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Magnetic resonance imaging (MRI) using 19F-based tracers has emerged as a promising multi-purpose noninvasive diagnostic tool and its application requires the use of various 19F-based tracers for the intended diagnostic purpose. In this study, we report a series of double-stimuli-responsive polymers for use as injectable implants, which were designed to form implants under physiological conditions, and to subsequently dissolve with different dissolution rates (t1/2 ranges from 30 to more than 250 days). Our polymers contain a high concentration of fluorine atoms, providing remarkable signal detectability, and both a hydrophilic monomer and a pH-responsive monomer that alter the biodistribution properties of the implant. The implant location and dissolution were observed using 19F MRI, which allows the anatomic extent of the implant to be monitored. The dissolution kinetics and biocompatibility of these materials were thoroughly analyzed. No sign of toxicity in vitro or in vivo or pathology in vivo was observed, even in chronic administration. The clinical applicability of our polymers was further confirmed via imaging of a rat model by employing an instrument currently used in human medicine.

Poly(2-oxazoline)s represent an emerging class of polymers with increasing potential in biomedical sciences. To date, most of the work on poly(2-oxazoline)-drug conjugates focused on poly(2-ethyl-2-oxazoline) (PEtOx), a biocompatible water-soluble polymer with biological properties similar to polyethylene glycol. However, the more hydrophilic poly(2-methyl-2-oxazoline) (PMeOx) shows better anti-fouling properties than PEtOx and thus indicates greater potential for the construction of polymer therapeutics. Herein, we synthesized for the first time a drug delivery system based on a linear PMeOx with a molar mass that is high enough (40 kDa) to exploit passive accumulation in the tumor by the enhanced permeation and retention effect. The anti-cancer drug doxorubicin is attached to the polymer carrier via an acid-sensitive hydrazone bond, which allows its pH-triggered release in the tumor. The in vitro study demonstrates successful cellular uptake of the PMeOx-doxorubicin conjugate via clathrin-mediated endocytosis, pH-sensitive drug release and high cytotoxicity against B16 melanoma cells. Finally, these properties were critically compared to the analogous systems based on the established PEtOx revealing that the more hydrophilic PMeOx carrier outperforms PEtOx in most of the parameters, showing higher maximal drug loading, superior cellular uptake, better anti-fouling properties, as well as improved in vitro anti-cancer efficiency. The study demonstrates the potential of PMeOx as a versatile platform for synthesis of new drug delivery systems.

In biomedicine, polymer blends are frequently applied in wound dressing design or drug delivery. Within these applications, poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are emerging as a popular matrix d...

International audience; Conjugation of drugs to polymers is a widely used approach to gain control over the release of therapeutics. In this contribution, salicylic acid, a multipurpose model drug, is conjugated to the biocompatible poly(2ethyl-2-oxazoline) (PEtOx). The drug is attached to the side chains of a polymer carrier through a hydrolytically cleavable ester linker, via a sequential postpolymerization modification. The chemical modulation of this ester, i.e., by primary or secondary alcohols, is demonstrated to greatly influence the ester hydrolysis rate. This crucial parameter allows us to tune the in vitro kinetics of the sustained drug release for periods exceeding a month in phosphate-buffered saline (PBS). The synthetic accessibility of the cleavable linker, together with the modularity of the drug release rate offered by this approach, highlights the utility of this class of polymers in the field of long-lasting drug delivery systems for persistent and chronic disease treatment.

In this report, we describe the synthesis and properties of poly(2-dialkylamino-2-oxazoline)s (PAmOx), a new class of thermoresponsive polymers. These polymers were synthesized by acylation of linear polyethyleneimine, as the conventional cationic ring-opening polymerization of the respective monomers led to extensive chain transfer reactions. The hydrophilicity of obtained poly(2-dialkylamino-2-oxazoline)s was highly dependent on the side-chain substituents, ranging from very hydrophilic poly(2-dimethylamino-2-oxazoline) to the hydrophobic poly(2-diisopropylamino-2-oxazoline). Notably, the poly(2-diethylamino-2-oxazoline) (PDEAOx) shows fast-response LCST behavior around room temperature (24 °C), as well as low Tg (−10 °C), which can be beneficial in the construction of new stimuli-responsive biomaterials. Overall, PAmOx represent a novel polymer platform for a wide range of possible applications.

