Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high... Show moreTumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary In-111-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used. Show less
We investigate the effect of polymer length dispersity on the properties of self-assembled micelles in solution by self-consistent field calculations. Polydispersity stabilizes micelles by raising... Show moreWe investigate the effect of polymer length dispersity on the properties of self-assembled micelles in solution by self-consistent field calculations. Polydispersity stabilizes micelles by raising the free energy barriers of micelle formation and dissolution. Most importantly, it significantly reduces the size fluctuations of micelles: Block copolymers of moderate polydispersity form more uniform particles than their monodisperse counterparts. We attribute this to the fact that the packing of the solvophobic monomers in the core can be optimized if the constituent polymers have different length. Show less
Settanni, G.; Schafer, T.; Muhl, C.; Barz, M.; Schmid, F. 2018
Nanoparticles coated with hydrophilic polymers often show a reduction in unspecific interactions with the biological environment, which improves their biocompatibility. The molecular determinants... Show moreNanoparticles coated with hydrophilic polymers often show a reduction in unspecific interactions with the biological environment, which improves their biocompatibility. The molecular determinants of this reduction are not very well understood yet, and their knowledge may help improving nanoparticle design. Here we address, using molecular dynamics simulations, the interactions of human serum albumin, the most abundant serum protein, with two promising hydrophilic polymers used for the coating of therapeutic nanoparticles, poly(ethyleneglycol) and poly-sarcosine. By simulating the protein immersed in a polymer-water mixture, we show that the two polymers have a very similar affinity for the protein surface, both in terms of the amount of polymer adsorbed and also in terms of the type of amino acids mainly involved in the interactions. We further analyze the kinetics of adsorption and how it affects the polymer conformations. Minor differences between the polymers are observed in the thickness of the adsorption layer, that are related to the different degree of flexibility of the two molecules. In comparison poly-alanine, an isomer of poly-sarcosine known to self-aggregate and induce protein aggregation, shows a significantly larger affinity for the protein surface than PEG and PSar, which we show to be related not to a different patterns of interactions with the protein surface, but to the different way the polymer interacts with water. (C) 2018 The Authors. Published by Elsevier B.V. Show less
Heller, P.; Zhou, J.; Weber, B.; Hobernik, D.; Bros, M.; Schmid, F.; Barz, M. 2017
Gene therapies enable therapeutic interventions at gene transcription and translation level, providing enormous potential to improve standards of care for multiple diseases. Nonviral transfection... Show moreGene therapies enable therapeutic interventions at gene transcription and translation level, providing enormous potential to improve standards of care for multiple diseases. Nonviral transfection agents and in particular polyplexes based on block ionomers are-besides viral vectors and cationic lipid formulations-among the most promising systems for this purpose. Block ionomers combine a hydrophilic noncharged block, e.g., polyethylene glycol (PEG), with a hydrophilic cationic block. For efficient transfection, however, endosomolytic moieties, e.g., imidazoles, are additionally required to facilitate endosomal escape, which raises the general question how to distribute these functionalities within the block copolymer. Combining molecular dynamics simulation with physicochemical and biological characterization, this work aims to provide a first rational for the influence of block ionomer microstructure on polyplex properties, e.g., size, shape, and transfection efficiency. Our findings underline that a triblock microstructure is most efficient in compacting pDNA, which reduces polyplex size, enhances stability against degradation by DNase I, and thus provides better transfection performance. Show less
We present a hybrid simulation method which allows one to study the dynamical evolution of self-assembling (co)polymer solutions in the presence of hydrodynamic interactions. The method combines an... Show moreWe present a hybrid simulation method which allows one to study the dynamical evolution of self-assembling (co)polymer solutions in the presence of hydrodynamic interactions. The method combines an established dynamic density functional theory for polymers that accounts for the nonlocal character of chain dynamics at the level of the Rouse model, the external potential dynamics (EPD) model, with an established Navier–Stokes solver, the Lattice Boltzmann (LB) method. We apply the method to study the self-assembly of nanoparticles and vesicles in two-dimensional copolymer solutions in a typical microchannel Poiseuille flow profile. The simulations start from fully mixed systems which are suddenly quenched below the spinodal line. In order to isolate effects caused by walls, we use a reverse Poiseuille flow geometry with periodic boundary conditions. We identify three stages of self-assembly, i.e., initial spinodal decomposition, particle nucleation, and particle growth (ripening). We find that (i) in the presence of shear the nucleation of droplets is delayed by an amount roughly proportional to the shear rate, (ii) shear flow greatly increases the rates of particle fusions, and (iii) in later stages of self-assembly stronger shear flows may induce irreversible shape transformation via finger formation, in particular in vesicle systems. The combination of these effects leads to an accumulation of particles close to the center of the Poiseuille flow profile, and the polymeric matter has a double peak distribution centered around the flow maximum. Show less
Sevink, G.J.A.; Schmid, F.; Kawakatsuc, T.; Milanod, G. 2017
