Mesoporous silica-supported lipid bilayers (protocells) for DNA cargo delivery to the spinal cord

Abstract

Amorphous mesoporous silica nanoparticles (‘protocells’) that support surface lipid bilayers recently characterized in vitro as carrier constructs for small drug and DNA delivery are reported here as highly biocompatible both in vitro and in vivo, involving the brain and spinal cord following spinal delivery into the lumbosacral subarachnoid space (intrathecal; i.t.). Specifically, positively charged, 1, 2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP) -cholesterol (DOTAP:Chol) liposome-formulated protocells revealed stable in vitro cargo release kinetics and cellular interleukin-10 (IL-10) transgene transfection. Recent approaches using synthetic non-viral vector platforms to deliver the pain-suppressive therapeutic transgene, IL-10, to the spinal subarachnoid space has yielded promising results in animal models of peripheral neuropathy, a condition involving aberrant neuronal communication within sensory pathways in the nervous system. Non-viral drug and gene delivery protocell platforms offer potential flexibility because cargo release-rates can be pH-dependent. We report here that i.t. delivery of protocells, with modified chemistry supporting a surface coating of DOTAP:Chol liposomes and containing the IL-10 transgene, results in functional suppression of pain-related behavior in rats for extended periods. This study is the first demonstration that protocell vectors offer amenable and enduring in vivo biological characteristics that can be applied to spinal gene delivery.

Nanoparticle Technologies in the Spinal Cord

“…Papastefanaki et al, 2015], polymers (poly(lactic-co-glycolic acid) [PLGA], polycaprolactone, etc.) [Chvatal et al, 2008;Papa et al, 2016], liposomes , and several other types [Basso et al, 2008;Cho et al, 2010;Dengler et al, 2013]. Different types of nanoparticles have intrinsic advantages and disadvantages, so careful selection of a particular nanoparticle type should be made based on the specific requirements of the study.…”

“…These exosomes -small extracellular vesicles released by cells -have shown potential in therapeutic applications [Rani and Ritter, 2015] and need to be further studied for spinal cord applications. Nanoparticle composites are being developed to use the properties of multiple materials in order to improve nanoparticle properties [Chen et al, 2007Bergen and Pun, 2008;Dengler et al, 2013]. Nanoparticles are also being decorated with targeting and BBB-crossing molecules in order to deliver nanoparticles from the blood stream to a site of interest [Son et al, 2011;Wiley et al, 2013;Clark and Davis, 2015].…”

Nanoparticle mediated delivery and small molecule triggered activation of proteins in the nucleus

“…Mesoporous silica nanoparticles (MSNs) are a versatile nanocarrier format that has been used for the delivery of chemotherapeutic agents[5,6], oligonucleotides[7,8], and proteins[9–11]. MSNs feature a stable framework to load and shelter cargo from proteases and the immune system and combine high cellular uptake efficiency with flexible surface functionalisation.…”

Magnetic Nanoparticle-Supported Lipid Bilayers for Drug Delivery

“…Indeed, analogous mesoporous silica nanoparticle-supported lipid bilayers (SLBs) have been described for delivery of small molecules, including peptides, 27 as well as for siRNA 28 and DNA delivery. 29 We report here the preparation of a self-assembling, magnetic nanoparticle-SLB tailored for biological applications with suitable size and charge character for efficient cellular internalization. To demonstrate the potential of the system as a nanocarrier for drug delivery, we prepared an amphiphilic derivative of the anticancer agent doxorubicin for incorporation into the supported bilayer.…”