Czech Academy of Sciences, Institute of Macromolecular Chemistry

Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covers the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer-drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving hydrophobic and electrostatic interactions, coordination chemistry, and encapsulation in porous materials. Principles of covalent conjugation of drugs with SPIONs including thermo- and pH-degradable bonds, amide linkage, redox-cleavable bonds, and enzymatically-cleavable bonds are also thoroughly described. Finally, results of clinical trials obtained with polymeric and magnetic carriers are analyzed highlighting the potential advantages and future directions in targeted anticancer therapy.

Abstract Eight persons from five institutions in different countries carried out polymerizations of aniline following the same preparation protocol. In a "standard" procedure, aniline hydrochloride was oxidized with ammonium peroxydisulfate in aqueous medium at ambient temperature. The yield of polyaniline was higher than 90 % in all cases. The electrical conductivity of polyaniline hydrochloride thus prepared was 4.4 ± 1.7 S cm -1 (average of 59 samples), measured at room temperature. A product with defined electrical properties could be obtained in various laboratories by following the same synthetic procedure. The influence of reduced reaction temperature and increased acidity of the polymerization medium on polyaniline conductivity were also addressed. The conductivity changes occurring during the storage of polyaniline were monitored. The density of polyaniline hydrochloride was 1.329 g cm -3 . The average conductivity of corresponding polyaniline bases was 1.4 x10­8 S cm -1 , the density being 1.245 g cm -1 . Additional changes in the conductivity take place during storage. Aging is more pronounced in powders than in compressed samples. As far as aging effects are concerned, their assessment is relative. The observed reduction in the conductivity by ~10 % after more than one-year storage is large but, compared with the low conductivity of corresponding polyaniline (PANI) base, such a change is negligible. For most applications, an acceptable level of conductivity may be maintained throughout the expected lifetime.

Polyaniline (PANI), a conducting polymer, was prepared by the oxidation of aniline with ammonium peroxydisulfate in various aqueous media. When the polymerization was carried out in the solution of strong (sulfuric) acid, a granular morphology of PANI was obtained. In the solutions of weak (acetic or succinic) acids or in water, PANI nanotubes were produced. The oxidation of aniline under alkaline conditions yielded aniline oligomers. Fourier transform infrared (FTIR) spectra of the oxidation products differ. A group of participants from 11 institutions in different countries recorded the FTIR spectra of PANI bases prepared from the samples obtained in the solutions of strong and weak acids and in alkaline medium within the framework of an IUPAC project. The aim of the project was to identify the differences in molecular structure of PANI and aniline oligomers and to relate them to supramolecular morphology, viz. the nanotube formation. The assignment of FTIR bands of aniline oxidation products is reported.

Abstract Polyaniline is one of the most important conducting and responsive polymers. A molecular mechanism for the oxidation of aniline is proposed. This mechanism explains the specific features of aniline oligomerization and polymerization in various acidity ranges. The formation of polyaniline precipitates, colloids and thin films is reviewed and discussed on the basis of the chemistry of aniline oxidation. The generation of nanostructures, i.e. granules, nanotubes, nanowires and microspheres, is also considered. Oligomers containing phenazine constitutional units play an important role in self‐assembly to form templates. Polyaniline chains then grow from these templates and produce the various individual morphologies. Copyright © 2008 Society of Chemical Industry

The objective of this study was to investigate the molecular weight (MW) and time-dependence of the phenomenon termed "the enhanced permeability and retention" (EPR) effect in solid tumor, in particular to determine and define the early phase accumulation of macromolecules in tumor and normal tissues and the relationship between blood concentration and tissue clearance. As a model, radioiodinated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers of MW ranging from 4.5 K to 800 K were administered i.v. to mice bearing sarcoma 180 tumor. Within 10 min all HPMA copolymers accumulated effectively in the tumor regardless of MW (1.0-1.5% of injected dose per g of tumor). However, higher MW copolymers (> 50 K) showed significantly increased tumor accumulation after 6 h, while the lower MW copolymers (< 40 K) were cleared rapidly from tumor tissue due to rapid diffusion back into the bloodstream. Blood clearance was also MW-dependent; the lower MW copolymers displayed rapid clearance, with kidney radioactivity of the copolymers of MW < 20 K representing 24% of injected dose per g kidney at 1 min after i.v. administration. Within 10 min these copolymers passed through the kidney and were excreted in the urine. Higher MW copolymers consistently showed kidney levels of 3-5% dose per g kidney in the early phase with no time-dependent accumulation in kidney. There was also no progressive accumulation in muscle or liver, regardless of polymer MW. These results suggest the "EPR effect" in solid tumor primarily arises from in the difference in clearance rate between the solid tumor and the normal tissues after initial penetration of the polymers into these tissues.

