The ability to tune size and morphology of self-assemblies is particularly relevant in the development of delivery systems. By tailoring such structural parameters, one can provide larger cargo spaces or produce nanocarriers that can be loaded by hydrophilic and hydrophobic molecules starting ideally from the same polymer building unit. We herein demonstrate that the morphology of block copolymer-based pH-triggered nanoplatforms produced from poly(2-methyl-2-oxazoline)m-b-poly[2-(diisopropylamino)-ethyl methacrylate]n (PMeOxm-b-PDPAn) is remarkably influenced by the overall molecular weight of the block copolymer, and by the selected method used to produce the self-assemblies. Polymeric vesicles were produced by nanoprecipitation using a block copolymer of relatively low molecular weight (Mn ∼ 10 kg.mol-1). Very exciting though, despite the high hydrophobic weight ratio (wPDPA > 0.70), this method conducted to the formation of core-shell nanoparticles when block copolymers of higher molecular weight were used, thus suggesting that the fast (few seconds) self-assembly procedure is controlled by kinetics rather than thermodynamics. We further demonstrated the formation of vesicular structures using longer chains via the solvent-switch approach when the "switching" to the bad solvent is performed in a time scale of a few hours (approximately 3 hs). We accordingly demonstrate that using fairly simple methods one can easily tailor the morphology of such block copolymer self-assemblies, thereby producing a variety of structurally different pH-triggered nanoplatforms via a kinetic or thermodynamically-controlled process. This is certainly attractive towards the development of nanotechnology-based cargo delivery systems.

• Klíčová slova
• Block copolymers, Micelles, Morphology control, Nanoprecipitation, Polymersomes, Solvent-switch, pH-responsiveness,
• Publikační typ
• časopisecké články MeSH

The reversible self-assembly of symmetrical block copolymers consisting of one hydrophobic block and one ionizable polyelectrolyte block of the same length has been studied in aqueous solutions by dissipative particle dynamics simulations. In addition to three standard dissipative particle dynamics forces (conservative soft repulsion, dissipative and stochastic forces), explicit interaction between smeared charges on ions and on ionized polymer beads described by the electrostatic potential with appropriately localized charges was taken into account. The self-assembly and properties of formed core-shell micelles were investigated as functions of the degree of ionization for systems differing in the hydrophobicity of the non-ionized polyelectrolyte block and in the compatibility of the polymer blocks. This study shows that micelles undergo massive dissociation with increasing degree of ionization. The simulation data compare well with the predictions of scaling theories for systems with soluble polyelectrolytes on a semi-quantitative level and broaden the knowledge of systems in poor solvents.

• Publikační typ
• časopisecké články MeSH

In recent years, polymerization-induced self-assembly (PISA) has emerged as a powerful method for the straightforward synthesis of polymer nanoparticles at high concentration. In this study, we describe for the first time the synthesis of poly(2-oxazoline) nanoparticles by dispersion cationic ring-opening polymerization-induced self-assembly (CROPISA) in n-dodecane. Specifically, a n-dodecane-soluble aliphatic poly(2-(3-ethylheptyl)-2-oxazoline) (PEHOx) block was chain-extended with poly(2-phenyl-2-oxazoline) (PPhOx). While the PhOx monomer is soluble in n-dodecane, its polymerization leads to n-dodecane-insoluble PPhOx, which leads to in situ self-assembly of the formed PEHOx-b-PPhOx copolymers. The polymerization kinetics and micellization upon second block formation were studied, and diverse nanoparticle dispersions were prepared, featuring varying block lengths and polymer concentrations, leading to dispersions with distinctive morphologies and physical properties. Finally, we developed a single-step protocol for the synthesis of polymer nanoparticles directly from monomers via gradient copolymerization CROPISA, which exploits the significantly greater reactivity of EHOx compared to that of PhOx during the statistical copolymerization of both monomers. Notably, this approach provides access to formulations with monomer compositions otherwise unattainable through the block copolymerization method. Given the synthetic versatility and application potential of poly(2-oxazolines), the developed CROPISA method can pave the way for advanced nanomaterials with favorable properties as demonstrated by using the obtained nanoparticles for stabilization of Pickering emulsions.

