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We present the synthesis and comprehensive evaluation of a novel 2‐oxazoline‐based polymer (polyPhOx) functionalized with phenyl groups, designed for the efficient adsorption of pharmaceutical contaminants from aqueous solutions. Employing living polymerization techniques (CROP) with two distinct initiators, we optimize reaction parameters including time, temperature, and initiator concentration. The rigorous characterization of the obtained polymer is depicted as well as the demonstration of its significant binding capacity for various pharmaceuticals, exploiting π–π and electrostatic interactions to achieve superior adsorption efficiency. Adsorption experiments are performed using high concentrations of model pharmaceuticals, including aspirin, ibuprofen, metoclopramide, pyramidone, oestradiol, and indomethacin, in hydroalcoholic solutions. Initial investigations confirm polyPhOx's exceptional efficacy, particularly with hydrophobic compounds such as oestradiol, achieving adsorption capacities of up to 56.67 mg g−1. Further validation in real environmental samples highlights the polymer's practical applicability, showing substantial removal rates even under complex matrix conditions and bringing hope for effective water purification solutions. Remarkably, polyPhOx retains high adsorption performance after 10 cycles, underscoring its potential for sustainable and cost‐effective water purification. This study not only introduces a promising material for environmental remediation but also demonstrates its robustness and reusability, paving the way for advanced wastewater treatment solutions targeting persistent pharmaceutical pollutants. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A hit-and-run vaccine system, with POx-Hmi/OVA nanovaccine firstly elicit OVA257-264 specific T cell responses, and then PMEBOx-MMP-OVA specifically deliver OVA257-264 peptides to decorate the tumor cell surface, thus results in T cell killing to tumor cells regardless the original surface epitopes. [Display omitted] Neoantigen cancer vaccines have been envisioned as one of the most promising means for cancer therapies. However, identifying neoantigens for tumor types with low tumor mutation burdens continues to limit the effectiveness of neoantigen vaccines. Herein, we proposed a "hit-and-run" vaccine strategy which primes T cells to attack tumor cells decorated with exogenous "neo-antigens". This vaccine strategy utilizes a peptide nanovaccine to elicit antigen-specific T cell responses after tumor-specific decoration with a nanocarrier containing the same peptide antigens. We demonstrated that a poly(2-oxazoline)s (POx) conjugated with OVA 257-264 peptide through a matrix metalloprotease 2 (MMP-2) sensitive linker could efficiently and selectively decorate tumor cells with OVA peptides in vivo. Then, a POx-based nanovaccine containing OVA 257-264 peptides to elicit OVA-specific T cell responses was designed. In combination with this hit-and-run vaccine system, an effective vaccine therapy was demonstrated across tumor types even without OVA antigen expression. This approach provides a promising and uniform vaccine strategy against tumors with a low tumor mutation burden. [ABSTRACT FROM AUTHOR]

Poly-(2-alkyl-2-oxazoline)-s (POx) bearing an aminophenyl end group were synthesized by cationic ring-opening polymerization; the polymers were then carefully characterized by NMR, size exclusion chromatography, and differential scanning nano calorimetry. The electroreduction of the diazonium salts of aniline terminated poly-(2-methyl-2-oxazoline) (PMeOx) and poly-(2-n-propyl-2-oxazoline) (PnPrOx) from aqueous solution on indium tin oxide (ITO) and gold (Au) and through a two-dimensional polystyrene (PS) template has been investigated. On all substrates, ultrathin layers of polymer are grafted and deposited. Modified surfaces were characterized by electrochemistry, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy. Nanoporous honeycomb POx structures have been obtained thanks to electrochemical growth in the interstitial spaces between self-assembled PS spheres. Finally, the wettability of the surfaces depends markedly on the chemical nature of the POx, with contact angles of 32° and 70° for modified surfaces with PMeOx and PnPrOx. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co‐delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)‐β expression using a polyoxazoline (POx)‐poly(lactic‐co‐glycolic) acid (PLGA) nanovaccine, while modulating the tumor‐associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti‐programmed cell death protein 1 (PD‐1) can constitute an alternative approach for cancer immunotherapy. POx‐Mannose (Man) nanovaccines generate antigen‐specific T‐cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)‐Man nanovaccines. This anti‐tumor effect induced by the POx‐Man nanovaccines is mediated by a CD8+‐T cell‐dependent mechanism, in contrast to the PEG‐Man nanovaccines. POx‐Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD‐1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti‐tumor effect induced by the combination of nanovaccines with the inhibition of both TAM‐ and PD‐1‐inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients. [ABSTRACT FROM AUTHOR]

