GDNF Gene Delivery via a 2-(Dimethylamino)ethyl Methacrylate Based Cyclized Knot Polymer for Neuronal Cell Applications

Abstract

Nonviral genetic therapeutic intervention strategies for neurological disorders hold great promise, but a lack of vector efficacy, coupled with vector toxicity, continue to hinder progress. Here we report the application of a newly developed class of polymer, distinctly different from conventional branched polymers, as a transfection agent for the delivery of glial cell line derived neurotrophic factor (GDNF) encoding gene. This new 2-(dimethylamino)ethyl methacrylate (DMAEMA) based cyclized knot polymer was studied for neuronal cell transfection applications, in comparison to branched polyethyleneimine (PEI). While showing a similar transfection profile over multiple cell types, the cyclized knot polymer showed far lower toxicity. In addition, transfection of Neu7 astrocytes with the GDNF encoding gene was able to cause neurite outgrowth when cocultured with dorsal root ganglia (DRGs). The cyclized knot polymer assessed here (PD-E 8%PEG), synthesized via a simple one-pot reaction, was shown to have great potential for neuronal gene therapy applications.

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

“…Consequently, the direct delivery of GDNF to the brain was the primary focus of translational research. Delivery strategies have included the direct administration of the molecule, its encapsulation in microspheres composed of biodegradable polymers to achieve a controlled release over a prolonged period of time, DNA nanoparticle gene transfer, and convection-enhanced delivery [76][77][78][79]. Interactions of GDNF with components of the extracellular matrix ,its activation of receptors other than RET/GFRα1, induction of anti-GDNF antibodies by recombinant GDNF are all factors hampering the use of the full molecule in therapy.…”

Prospects for polymer therapeutics in Parkinson's disease and other neurodegenerative disorders

“…There is therefore perhaps a tradeoff between simplicity/translation to the clinic/viable upscale (supply), and complexity/efficiency/demand. The aim of much of Wang's research is therefore to make simple and efficient vectors as a starting point which contain free vinyl groups [71,96,97] to allow simple post synthesis functionalization via Michael addition for example with antibody fragments [98]. However, more complex delivery systems may include multiple functional moieties such as a polymalic acid vector developed for systemic delivery of antisense oligonucleotides against glioblastoma (see Fig.…”

“…Depending on whether a macroscale hydrogel is being designed or a nanoscale drug delivery device, the polymer structure may be vastly different. The desired structure will not only determine whether crosslinking monomers (such as divinyls) are used, but also how drugs are loaded [130], nucleic acid interactions [96,131,132], and mechanical properties [133] to name but a few.…”

“…9), single cyclized molecules can be formed which can be used for gene vectors for neural cells (Fig. 13) [78,96].…”

Novel pH- and temperature-responsive polymer: Tertiary amine starch ether

“…PDMA has antibacterial, hemostatic, and anticancer activity (Rawlinson et al, 2010). It has been employed in the preparation of new drug or gene delivery systems because of excellent biocompatibility (Newland et al, 2013;Peng et al, 2011). The cloud points of PDMA can be easily turned by adjusting the pH of the aqueous solution.…”