The course of aniline oxidation with ammonium peroxydisulfate in aqueous solutions has been investigated. The reaction was terminated at various times and the intermediates collected. Besides the precipitates, the films deposited in situ on silicon windows have also been studied. The kinetic course of polymerization is controlled by the acidity level, which changes during the polymerization from pH 8 to a final value close to pH 1. It has two distinct exothermic phases. Gel-permeation chromatography indicates that aniline oligomers are produced at first at high pH, while polyaniline follows after the pH becomes sufficiently low. The growth of polyaniline nanotubes was observed by optical microscopy and confirmed by electron microscopy. The molecular structure of the reaction intermediates was studied in detail by FTIR spectroscopy. Oxidation products are markedly sulfonated, and they contain phenazine units. Aniline oligomers are more soluble in chloroform than the polymer fraction, which contains nanotubes.

Polyethylene oxide(PEO)-containing nonionic polymeric surfactants were studied as a possible means to produce PEO-rich surfaces by a simple coating treatment of a common hydrophobic medical material--polyethylene. Surface tension and adsorption properties of PEO/polypropylene oxide(PPO) and PEO/polybutylene oxide(PBO) block copolymer surfactants on a hydrophobic surface (low density polyethylene, LDPE) were investigated, using the Wilhelmy plate surface tension technique and x-ray photoelectron spectroscopy(XPS). The protein resistance of the surfactant-treated surfaces was evaluated by XPS and 125I-labeled proteins. The data presented indicate that adsorption of the surfactants on LDPE is dependent on the molecular geometry of the surfactants. Adsorption of human albumin was significantly decreased on the surfactant-treated LDPE surfaces, as compared with the untreated surface. Surfactants suitable for the preparation of PEO-rich surfaces and possible mechanisms for their protein resistance are discussed.

A copolymer of N-(2-hydroxypropyl) methacrylamide (HPMA) and N-methacryloyltyrosinamide was prepared and fractionated using Sepharose 4B/6B (1:1) chromatography to produce eight HPMA copolymer fractions of narrow polydispersity and mean molecular weight (Mw) ranging from 12 to 778 kD. These fractions were radioiodinated and injected intravenously, subcutaneously, and intraperitoneally into rats. Their bloodstream-concentration profiles were monitored and rates of excretion assessed. Following intravenous administration the circulating blood volume available to the copolymers was not molecular-weight-dependent. A molecular-weight threshold limiting glomerular filtration was identified at approximately 45 kD, and preparations greater than this threshold were lost from the bloodstream only slowly by extravasation. Molecular weight did not influence the movement of copolymers from the peritoneal compartment to the bloodstream after intraperitoneal injection. The transfer rates observed could be accounted for by bulk phase lymphatic drainage alone, no transcapillary routes being implicated. Following subcutaneous administration the largest HPMA copolymer fraction (Mw = 778 kD, diameter approximately 30 nm) showed increased retention at the site of the injection, approximately 20% of the dose remaining there after 21 days. This could result from physical restriction of movement or from internalization into local phagocytic cells. The smaller copolymer fractions moved readily into the bloodstream whence they were either lost in the urine or they gradually penetrated into other tissues and organs. Long-term (21 days) body distribution of copolymers following both intraperitoneal and subcutaneous administration showed size-dependent accumulation in organs of the reticuloendothelial system.