This study presents a systematic comparison of the antifouling properties of water‐soluble poly(2‐oxazoline) (PAOx) and poly(2‐oxazine) (PAOzi) brushes grafted to gold surfaces. PAOx and PAOzi are emerging polymer classes in biomedical sciences and are being considered superior alternatives to widely used polyethylene glycol (PEG). Four different polymers, poly(2‐methyl‐2‐oxazoline) (PMeOx), poly(2‐ethyl‐2‐oxazoline) (PEtOx), poly(2‐methyl‐2‐oxazine) (PMeOzi), and poly(2‐ethyl‐2‐oxazine) (PEtOzi), each of them in three different chain lengths, are synthesized and characterized for their antifouling properties. Results show that all polymer‐modified surfaces display better antifouling properties than bare gold surfaces as well as analogous PEG coatings. The antifouling properties increase in the following order: PEtOx < PMeOx ≈ PMeOzi < PEtOzi. The study suggests that the resistance to protein fouling derives from both surface hydrophilicity and the molecular structural flexibility of the polymer brushes. PEtOzi brushes with moderate hydrophilicity show the best antifouling performance, possibly due to their highest chain flexibility. Overall, the research contributes to the understanding of antifouling properties in PAOx and PAOzi polymers, with potential applications in various biomaterials. [ABSTRACT FROM AUTHOR]

Light‐responsive polymers are a prospective area of smart materials. The increasing number of potential applications of these materials require the development of new polymers sensitive to external irradiation. However, most of the polymers reported so far are represented by poly(meth)acrylates. In this work, the straightforward approach is proposed to the synthesis of light‐responsive poly(2‐oxazoline)s via cationic ring‐opening polymerization of 2‐azobenzenyl‐2‐oxazoline (2‐(4‐(phenyldiazenyl)phenyl)‐2‐oxazoline). Polymerization kinetics studies reveal significant activity of the new monomer in both homopolymerization and copolymerization with 2‐ethyl‐2‐oxazoline. The difference in monomer reactivity allows obtaining both gradient and block copolymers via simultaneous or subsequent one‐pot polymerization, respectively, leading to a set of well‐defined gradient and block copoly(2‐oxazoline)s with 10–40% of azobenzene units. Due to their amphiphilic nature, the materials self‐assemble in water, which is proven by dynamic light scattering and transmission electron microscopy. The change in polarity caused by the isomerization of azobenzene fragments in response to UV light irradiation results in a change of nanoparticle size. The obtained results provide a new impulse for the development of light‐responsive materials based on poly(2‐oxazoline)s. [ABSTRACT FROM AUTHOR]

With the advancement of medical technology, the previous biomedical material platforms have been unable to meet the increasingly diverse application requirements, and the emergence of poly(2-oxazoline)s provides an opportunity to develop the next generation of biomedical materials. The highly tunable structure and function of poly(2-oxazoline)s, with excellent physical and biological properties, have shown great potential for application in the initial exploratory work. Currently, there are a lot of applied studies related to the water solubility, invisibility, and thermoresponsive of poly(2-oxazoline)s, mainly focused on drug delivery, protein modification, gene carriers, anti-fouling interface, cell sheet engineering, and hydrogel. This paper describes the preparation and physicochemical properties of poly(2-oxazoline)s and reviews the recent applications of poly(2-oxazoline)s in the biomedical field. [ABSTRACT FROM AUTHOR]

Chiral separation membranes have shown great potential for the efficient separation of racemic mixtures into enantiopure components for many applications, such as in the food and pharmaceutical industries; however, scalable fabrication of membranes with both high enantioselectivity and flux remains a challenge. Herein, enantiopure S‐poly(2,4‐dimethyl‐2‐oxazoline) (S‐PdMeOx) macromonomers were synthesized and used to prepare a new type of enantioselective membrane consisting of a chiral S‐PdMeOx network scaffolded by graphene oxide (GO) nanosheets. The S‐PdMeOx‐based membrane showed a near‐quantitative enantiomeric excess (ee) (98.3±1.7 %) of S‐(−)‐limonene over R‐(+)‐limonene and a flux of 0.32 mmol m−2 h−1. This work demonstrates the potential of homochiral poly(2,4‐disubstituted‐2‐oxazoline)s in chiral discrimination and provides a new route to the development of highly efficient enantioselective membranes using synthetic homochiral polymer networks. [ABSTRACT FROM AUTHOR]