One-pot synthesis of gradient copolymers by statistical copolymerization represents an elegant route to amphiphilic copolymers as a basis for micellar systems. Herein, we propose a robust strategy to control the monomer distribution along the gradient copolymer chain by appropriate selection of the polymerization solvent. The gradient formation was investigated for copolymerizations of the hydrophilic 2-methyl-2-oxazoline (MeOx) and the hydrophobic 2-phenyl-2-oxazoline (PhOx) using sulfolane and acetonitrile as the polymerization solvents revealing a striking difference. In sulfolane, a quasi-block (CP2) like character was observed, whereas acetonitrile led to a more gradient-like (CP3) copolymer. The monomer distribution was found to have an impact on the micellization behavior of both amphiphilic copolymers, which was also compared with the analogous block copolymer (CP1). CP1 led to the formation of the smallest micelles, followed by a somewhat larger structure formed by CP2, while CP3 self-assembles into significantly larger nanoparticles. These findings open up a route to new amphiphilic copolymer systems with precisely fine-tuned architecture.

In this communication, we report for the first time the synthesis of defined high molar mass poly(2-methyl-2-oxazoline) (PMeOx), a water-soluble polymer with excellent anti-fouling properties. So far, there has been no report on low dispersity (Đ < 1.2) PMeOx longer than 10 kg mol−1. Higher molar mass would be beneficial for synthesis of polymer–drug conjugates, excipients as well as for other biomedical applications. We report our attempts to prepare defined high molar mass PMeOx via living cationic ring-opening polymerization (CROP) of its monomer using our optimized method that failed due to extensive chain transfer and chain coupling side reactions. Therefore, we proposed an alternative strategy to high molar mass PMeOx based on acetylation of well-defined linear polyethyleneimine (PEI) prepared by controlled side-chain hydrolysis of defined high molar mass PEtOx. This method allowed us to synthesize a series of low-dispersity PMeOx up to 58 kg mol−1 (Đ = 1.07). Considering the biomedical potential of PMeOx, the synthesis of such polymers might open a way to a new class of effective polymer-based therapeutics.

Poly(2-alkyl-2-oxazoline)s (PAOx) are regaining interest for biomedical applications. However, their full potential is hampered by the inability to synthesise uniform high-molar mass PAOx. In this work, we proposed alternative intrinsic chain transfer mechanisms based on 2-oxazoline and oxazolinium chain-end tautomerisation and derived improved polymerization conditions to suppress chain transfer, allowing the synthesis of highly defined poly(2-ethyl-2-oxazoline) s up to ca. 50 kDa (dispersity (D)

Magnetic resonance imaging using fluorinated contrast agents (19F MRI) enables to achive highcontrast in images due to the negligible fluorine background in living tissues. In this pilot study, we developed new biocompatible, temperature-responsive, and easily synthesized polymeric nanogels containing a sufficient concentration of magnetically equivalent fluorine atoms for 19F MRI purposes. The structure of the nanogels is based on amphiphilic copolymers containing two blocks, a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) or poly(2-methyl-2-oxazoline) (PMeOx) block, and a thermoresponsive poly[N(2,2difluoroethyl)acrylamide] (PDFEA) block. The thermoresponsive properties of the PDFEA block allow us to control the process of nanogel self-assembly upon its heating in an aqueous solution. Particle size depends on the copolymer composition, and the most promising copolymers with longer thermoresponsive blocks form nanogels of suitable size for angiogenesis imaging or the labeling of cells (appr...

The sensitivity of biocompatible polymers to ionizing radiation plays a crucial role for the construction of polymer radiopharmaceutics, simultaneous radiotherapy and therapy with polymeric drugs, and the radiation sterilization of polymer samples. Herein, we answer the crucial but generally overlooked question of radiation stability of water-soluble biocompatible polymers that are used in designing of polymer radiotherapeutics. We ranked five different classes of widely used water-soluble polymers according to their sensitivity to the beta or gamma radiation, providing the guidelines for selection of appropriate polymers that will be in contact with radiation. As a result, poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) and poly(N-vinyl-2-pyrrolidone) (PVP) proved to be more resistant against ionizing radiation than poly(ethylene oxide) (PEO) or poly(2-ethyl-2-oxazoline) (PEtOx), which were crosslinked rapidly. Nevertheless, irradiation of PEtOx and PEO homopolymers appeared to be a fast and straightforward route to their respective hydrogels. Special emphasis was put on the beta radiation preparation of PEtOx hydrogels, which was never described before. Irradiation of poly(N-isopropyl acrylamide) (PNIPAM) in solution leads to its hydrophilization and an increase in its cloud point temperature.