Record power conversion efficiencies (PCEs) of perovskite solar cells (PSCs) have been obtained with the organic hole transporter 2,2′,7,7′-tetrakis( N , N -di- p -methoxyphenyl-amine)9,9′-spirobifluorene (spiro-OMeTAD). Conventional doping of spiro-OMeTAD with hygroscopic lithium salts and volatile 4- tert -butylpyridine is a time-consuming process and also leads to poor device stability. We developed a new doping strategy for spiro-OMeTAD that avoids post-oxidation by using stable organic radicals as the dopant and ionic salts as the doping modulator (referred to as ion-modulated radical doping). We achieved PCEs of &gt;25% and much-improved device stability under harsh conditions. The radicals provide hole polarons that instantly increase the conductivity and work function (WF), and ionic salts further modulate the WF by affecting the energetics of the hole polarons. This organic semiconductor doping strategy, which decouples conductivity and WF tunability, could inspire further optimization in other optoelectronic devices.

Simple spectrophotometric method for the estimation of accessible amino groups and preparation of polyurethane nanocomposites.

Abstract Pseudocapacitors or redox capacitors that synergize the merits of batteries and double‐layer capacitors are among the most promising candidates for high‐energy and high‐power energy storage applications. 2D transition metal carbides (MXenes), an emerging family of pseudocapacitive materials with ultrahigh rate capability and volumetric capacitance, have attracted much interest in recent years. However, MXenes have only been used as negative electrodes as they are easily oxidized at positive (anodic) potential. To construct a high‐performance MXene‐based asymmetric device, a positive electrode with a compatible performance is highly desired. Herein, an ultrafast polyaniline@MXene cathode prepared by casting a homogenous polyaniline layer onto a 3D porous Ti 3 C 2 T x MXene is reported, which enables the stable operation of MXene at positive potentials because of the enlarged work function after compositing with polyaniline, according to the first‐principle calculations. The resulting flexible polyaniline@MXene positive electrode demonstrates a high volumetric capacitance of 1632 F cm −3 and an ultrahigh rate capability with 827 F cm −3 at 5000 mV s −1 , surpassing all reported positive electrodes. An asymmetric device is further fabricated with MXene as the anode and polyaniline@MXene as the cathode, which delivers a high energy density of 50.6 Wh L −1 and an ultrahigh power density of 127 kW L −1 .

Aniline was oxidized with ammonium peroxydisulfate in solutions of strong acid (0.1 M sulfuric acid), weak acid (0.4 M acetic acid), or alkali (0.2 M ammonium hydroxide). The properties of the oxidation products and their morphology are controlled by the initial acidity of the medium and the acidity profile during the oxidation; the acidity increases because sulfuric acid is a byproduct. Conducting polyaniline nanogranules, nanotubes, or nonconducting oligoaniline microspheres were obtained, respectively. FTIR spectra suggest that the oligomers produced by the oxidation of neutral aniline molecules at the beginning of oxidation are similar, regardless of the acidity of the medium. Neutral aniline molecules, prevailing under alkaline conditions, are easily oxidized to aniline oligomers composed of ortho- and para-coupled aniline constitutional units. Ortho-coupled units are further converted by oxidative intramolecular cyclization to phenazines. It is proposed that, in acidic media, N-phenylphenazine units constitute the initiation centers for the subsequent polymerization of aniline, which takes place at pH < 2 when the intermediate pernigraniline chains become protonated. Anilinium cations, which dominate in strongly acidic media, are difficult to oxidize to oligomers, but they easily participate in the formation of polymer chains once their growth has started. The self-organization of phenazine units is responsible for the generation of polyaniline nanotubes. Partial sulfonation of aromatic amines occurs at higher pH, especially in alkaline media. The sulfonated oligomers stabilize aniline emulsions and enable the formation of oligoaniline microspheres, when the miscibility of aniline with aqueous medium is limited. The final oxidation products obtained in alkaline conditions contain only low-molecular-weight oligomers; the polymeric component is the dominating product only in strongly acidic media. Both components are present in various proportions when the oxidation takes place at intermediate pH ranges.