• Klíčová slova
• CROP, Copolymerization, Nanoparticles, PISA, Poly(2-oxazoline)s,
• Publikační typ
• časopisecké články MeSH

Amphiphilic gradient copolymers represent a promising alternative to extensively used block copolymers due to their facile one-step synthesis by statistical copolymerization of monomers of different reactivity. Herein, an in-depth analysis is provided of micelles based on amphiphilic gradient poly(2-oxazoline)s with different chain lengths to evaluate their potential for micellar drug delivery systems and compare them to the analogous diblock copolymer micelles. Size, morphology, and stability of self-assembled nanoparticles, loading of hydrophobic drug curcumin, as well as cytotoxicities of the prepared nanoformulations are examined using copoly(2-oxazoline)s with varying chain lengths and comonomer ratios. In addition to several interesting differences between the two copolymer architecture classes, such as more compact self-assembled structures with faster exchange dynamics for the gradient copolymers, it is concluded that gradient copolymers provide stable curcumin nanoformulations with comparable drug loadings to block copolymer systems and benefit from more straightforward copolymer synthesis. The study demonstrates the potential of amphiphilic gradient copolymers as a versatile platform for the synthesis of new polymer therapeutics.

• Klíčová slova
• gradient copolymers, nanomedicine, poly(2-oxazoline)s, self-assembly,
• MeSH
• hydrofobní a hydrofilní interakce MeSH
• kurkumin * chemie   MeSH
• micely * MeSH
• nosiče léků chemie   MeSH
• polymery chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kurkumin * MeSH
• micely * MeSH
• nosiče léků MeSH
• polymery MeSH

Aqueous solutions of self-assembled nanoparticles formed by biocompatible diblock copolymers of poly(epsilon-caprolactone)-block-poly(ethylene oxide) (PCL-PEO) with the same molar mass of the PEO block (5000 g mol-1) and three different molar masses of the PCL block (5000, 13 000, and 32 000 g mol-1) have been prepared by a fast mixing the copolymer solution in a mild selective solvent, tetrahydrofuran (THF)/water, with an excess of water, that is, by quenching the reversible micellization equilibrium, and a subsequent removal of THF by dialysis of the water-rich solution against water. The prepared nanoparticles have been characterized by static and dynamic light scattering and atomic force microscopy imaging. It was found that stable monodisperse nanoparticles are formed only if the initial mixed solvent contained 90 vol % THF. The results show that the prepared nanoparticles are spherical vesicles with relatively thick hydrophobic walls, that is, spherical core/shell nanoparticles with the hollow core filled with the solvent.

• MeSH
• furany chemie   MeSH
• micely MeSH
• mikroskopie atomárních sil MeSH
• nanočástice chemie   MeSH
• nosiče léků MeSH
• polyestery chemie   MeSH
• polyethylenglykoly chemie   MeSH
• polymery chemie   MeSH
• radiační rozptyl MeSH
• rozpouštědla chemie   MeSH
• rozpustnost MeSH
• statistické modely MeSH
• světlo MeSH
• voda chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• furany MeSH
• micely MeSH
• nosiče léků MeSH
• polycaprolactone MeSH Prohlížeč
• polyestery MeSH
• polyethylenglykoly MeSH
• polymery MeSH
• rozpouštědla MeSH
• tetrahydrofuran MeSH Prohlížeč
• voda MeSH

New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rh of approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.

• Klíčová slova
• EPR effect, HPMA copolymer, Micellar drug conjugate, Multidrug resistance, P-glycoprotein inhibitor, Poly(propylene oxide),
• MeSH
• akrylamidy aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• chemorezistence účinky léků   MeSH
• doxorubicin aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• micely * MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• nosiče léků aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• polymery aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• propylenglykoly aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• protinádorová antibiotika aplikace a dávkování   chemie   farmakokinetika   terapeutické užití   MeSH
• tumor burden účinky léků   MeSH
• uvolňování léčiv MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• doxorubicin MeSH
• micely * MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• polymery MeSH
• polypropylene glycol MeSH Prohlížeč
• propylenglykoly MeSH
• protinádorová antibiotika MeSH

Design and preparation of functional nanomaterials with specific properties requires precise control over their microscopic structure. A prototypical example is the self-assembly of diblock copolymers, which generate highly ordered structures controlled by three parameters: the chemical incompatibility between blocks, block size ratio and chain length. Recent advances in polymer synthesis have allowed for the preparation of gradient copolymers with controlled sequence chemistry, thus providing additional parameters to tailor their assembly. These are polydisperse monomer sequence, block size distribution and gradient strength. Here, we employ dissipative particle dynamics to describe the self-assembly of gradient copolymer melts with strong, intermediate, and weak gradient strength and compare their phase behavior to that of corresponding diblock copolymers. Gradient melts behave similarly when copolymers with a strong gradient are considered. Decreasing the gradient strength leads to the widening of the gyroid phase window, at the expense of cylindrical domains, and a remarkable extension of the lamellar phase. Finally, we show that weak gradient strength enhances chain packing in gyroid structures much more than in lamellar and cylindrical morphologies. Importantly, this work also provides a link between gradient copolymers morphology and parameters such as chemical incompatibility, chain length and monomer sequence as support for the rational design of these nanomaterials.