The lack of cellular and tissue specificities in conventional chemotherapies along with the generation of a complex tumor microenvironment (TME) limits the dosage of active agents that reaches tumor sites, thereby resulting in ineffective responses and side effects. Therefore, the development of selective TME-responsive nanomedicines is of due relevance toward successful chemotherapies, albeit challenging. In this framework, we have synthesized novel, ready-to-use ROS-responsive amphiphilic block copolymers (BCs) with two different spacer chemistry designs to connect a hydrophobic boronic ester-based ROS sensor to the polymer backbone. Hydrodynamic flow focusing nanoprecipitation microfluidics (MF) was used in the preparation of well-defined ROS-responsive PSs; these were further characterized by a combination of techniques [

We describe a new approach to depot drug delivery in which a copolymer poly[N-isopropyl acrylamide-co-N-(3-imidazolylpropyl)methacrylamide] (PNIPAM-co-ImPM) is considered as the main object and matrix for a new formulation strategy that provides the controlled and sustained release of an incorporated drug. The relatively low content of ImPM groups (1.6 mol%) was determined to be sufficient to introduce pH-sensitive behavior to the polymer. Together with NIPAM units, which possess a thermo-sensitive behavior, a dual sensitivity was imparted to the polymer that was investigated by means of turbidimetry and dynamic light scattering. A change in pH from 9 down to 4 was observed to result in the increase of the polymer transition temperature from 32 to 70 °C. The separation process is also accompanied with the formation of ca. 150–300 nm particles while above the transition temperature. The pH value of approximately 6.5 was defined as a boundary value, where certain properties of the system significantly change. This observation assumes a potential attractiveness of the system for biological applications in which injection is possible using a liquid form at pH ca. 5 without the risk of injection needle obstruction. In this way, a depot is formed at the application site upon simultaneously heating to body temperature and increasing the pH to the physiological value of 7.4. An in vivo experiment using the polymer in PBS (pH = 5.0) with paliperidone as a model drug showed excellent results regarding the release of the drug from a depot. The putative mechanism of action for our depot system is thoroughly described in the article.

Even though functional copolymers with a low percentage of functional comonomer units (up to 20 mol%) are widely used, for instance for the development of polymer therapeutics and hydrogels, insights in the functional group distribution over the actual chains are lacking and the average composition is conventionally used to describe the functionalization degree. Here we report the visualization of the monomer distribution over the different polymer chains by a synergetic combination of experimental and theoretical analysis aiming at the construction of functionality-chain length distributions (FUNC-CLDs). A successful design of the chemical structure of the comonomer pair, the initial functional comonomer amount (13 mol%), and the temperature (100 °C) is performed to tune the FUNC-CLD of copoly(2-oxazoline)s toward high functionalization degree for both low (100) and high (400) target degrees of polymerization. The proposed research strategy is generic and extendable to a broad range of copolymerization chemistries, including reversible deactivation radical polymerization., Understanding the functional group distribution in a polymer chain has been difficult, but this information can be very useful. Here the authors visualize the monomer distribution in individual polymer chains by combining experimental and theoretical analysis of the construction of functionality-chain length distributions.

Herein, we describe a new method for the synthesis of superhydrophilic poly(2-alkyl-2-oxazoline)s (PAOx) from poly(2-ethyl-2-oxazoline) (PEtOx). A well-defined linear polyethylenimine was prepared from PEtOx by controlled acidic hydrolysis of its side-chains followed by reacylation with different carboxylic acids. Using this protocol, we obtained a series of new hydrophilic PAOx containing side-chain ether groups with potential in biomaterials science. The relative hydrophilicity of the polymers was assessed, revealing that poly(2-methoxymethyl-2-oxazoline) (PMeO-MeOx) is the most hydrophilic PAOx reported to date. Additionally, the amorphous poly(2-methoxy-ethoxy-ethoxymethyl-2-oxazoline) (PDEGOx) shows the lowest reported glass transition temperature (-25 degrees C) within the PAOx family to date. The biomedical potential of the prepared polymers was further fortified by an in vitro cytotoxicity study, where all polymers appeared to be noncytotoxic. The described synthetic protocol is universal and can be extremely versatile, especially for PAOx that are difficult to prepare by conventional cationic ring-opening polymerization due to the monomer interference and/or degradation.

