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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.

SUBMITTER: Newland B

PROVIDER: S-EPMC3630533 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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GDNF gene delivery via a 2-(dimethylamino)ethyl methacrylate based cyclized knot polymer for neuronal cell applications.

Newland B B Abu-Rub M M Naughton M M Zheng Y Y Pinoncely A V AV Collin E E Dowd E E Wang W W Pandit A A

ACS chemical neuroscience 20130211 4

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 kno ...[more]

PMID: 23391146

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Project description:Lignin is a natural renewable biomass resource with great potential for applications, while its development into high value-added molecules or materials is rare. The development of biomass lignin as potential nonviral gene delivery carriers was initiated by our group through the "grafting-from" approach. Firstly, the lignin was modified into macroinitiator using 2-bromoisobutyryl bromide. Then cationic polymer chains of poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) were grown from the lignin backbone using atom transfer radical polymerization (ATRP) to yield lignin-PDMAEMA graft copolymers (LPs) with branched structure. To gain a deep understanding of the relationship between the nonviral gene transfection efficiency of such copolymers and their structural and compositional factors, herein eight lignin-based macroinitiators with different modification degrees (MDs, from 3.0 to 100%) were synthesized. Initiated by them, a series of 20 LPs were synthesized with varied structural factors such as grafting degree (GD, which is equal to MD, determining the cationic chain number per lignin macromolecule), cationic chain length (represented by number of repeating DMAEMA units per grafted arm or degree of polymerization, DP) as well as the content of N element (N%) which is due to the grafted PDMAEMA chains and proportional to molecular weight of the LPs. The in vitro gene transfection capability of these graft copolymers was evaluated by luciferase assay in HeLa, COS7 and MDA-MB-231cell lines. Generally, the copolymers LP-12 (N% = 7.28, MD = 36.7%, DP = 13.6) and LP-14 (N% = 6.05, MD = 44.4%, DP = 5.5) showed good gene transfection capabilities in the cell lines tested. Overall, the performance of LP-12 was the best among all the LPs in the three cell lines at the N/P ratios from 10 to 30, which was usually several times higher than PEI standard. However, in MDA-MB-231 at N/P ratio of 30, LP-14 showed the best gene transfection performance among all the LPs. Its gene transfection efficiency was ca. 11 times higher than PEI standard at this N/P ratio. This work demonstrated that, although the content of N element (N%) which is due to the grafted PDMAEMA chains primarily determines the gene transfection efficiency of the LPs, it is not the only factor in explaining the performance of such copolymers with the branched structure. Structural factors of these copolymers such as grafting degree and cationic chain length could have a profound effect on the copolymer performance on gene transfection efficiency. Through carefully adjusting these factors, the gene transfection efficiency of the LPs could be modulated and optimized for different cell lines, which could make this new type of biomass-based biomaterial an attractive choice for various gene delivery applications.

Project description:ObjectivesThe susceptibility of methacrylates to hydrolytic and enzymatic degradation may be a contributing factor limiting the clinical lifespan of resin composite restorations. The elimination of labile ester bonds is a potential advantage of methacrylamides, which have been shown to produce more stable restorative interfaces. The rationale of this study is to design hydrolytically and enzymatically stable adhesive monomers, with the added benefit of being able to form crosslinked networks. The objective of this study was to synthesize difunctional, hybrid methacrylate-methacrylamide monomers, and evaluate them as potential monomers for dental adhesives.Materials and methodsHEMA, TEGDMA (controls) or secondary methacrylamides (HEMAM - commercially available, 2EM and 2dMM - newly synthesized) either bearing a hydroxyl group or a methacrylate functionality (Hybrids-Hy), were added at 40mass% to bisGMA. The photoinitiator system consisted of 2-dimethoxyphenyl acetophenone (DMPA) and diphenyl iodonium hexafluorophosphate (DPI-PF6) at 0.2 and 0.4mass%, respectively. Polymerization kinetics were followed in real-time by near-IR spectroscopy during light activation at 630mW/cm2 for 300s. Water sorption and solubility (WS, SL) were measured according to ISO 4049. Storage modulus in shear (G') for 300s was obtained by oscillatory rheometry. For the microtensile bond strength (μTBS), fully formulated adhesives containing 40vol% ethanol were used to restore caries-free human third molars. Bonded specimens with 1mm2 cross-sectional area were tested after 48h and 6 months storage in water at 37°C. Single bond (SB) was tested as a commercial control. Data were analysed with one-way ANOVA and Tukey's test and Student's t-test (α=0.05).ResultsIn general, hybrid versions showed lower polymerization rate and degree of conversion, whereas the methacrylate controls, HEMA and TEGDMA, showed the highest values. The hybrid versions showed lower values of WS and SL than their monofunctional versions. HEMAM Hy showed the highest values of G' and TEGDMA, 2EM, and 2dMM-Hy the lowest. The μTBS values between 48h and 6 months were statistically reduced only for the HEMA and both 2dMM materials. The formulation containing the monofunctional methacrylamide (HEMAM) showed only 9% reduction in μTBS after 6 months of aging, while the other groups showed a decrease ranging between 18% and 33%.ConclusionOverall, hybrid monomers showed lower reactivity than their analogous monofunctional versions, but had markedly lower water sorption. Shear storage modulus was affected differently by the addition of the second functionality. HEMAM-containing systems were able to maintain stable long-term dentin bond strength, which demonstrates that bonding stability is a result of the complex interplay among the factors studied.Clinical significanceThe novel monomers showed here are potential alternatives to the current methacrylate adhesives, with selected formulations presenting greater bond stability.

Dataset Information

GDNF gene delivery via a 2-(dimethylamino)ethyl methacrylate based cyclized knot polymer for neuronal cell applications.

Publications

GDNF gene delivery via a 2-(dimethylamino)ethyl methacrylate based cyclized knot polymer for neuronal cell applications.

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