Gene-activated and cell-migration guiding PEG matrices based on three dimensional patterning of RGD peptides and DNA complexes
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Matrix (chemical analysis)
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The development of gene therapy puts forward the requirements for efficient delivery of genetic information into diverse cells. However, in some cases of transfection, especially those for transfecting some primary cells and for delivering large size plasmid DNA (pDNA), the existing conventional transfection methods show poor efficiency. How to further improve transfection efficiency in these hard-to-achieve issues remains a crucial challenge. Here, we report a photothermal-assisted surface-mediated gene delivery based on a polydopamine-polyethylenimine (PDA-PEI) surface. The PDA-PEI surface was prepared through PEI-accelerated dopamine polymerization, which showed efficiency in the immobilization of PEI/pDNA polyplexes and remarkable photothermal properties. Upon IR irradiation, we observed improved transfection efficiencies of two important hard-to-achieve transfection issues, namely the transfection of primary endothelial cells, which are kinds of typical hard-to-transfect cells, and the transfection of cells with large-size pDNA. We demonstrate that the increases of transfection efficiency were due to the hyperthermia-induced pDNA release, the local cell membrane disturbance, and the polyplex internalization. This work highlights the importance of local immobilization and release of pDNA to gene deliveries, showing great potential applications in medical devices in the field of gene therapy.
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Poly(ethylene) glycol monomethyl ethers (Peg-mmes) are a series of methyl substituted poly(ethylene) glycols that have been used with some success in the crystallization of a number of hydrophobic proteins. Crystallization of a lipase from Humicola lanuginosa complexed with the C12 substrate analogue from Peg-mme 5000, an endoglucanase 1 and a 59 kDa fragment of human topoisomerase IIalpha crystallized from Peg-mme are described. The use of Peg-mme for improving the quality of crystals previously grown from normal poly(ethylene) glycol 8000 is also described. We suggest that these modified Peg-mmes should be regularly used in screening for crystallization.
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The success of gene therapy is largely dependent on the delivery vector system. Efficient transfection and nontoxicity are two of the most important requirements of an ideal gene delivery vector. To generate both an efficient and nontoxic vector, we rationally constructed polymeric vectors to have simultaneous multiple functions, i.e., controlled degradation, an endosome disruptive function, and positive charges. Remarkably, the transfection efficiency of network poly(amino ester) (n-PAE) synthesized in this manner was comparable to that of polyethylenimine (PEI), one of the most efficient polymeric gene delivery vectors reported to date. However, there was a marked difference in cytotoxicity between the polymers. The majority of PEI-transfected cells were granulated and dead, whereas most of the cells transfected with n-PAE were viable and healthy. Successive events of efficient endosome escape of n-PAE/DNA polyplex and n-PAE biodegradation should result in high transfection efficiency and favorable cell viability response. The n-PAE-mediated transfection was also very efficient in the presence of serum. These data show that the approach we applied is a very appropriate way of making an ideal gene delivery carrier.
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The rapid developments of gene therapy are benefit from the construction of efficient gene vectors, which help therapy genes efficiently overcome the barriers in the transport and transfection. Condensing DNA into nanoparticles is a crucial role in gene transfection, and the electrostatic interactions of synthetic cationic liposomes and cationic polymers with DNA are generally used for condensing DNA. Recent research has shown that the introduction of the hydrophobic interaction, hydrogen bonding, and coordinative interactions to the gene delivery vectors is also very important for DNA condensation, delivery, and transfection. This review focuses on the four types of interactions in condensed DNA nanoparticles, which could provide a new perspective for improving gene transfection efficacy.
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As it has been generally reported that oppositely charged cationic liposomes (CLs) are superior to either neutral or anionic liposomes as gene delivery carrier, interest in the properties, structures, transfection mechanism of CLs and so forth arises unprecedentedly. However, our understanding about the mechanism of CLs-gene complexes (lipoplex)-cell interaction and factors influencing the transfection efficiency (TE) of CLs remains poor. In this article, we describe some new results aimed at elucidating the relationship between the chemical-physical properties of lipoplex with TE and introducing recent applications of CLs in gene therapy.