Inspired by the increasing popularity of poly(2-ethyl-2-oxazoline) (PEtOx) for biomedical applications, this study reports the complete and thorough solution analysis of the homologous series of biocompatible PEtOx samples in a very broad range of molecular weights ranging from 11.2 x 10(3) g mol(-1) up to 260 x 10(3) g mol(-1). The main focus of the research was on the determination of the conformational properties of PEtOx macromolecules at a temperature of 37 degrees C in phosphate buffered saline (PBS) simulating the parameters of physiological media. The polymers were studied in PBS solutions by analytical ultracentrifugation, dynamic light scattering (DLS), translational diffusion, and intrinsic viscosity measurements in a temperature range from 15 degrees C up to 72 degrees C. The complete set of Kuhn-Mark-Houwink-Sakurada scaling relationships revealed linear trends over the whole range of the studied molar masses, while the determined scaling indices at 37 degrees C correspond to the coil conformation in a thermodynamically good solvent ([eta] = 0.045 x M-0.62, s(0) = 0.010 x M-0.46 and D-0 = 1750 x M-0.54). Based on the intrinsic viscosity values (most sensitive characteristic to the size variations of polymer coils, [eta] similar to r(3)), it was demonstrated that PEtOx macromolecules in PBS solutions undergo a transition from swollen polymer coils with gradual deterioration of thermodynamic quality of solutions within the temperature range of 15-45 degrees C, reaching theta-conditions at 55 degrees C with further precipitation at 62-72 degrees C. Also, to the best of our knowledge, the conformational parameters (equilibrium rigidity/the Kuhn segment length and the diameter of the polymer chain) of PEtOx macromolecules were evaluated under physiological conditions for the first time and constitute A = 1.8 +/- 0.3 nm and d = 0.7 +/- 0.4 nm. These equilibrium rigidity values classify PEtOx as a flexible macromolecule with rigidity similar to that of poly(ethylene glycol). For the first time, we were able to demonstrate a direct influence of thermosensitivity on the rigidity of the biocompatible polymer: PEtOx. The Kuhn segment length is undoubtedly decreasing when approaching the LCST.

We designed and synthesized a new delivery system for the anticancer drug doxorubicin based on a biocompatible hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) carrier with linear architecture and narrow molar mass distribution. The drug is connected to the polymer backbone via an acid-sensitive hydrazone linker, which allows its triggered release in the tumor. The in vitro studies demonstrate successful cellular uptake of conjugates followed by release of the cytostatic cargo. In vivo experiments in EL4 lymphoma bearing mice revealed prolonged blood circulation, increased tumor accumulation and enhanced antitumor efficacy of the PEtOx conjugate having higher molecular weight (40 kDa) compared to the lower molecular weight (20 kDa) polymer. Finally, the in vitro and in vivo anti-cancer properties of the prepared PEtOx conjugates were critically compared with those of the analogous system based on the well-established PHPMA carrier. Despite the relatively slower intracellular uptake of PEtOx conjugates, resulting also in their lower cytotoxicity, there are no substantial differences in in vivo biodistribution and anti-cancer efficacy of both classes of polymer-Dox conjugates. Considering the synthetic advantages of poly(2-alkyl-2-oxazoline)s, the presented study demonstrates their potential as a versatile alternative to well-known PEO- or PHPMA-based materials for construction of drug delivery systems.

Poly(2-oxazoline)s (in literature abbreviated as PAOx, POx, or POZ, herein referred to as PAOx) represent an emerging class of biocompatible polymers outperforming polyethylene glycol (PEG) in many aspects, including their high synthetic versatility and structural modularity. In this review, we provide a brief introduction to PAOx chemistry and biology to sketch their potential in biomaterials science. Further, we provide a detailed comprehensive overview of the literature on PAOx-protein conjugates with emphasis on their critical evaluation and comparison with analogous systems based on PEG. Based on this literature overview, PAOx seem to be an excellent alternative to PEG in the construction of therapeutic polymer-protein conjugates.

A combination of new thermoresponsive statistical polyoxazolines, poly[(2-butyl-2-oxazoline)-stat-(2-isopropyl-2-oxazoline)] [pBuOx-co-piPrOx], with different hydrophobic moieties and F127 surfactant as a template system for the creation of thermosensitive nanoparticles for radionuclide delivery has recently been tested [Pánek, Filippov, Hrubý, Rabyk, Bogomolova, Kučka & Stěpánek (2012).Macromol. Rapid Commun.33, 1683–1689]. It was shown that the presence of the thermosensitive F127 triblock copolymer in solution reduces nanoparticle size and polydispersity. This article focuses on a determination of the internal structure and solution properties of the nanoparticles in the temperature range from 288 to 312 K. Here, it is demonstrated that below the cloud point temperature (CPT) the polyoxazolines and F127 form complexes that co-exist in solution with single F127 molecules and large aggregates. When the temperature is raised above the CPT, nanoparticles composed of polyoxazolines and F127 are predominant in solution. These nanoparticles could be described by a spherical shell model. It was found that the molar weight and hydrophobicity of the polymer do not influence the size of the outer radius and only slightly change the inner radius of the nanoparticles. At the same time, molar weight and hydrophobicity did affect the process of nanoparticle formation. In conclusion, poly(2-oxazoline) molecules are fully incorporated inside of F127 micelles, and this result is very promising for the successful application of such systems in radionuclide delivery.

It is demonstrated that glycogen as a biodegradable and inexpensive material coming from renewable resources can be used as a carrier for the construction of in vivo imaging nanoagents. The model system considered is composed of glycogen modified with gadolinium and fluorescent labels. Systematic studies of properties of these nanocarriers by a variety of physical methods and results of in vivo tests of biodegradability are reported. This represents, to the authors' best knowledge, the first such use of glycogen.