Abstract One promising way to store and distribute large amounts of renewable energy is water electrolysis, coupled with transport of hydrogen in the gas grid and storage in tanks and caverns. The intermittent availability of renewal energy makes it difficult to integrate it with established alkaline water electrolysis technology. Proton exchange membrane (PEM) water electrolysis (PEMEC) is promising, but limited by the necessity to use expensive platinum and iridium catalysts. The expected solution is anion exchange membrane (AEM) water electrolysis, which combines the use of cheap and abundant catalyst materials with the advantages of PEM water electrolysis, namely, a low foot print, large operational capacity, and fast response to changing operating conditions. The key component for AEM water electrolysis is a cheap, stable, gas tight and highly hydroxide conductive polymeric AEM. Here, we present target values and technical requirements for AEMs, discuss the chemical structures involved and the related degradation pathways, give an overview over the most prominent and promising commercial AEMs (Fumatech Fumasep® FAA3, Tokuyama A201, Ionomr Aemion™, Dioxide materials Sustainion®, and membranes commercialized by Orion Polymer), and review their properties and performances of water electrolyzers using these membranes.

Abstract Basing on the fact that only short layers of a chromatographic column contribute to the separation in the interaction chromatography, 1 mm thick membranes from macroporous methacrylate polymer provided with functional groups were synthetized and used for protein separation. The chromatograms show that the separation is fully comparable with that experienced on a filled column but the advantage of a membrane is up to two orders of magnitude lower pressure during the process and very high loading reaching up to 40 g/m2. This recommends the high performance membrane chromatography also for large scale preparative separations.

The paper presents a critical overview on magnetic nanoparticles and microspheres used as separation media in different fields of chemistry, biochemistry, biology, and environment protection. The preparation of most widely used magnetic iron oxides in appropriate form, their coating or encapsulation in polymer microspheres, and functionalization is discussed in the first part. In the second part, new developments in the main application areas of magnetic composite particles for separation and catalytical purposes are briefly described. They cover separations and isolations of toxic inorganic and organic ions, proteins, and other biopolymers, cells, and microorganisms. Only selected number of relevant papers could be included due to the restricted extent of the review.

Lipids and lipopolymers self-assembled into biocompatible nano- and mesostructured functional materials offer many potential applications in medicine and diagnostics. In this Account, we demonstrate how high-resolution structural investigations of bicontinuous cubic templates made from lyotropic thermosensitive liquid-crystalline (LC) materials have initiated the development of innovative lipidopolymeric self-assembled nanocarriers. Such structures have tunable nanochannel sizes, morphologies, and hierarchical inner organizations and provide potential vehicles for the predictable loading and release of therapeutic proteins, peptides, or nucleic acids. This Account shows that structural studies of swelling of bicontinuous cubic lipid/water phases are essential for overcoming the nanoscale constraints for encapsulation of large therapeutic molecules in multicompartment lipid carriers. For the systems described here, we have employed time-resolved small-angle X-ray scattering (SAXS) and high-resolution freeze-fracture electronic microscopy (FF-EM) to study the morphology and the dynamic topological transitions of these nanostructured multicomponent amphiphilic assemblies. Quasi-elastic light scattering and circular dichroism spectroscopy can provide additional information at the nanoscale about the behavior of lipid/protein self-assemblies under conditions that approximate physiological hydration. We wanted to generalize these findings to control the stability and the hydration of the water nanochannels in liquid-crystalline lipid nanovehicles and confine therapeutic biomolecules within these structures. Therefore we analyzed the influence of amphiphilic and soluble additives (e.g. poly(ethylene glycol)monooleate (MO-PEG), octyl glucoside (OG), proteins) on the nanochannels' size in a diamond (D)-type bicontinuous cubic phase of the lipid glycerol monooleate (MO). At body temperature, we can stabilize long-living swollen states, corresponding to a diamond cubic phase with large water channels. Time-resolved X-ray diffraction (XRD) scans allowed us to detect metastable intermediate and coexisting structures and monitor the temperature-induced phase sequences of mixed systems containing glycerol monooleate, a soluble protein macromolecule, and an interfacial curvature modulating agent. These observed states correspond to the stages of the growth of the nanofluidic channel network. With the application of a thermal stimulus, the system becomes progressively more ordered into a double-diamond cubic lattice formed by a bicontinuous lipid membrane. High-resolution freeze-fracture electronic microscopy indicates that nanodomains are induced by the inclusion of proteins into nanopockets of the supramolecular cubosomic assemblies. These results contribute to the understanding of the structure and dynamics of functionalized self-assembled lipid nanosystems during stimuli-triggered LC phase transformations.