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The aim of the present study was to improve transfection efficiency using different combinations of cationic liposomes, linear polyethylenimine and DNA. A novel gene delivery system (lipopolyplex) was developed by premixing cationic liposomes containing cholesterol or oligoamine modified cholesterol (derivative I-III) and linear polyethyleneimines (PEIs) following addition of plasmid at three different C/P ratios. The resultant complexes were characterized for their size, zeta potential and ability of DNA condensation. Luciferase reporter gene was used for determination of transfection efficiency in Neuro2A cells. Mean particle size of prepared complexes was less than 200 nm and they showed positive surface charge. The transfection efficiency of vectors was reduced by increasing in carrier concentration/plasmid DNA ratio (C/P ratio) while gene expression of cationic liposome or PEI was increased at higher C/P ratios. Complexes composed of PEI 2.5 or 250 kDa and liposome containing derivative I had the highest transfection activity. Furthermore, non-viral vectors described in this study showed low cytotoxicity. The results show that small and large molecular weight linear PEI in combination with liposome have little toxicity and may enhance transfection efficiency. Keywords: Cationic liposome, Cytotoxicity, Gene delivery, Lipopolyplex, Polyethylenimine, Transfection, Cholesterol derivatives, Nanostructures, Non-viral gene delivery, Nanocomplexes
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This article studies the self-assembly of alginate-graft-poly(ethylene glycol) (Alg-g-PEG) and α-cyclodextrin (α-CD) in aqueous solution. It was found that they could form hollow spheres because of the formation of coil-rod Alg-g-PEG/α-CD inclusion complexes. In these Alg-g-PEG/α-CD complexes, the α-CDs are stacked along the PEG side chains to form a rod block, and alginate main chains act as a coil block. More rod-like blocks in Alg-g-PEG/α-CD favor the formation of small assemblies. The assemblies of Alg-g-PEG/α-CD show a dependence on concentration, temperature, pH, and salt concentration. At low concentration (below 0.125%) or high temperature (above 32 °C), Alg-g-PEG/α-CD particles were unstable and disrupted. Increasing the salt or decreasing the pH resulted in the aggregation of Alg-g-mPEG/α-CD particles, as detected by the increase in the recorded hydrodynamic diameter (D(h)).
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Gene therapy demonstrates promising prospects on cardiovascular diseases. However, nonviral gene delivery system has relatively low transfection efficiency, especially for endothelial cells (ECs). Herein, typical cell-penetrating peptide (TAT), nuclear localization signals (NLSs), and REDV functional peptide have been used to prepare multitargeting complexes. These complexes exhibit higher transfection efficiency owing to the targeting sequences of REDV and NLSs as well as the cell-penetrating function of TAT. The multifunction of the complexes provides high cell uptake, endo/lysosomal escape, and nucleus accumulation of the encapsulated DNA. Thus these multitargeting complexes can provide a potential platform for gene delivery, especially for EC transfection.
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Pre-existing and induced anti-poly(ethylene glycol) (PEG) antibodies (abs) have been shown to be related with limitation of therapeutic efficacy and reduction in tolerance of several therapeutic agents. However, the current methods to detect anti-PEG abs are tedious and usually lack quantification. A facile, rapid, sensitive, and reliable technique to detect anti-PEG abs is highly desired in both research and clinic settings. In this work, we have presented a surface plasmon resonance (SPR) biosensor technique for the detection of anti-PEG abs and compared three PEG surface chemistries. Methoxy-PEG (mPEG) 5k was found to have the best performance. The detection of anti-PEG abs directly from diluted blood serum was achieved within 40 min. Detection sensitivity is as good as or better than enzyme-linked immunosorbent assay (ELISA). Furthermore, different antibody isotypes can be quantitatively differentiated by adopting secondary antibodies. A pilot study has been performed to analyze clinical blood samples using this technology, demonstrating its potential as a convenient and powerful method to prescreen and monitor anti-PEG abs in the patients before or after they receive treatment with PEG-containing drugs.
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