Lipidic poly(2-oxazoline)s were synthesised using a simple one-pot method. They replaced PEG-based Pluronic F-127 and stabilised drug-loaded monoolein cubosomes. [Display omitted] Cubosomes are promising delivery vehicles for a wide range of drugs and biomolecules. Polymers such as the polyethylene glycol (PEG)-based Pluronic F-127 have been widely used for dispersing and stabilising lipid cubosomes. However, due to the PEG-immunogenicity, and pre-existing anti-PEG antibodies in some individuals, the efficacy of PEG-stabilised nanomedicines has been reduced. In this study, we hypothesise that lipidic poly(2-oxazoline)s have the potential to stabilise cubosomes, which can be used to encapsulate a hydrophobic drug similar to cubosomes stabilised with F-127. Two lipidic polymers consisting of an oleyl (OA) chain connected to a poly(2-methyl-2-oxazoline) backbone were synthesised using cationic ring-opening polymerisation (PMeOx 40 -OA and PMeOx 80 -OA). The PMeOx n -OA stabilised monoolein cubosomes were compared to F-127 cubosomes in particle size, stability, mesophase structure, and biocompatibility. The obtained PMeOx n -OA were well-defined (low dispersity) and had a high degree of OA functionalisation (≥95%). These polymers were as good as F-127 in producing well dispersed monoolein cubosomes and maintained the internal cubic structure. The cubosomes stabilised with PMeOx n -OA showed lower cytotoxic effect compared to F-127 stabilised cubosomes against OVCAR-3 cells. Furthermore, the PMeOx n -OA cubosomes significantly improved the solubility of SN-38, a poorly water-soluble cancer drug. [ABSTRACT FROM AUTHOR]

Poly(2-oxazoline)s are the synthetic polymers that are the products of the cationic ring-opening polymerization (CROP) of 2-oxazoline monomers. Due to their beneficial properties, from which biocompatibility, stealth behavior, high functionalization possibilities, low dispersity, stability, nonionic character, and solubility in water and organic solvents should be noted, they have found many applications and gained enormous interest from scientists. Additionally, with high versatility attainable through copolymerization or through post-polymerization modifications, this class of polymeric systems has been widely used as a polymeric platform for novel biomedical applications. The chemistry of polymers significant expanded into biomedical applications, in which polymeric networks can be successfully used in pharmaceutical development for tissue engineering, gene therapies, and also drug delivery systems. On the other hand, there is also a need to create 'smart' polymer biomaterials, responsive to the specified factor, that will be sensitive to various environmental stimuli. The commonly used stimuli-responsive biomedical materials are based mostly on temperature-, light-, magnetic-, electric-, and pH-responsive systems. Thus, creating selective and responsive materials that allow personalized treatment is in the interest of the scientific world. This review article focuses on recent discoveries by Polish scientists working in the field of stimuli-responsive poly(2-oxazoline)s, and their work is compared and contrasted with results reported by other world-renowned specialists. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of non-apoptotic iron induced cell death mechanism implicated in neurodegeneration, yet can be ameliorated with potent radical scavengers such as ferrostatin-1 (Fer-1). Currently, Fer-1 suffers from low water solubility, poor biodistribution profile and is unsuitable for clinical application. Fer-1 polymer-drug conjugates (PDCs) for testing as an anti-ferroptosis therapeutic candidate have yet to be described. Here, we report the synthesis and characterization of a library of water-soluble Fer-1 based poly(2-oxazoline)-drug conjugates. The cationic ring opening polymerization (CROP) of water-soluble 2-oxazoline monomers, and a novel protected aromatic aldehyde 2-oxazoline (DPhOx), produced defined copolymers, which after deprotection were available for modification with Fer-1 via reductive amination and Schiff base chemistry. The conjugates were tested for their activity against RSL3-induced ferroptosis in vitro, and first structure-activity relationships were established. Irreversibly conjugated Fer-1 PDCs possessing an arylamine structural motif showed a greatly increased anti-ferroptosis activity compared to reversibly (Schiff base) linked Fer-1. Overall, this work introduces the first active ferrostatin-PDCs and a new highly tuneable poly(2-oxazoline)-based PDC platform, which provides access to next generation polymeric nanomaterials for anti-ferroptosis applications. [Display omitted] • New aromatic aldehyde 2-oxazoline synthesized and successfully polymerized. • Library of water-soluble poly(2-oxazoline) (POx)-Ferrostatin-1 conjugates prepared. • POx-Ferrostatin-1 conjugates rescue cells in RSL3-induced ferroptosis model. • Schiff-conjugation is highly stable in vitro and is outperformed by reduced version. • Hydrophilic/hydrophobic balance influences POx-Ferrostatin-1 activity in vitro. [ABSTRACT FROM AUTHOR]

