdl.handle.net/1803/11228
    : 2014-04-16

    Abstract

    Clinical translation of RNA interference has been impeded by the lack of safe and effective technologies for cytoplasmic delivery to target cells. Regenerative medicine is a potentially high impact but relatively underexplored application area for short interfering RNA (siRNA) therapies. We have developed a versatile, biodegradable, and injectable polyester urethane (PEUR) tissue scaffold-based approach for sustained and tunable gene silencing at local tissue sites. Tissue regenerative PEUR scaffold-based delivery of endosomolytic nanoparticles (si-NPs) achieved over 90% in vivo gene silencing sustained for 35 days at a low dose of 200 µg/kg siRNA/mouse. Addition of the excipient trehalose was used to control the rate of si-NP release, which enabled modulation of the temporal gene silencing profile in vivo. Finally, prolyl hydroxylase domain 2 (PHD2) silencing studies demonstrated that this platform can promote functional tissue regenerative responses in vivo by increasing vascular volume 3-fold. This versatile system provides an efficient platform to investigate loss of function phenotypes in basic tissue engineering studies and can be therapeutically applied to silence genes that are deleterious to tissue regeneration.
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