Title: Biodistribution and biocompatibility of mesoporous silica nanoparticles
Authors: Daniel R. Moezzi, Erin D. Milligan, Sergio Torres, Audra Kerwin, Jeff C. Brinker, Tamara L. Anderson, Jeffrey P. Norenberg
Affiliations:
Abstract: The focus for gene therapy treatment of disease in recent years has shifted towards the development of non-viral carrier systems because of their biocompatibility and low immunogenicity. We have recently characterized drug carriers consisting of amorphous silica nanoparticle cores (~ 150-200 nm) containing pores (~2.5 nm pore diameter) that act to increase the surface area for cargo loading onto the silica cores. The silica cores support lipid bilayers, and are referred to as 'protocells', which may be promising gene and drug delivery carriers to brain and spinal cord following peri-spinal delivery into the subarachnoid space (intrathecal; i.t.). Specifically, positively charged, 1, 2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP) -cholesterol (DOTAP:Chol) liposome-formulated protocells revealed in vitro cargo release of Dextran Tetramethyl rhodamine (DexRho), which is a small molecule ~2nm that can load onto the pores, with release of up to ~40% at pH 7.4 for 1 week. Robust cellular IL-10 transgene transfection in cell cultures delivered by protocells was also observed. However, little work has been conducted on treatment possibilities for neurological diseases such as chronic neuropathic pain. In the present work, we examined the biodistribution using small animal Single Photon Emission Computed Tomography (SPECT) following Iodinated (I125)-protocells injected by i.t. or intravenous (i.v.) route. Following i.v. and i.t. I125-protocells in separate groups of rats (N=2), SPECT imaging (dorsal, ventral, and cross-sections) was evaluated at 0,5,24 and at weekly intervals for 8 weeks, or until I125-protocells were no longer detected. SPECT imaging is ongoing, however, i.v. I125-protocells rapidly localize to the lungs and redistribute to the filter organs. Conversely, i.t. I125-protocells remain highly localized with little diffusion. Additionally, the biocompatibility of I125-protocells, or their constituents, were examined in-vitro in murine macrophage cells (RAW 264.7). Pilot data indicate that protocells do not elevate nitric oxide, a pro-inflammatory molecule released during inflammation or other proinflammatory cytokines. Protocell vectors offer amenable biological characteristics for therapeutic gene transfer.