Hydrogen adsorption using a series of nanoporous synthetic polymers has been studied. Promising results were obtained during the screening of commercially available porous polymer beads; of the polymers considered, hypercrosslinked Hypersol-Macronet MN200 resin exhibited the highest adsorption capacity for hydrogen. This initial success triggered the development of our own high surface area hypercrosslinked materials. Subjecting gel-type and macroporous vinylbenzyl chloride-based precursors swollen in dichloroethane to a Friedel−Crafts reaction catalyzed by iron trichloride afforded beads with surface areas of 1 930 and 1 300 m2/g, respectively, as calculated using the BET equation. The former polymer reversibly stores up to 1.5 wt % H2 at a pressure of 0.12 MPa and a temperature of 77.3 K. The initial heat of adsorption of hydrogen molecules onto this polymer is 6.6 kJ/mol.

Enhanced permeability and retention (EPR) and the (over-) expression of angiogenesis-related surface receptors are key features of tumor blood vessels. As a consequence, EPR-mediated passive and Arg-Gly-Asp (RGD) and Asn-Gly-Arg (NGR) based active tumor targeting have received considerable attention in the last couple of years. Using several different in vivo and ex vivo optical imaging techniques, we here visualized and quantified the benefit of RGD- and NGR-based vascular vs EPR-mediated passive tumor targeting. This was done using ∼ 10 nm sized polymeric nanocarriers, which were either labeled with DY-676 (peptide-modified polymers) or with DY-750 (peptide-free polymers). Upon coinjection into mice bearing both highly leaky CT26 and poorly leaky BxPC3 tumors, it was found that vascular targeting did work, resulting in rapid and efficient early binding to tumor blood vessels, but that over time, passive targeting was significantly more efficient, leading to higher overall levels and to more efficient retention within tumors. Although this situation might be different for larger carrier materials, these insights indicate that caution should be taken not to overestimate the potential of active over passive tumor targeting.

Poly(2-alkyl-2-oxazoline)s are biocompatible polymers with polypeptide-isomeric structures that are attracting increasing interest as biomaterials for drug, gene, protein, and radionuclide delivery. They are, however, still relatively new in comparison to other classes of hydrophilic water-soluble polymers already established for such use, including poly(ethylene oxide), polyvinylpyrrolidone, and polymethacrylamides such as poly[N-(2-hydroxypropyl)methacrylamide]. This feature article critically compares the synthetic aspects and physicochemical and biological properties of poly(2-alkyl-2-oxazoline)s and these commonly studied polymers in terms of their suitability for biomedical applications.

In the primary walls of growing plant cells, the glucose polymer cellulose is assembled into long microfibrils a few nanometers in diameter. The rigidity and orientation of these microfibrils control cell expansion; therefore, cellulose synthesis is a key factor in the growth and morphogenesis of plants. Celery (Apium graveolens) collenchyma is a useful model system for the study of primary wall microfibril structure because its microfibrils are oriented with unusual uniformity, facilitating spectroscopic and diffraction experiments. Using a combination of x-ray and neutron scattering methods with vibrational and nuclear magnetic resonance spectroscopy, we show that celery collenchyma microfibrils were 2.9 to 3.0 nm in mean diameter, with a most probable structure containing 24 chains in cross section, arranged in eight hydrogen-bonded sheets of three chains, with extensive disorder in lateral packing, conformation, and hydrogen bonding. A similar 18-chain structure, and 24-chain structures of different shape, fitted the data less well. Conformational disorder was largely restricted to the surface chains, but disorder in chain packing was not. That is, in position and orientation, the surface chains conformed to the disordered lattice constituting the core of each microfibril. There was evidence that adjacent microfibrils were noncovalently aggregated together over part of their length, suggesting that the need to disrupt these aggregates might be a constraining factor in growth and in the hydrolysis of cellulose for biofuel production.