• Klíčová slova
• block copolymers, dissipative particle dynamics, gradient copolymers, gradient strength, microphase separation, nanomaterials, self-assembly,
• Publikační typ
• časopisecké články MeSH

The self-assembly thermodynamics of pH-sensitive di-block and tri-block gradient copolymers of acrylic acid and styrene was studied for the first time using isothermal titration calorimetry (ITC) and dynamic light scattering (DLS) performed at varying pH. We were able to monitor each step of micellization as a function of decreasing pH. The growth of micelles is a multi-stage process that is pH dependent with several exothermic and endothermic components. The first step of protonation of the acrylic acid monomer units was accompanied mainly by conformational changes and the beginning of self-assembly. In the second stage of self-assembly, the micelles become larger and the number of micelles becomes smaller. While solution acidity increases, the isothermal calorimetry data show a broad deep minimum corresponding to an exothermic process attributed to an increase in the size of hydrophobic domains and an increase in the structure's hydrophobicity. The minor change in heat capacity (ΔCp) confirms the structural changes during this exothermic process. The exothermic process terminates deionization of acrylic acid. The pH-dependence of the ζ-potential of the block gradient copolymer micelles exhibits a plateau in the regime corresponding to the pH-controlled variation of the micellar dimensions. The onset of micelle formation and the solubility of the gradient copolymers were found to be dependent on the length of the gradient block.

• Publikační typ
• časopisecké články MeSH

The influence of magnetite nanoparticles coated with poly(acrylic acid) (Fe3O4@PAA NPs) on the organization of block copolymer thin films via a self-assembly process was investigated. Polystyrene-b-poly(4-vinylpyridine) films were obtained by the dip-coating method and thoroughly examined by X-ray reflectivity, transmission electron microscopy, atomic force microscopy, and grazing incidence small-angle scattering. Magnetic properties of the films were probed via superconducting quantum interference device (SQUID) magnetometry. It was demonstrated that due to the hydrogen bonding between P4VP and PAA, the Fe3O4@PAA NPs segregate selectively inside P4VP domains, enhancing the microphase separation process. This in turn, together with employing carefully optimized dip-coating parameters, results in the formation of hybrid thin films with highly ordered nanostructures. The addition of Fe3O4@PAA nanoparticles does not change the average interdomain spacing in the film lateral nanostructure. Moreover, it was shown that the nanoparticles can easily be removed to obtain well-ordered nanoporous templates.

• Klíčová slova
• block copolymer, magnetite nanoparticles, self-assembly, thin films,
• Publikační typ
• časopisecké články MeSH

The amphiphilic polystyrene- block-poly((sulfamate-carboxylate)isoprene) (PS-PISC) diblock copolymer was synthesized from the precursor diblock copolymer polystyrene- block-isoprene by reaction with chlorosulfonyl isocyanate. The structure and behavior of self-assembled PS-PISC nanoparticles was studied in alkaline and acidic aqueous solutions by a combination of static and dynamic light scattering, analytical ultracentrifugation, atomic force and cryogenic transmission electron microscopies, NMR spectroscopy, potentiometric titration, and fluorometry using pyrene as a polarity-sensitive fluorescent probe. It was found that PS-PISC exists in aqueous solutions in the form of micellar aggregates. The aggregation tendency increases with decreasing effective charge density in the shell, that is, with decreasing pH of the solution, and aggregates found in alkaline aqueous media have much smaller molar masses than those formed in acidic media. The latter are dense, collapsed structures with immobile PISC domains in which most of the COOH and NH 2 (+)SO 3 (-) groups are buried inside of the nanoparticles. The swelling of PISC domains and disentanglement of PISC chains after addition of a base are slow processes occurring on the time scale of days.

• Publikační typ
• časopisecké články MeSH