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Polydepsipeptide Block-Stabilized Polyplexes for Efficient Transfection of Primary Human Cells
(2017)
The rational design of a polyplex gene carrier aims to balance maximal effectiveness of nucleic acid transfection into cells with minimal adverse effects. Depsipeptide blocks with an M (n) similar to 5 kDa exhibiting strong physical interactions were conjugated with PEI moieties (2.5 or 10 kDa) to di- and triblock copolymers. Upon nanoparticle formation and complexation with DNA, the resulting polyplexes (sizes typically 60-150 nm) showed remarkable stability compared to PEI-only or lipoplex and facilitated efficient gene delivery. Intracellular trafficking was visualized by observing fluorescence-labeled pDNA and highlighted the effective cytoplasmic uptake of polyplexes and release of DNA to the perinuclear space. Specifically, a triblock copolymer with a middle depsipeptide block and two 10 kDa PEI swallowtail structures mediated the highest levels of transgenic VEGF secretion in mesenchymal stem cells with low cytotoxicity. These nanocarriers form the basis for a delivery platform technology, especially for gene transfer to primary human cells.
Mimicking the binding epitopes of protein-protein interactions by using small peptides is important for generating modular biomimetic systems. A strategy is described for the design of such bioactive peptides without accessible structural data for the targeted interaction, and the effect of incorporating such adhesion peptides in complex biomaterial systems is demonstrated. The highly repetitive structure of decorin was analyzed to identify peptides that are representative of the inner and outer surface, and it was shown that only peptides based on the inner surface of decorin bind to collagen. The peptide with the highest binding affinity for collagenI, LHERHLNNN, served to slow down the diffusion of a conjugated dye in a collagen gel, while its dimer could physically crosslink collagen, thereby enhancing the elastic modulus of the gel by one order of magnitude. These results show the potential of the identified peptides for the design of biomaterials for applications in regenerative medicine.
Polyester networks can be prepared by ultraviolet (UV)-light-induced radical polymerization of methacrylate functionalized oligo(epsilon-caprolactone)s. The properties and functions of the obtained materials depend on defined network structures and may be altered, if crosslinking would occur by side reactions in other positions than the methacrylate endgroups. In order to explore whether and to which extent such side reactions occur, network synthesis as well as related model reactions were performed in the absence of photoinitiator. Hereby precursor structures (linear and four-arm star-shaped) and reaction conditions (in solution and in the melt) were varied. Unspecific side reactions were found only upon extensive UV irradiation for 60min (26 mW cm(-2)) with minor but detectable alterations of physicochemical properties of the networks. The analysis of model reactions suggested minor photolytic cleavage of ester bonds during polymer network synthesis. However, the effect of these side reactions on network properties and functions appeared to be less relevant than an incomplete precursor integration because of a too short UV irradiation for crosslinking. Copyright (c) 2014 John Wiley & Sons, Ltd.
Purpose: Polymer networks with adjustable properties prepared from endgroup-functionalized oligoesters by UV-crosslinking in melt have evolved into versatile multifunctional biomaterials. In addition to the molecular weight or architecture of precursors, the reaction conditions for crosslinking are pivotal for the polymer network properties. Crosslinking of precursors in solution may facilitate low-temperature processes and are compared here to networks synthesized in melt.
Methods: Oligo(epsilon-caprolactone)-(z) methacrylate (oCL-(z) IEMA) precursors with a linear (z = di) or a four-armed star-shaped (z = tetra) architecture were crosslinked by radical polymerization in melt or in solution with UV irradiation. The thermal, mechanical, and swelling properties of the polymer networks obtained were characterized.
Results: Crosslinking in solution resulted in materials with lower Young's moduli (E), lower maximum stress (sigma(max)), and higher elongation at break (epsilon(B)) as determined at 70 degrees C. Polymer networks from 8 kDa star-shaped precursors exhibited poor elasticity when synthesized in the melt, but can be established as stretchable materials with a semi-crystalline morphology, a high gel-content, and a high elongation at break when prepared in solution.
Conclusions: The crosslinking condition of methacrylate functionalized precursors significantly affected network properties. For some types of precursors such as star-shaped telechelics, synthesis in solution provided semi-crystalline elastic materials that were not accessible from crosslinking in melt.