Poly(2‐alkyl/aryl‐2‐oxazoline)s (PAOxs) have gained immense attraction in the polymer research community because of their relative ease of microwave‐assisted synthesis, tailor‐made properties and, most importantly, recent recognition as an upcoming polymer platform for many medical and biological applications (next generation polymer therapeutics/biomaterials). The materials and solution properties of PAOx can be easily tuned by changing the side chain functionalities. This review describes very recent advances in structures and side‐chain‐dependent properties of PAOx that are reported in the literature from 2017 and onwards. The review starts with providing an encyclopaedic overview of newly reported PAOx homopolymers, including their design strategies and limitations. Subsequently, their side‐chain‐dependent thermal and solution properties are discussed. © 2022 Society of Industrial Chemistry. [ABSTRACT FROM AUTHOR]

Min Xu,1,2,* Chong Yao,3,* Wei Zhang,1 Shen Gao,1 Hao Zou,1 Jing Gao1,4 1School of Pharmacy, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 2Department of Pharmacy, Changzheng Hospital, Shanghai, 200003, People’s Republic of China; 3Clinical Pharmacy Center, Department of Pharmacy, Chinese PLA General Hospital, Beijing, 100850, People’s Republic of China; 4State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Gao; Hao ZouSchool of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Yangpu District, Shanghai, People’s Republic of ChinaTel +86-10-6687-4665Email gjsmmu@126.com; haozou@smmu.edu.cnPurpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research.Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo.Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.Keywords: poly(2-oxazoline)s, micelle, docetaxel, high loading, anti-cancer activity

New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug‐resistance. We previously developed amine‐pendent poly(2‐oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium‐pendent POXs, inspired by cell‐penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents. [ABSTRACT FROM AUTHOR]

Colorimetric nanofibers provide visual, easy‐to‐interpret sensors for personal use as well as advanced applications. The potential of 2‐n‐butyl‐2‐oxazoline (B) and 2‐ethyl‐2‐oxazoline (E) statistical copolymers as a universal, versatile support platform for nanofibrous halochromic sensor design is demonstrated. These polymers are electrospinnable from eco‐friendly solvent systems, while wettability, moist adsorption capacity, and water‐solubility of the membranes can be easily tuned by changing the B/E monomer ratio, ensuring wide applicability. The halochromic sensing functionality is introduced by incorporating the alizarin yellow R (AYR) chromophore, which is covalently modified with an ethyl ester‐group or a short poly(2‐n‐butyl‐2‐oxazoline) chain, which is demonstrated to simultaneously prevent dye‐leaching and allows tuning of the halochromic pH‐sensing window. The colorimetric nanofibrous sensors reversibly respond toward aqueous solutions of different pH, (hydrochloric) acid and alkaline (ammonia) vapors, and several biogenic amines with detection limits as low as 5 ppb. Tunability of sensor responsivity, sensitivity, and pKa via manipulation of dye–polymer interactions, determined by support polymer structure and semi‐crystallinity, as well as the chain length of the AYR‐modified polymer, are discussed. Preliminary proof‐of‐principle studies indicate the potential of the developed sensors for sub‐ppm biogenic amine vapor detection, which may serve as the basis for future applications in food packaging or breath analysis. [ABSTRACT FROM AUTHOR]

Cyclic macromolecules do not feature chain ends and are characterized by a higher effective intramolecular repulsion between polymer segments, leading to a higher excluded‐volume effect and greater hydration with respect to their linear counterparts. As a result of these unique properties, hydrogels composed of cross‐linked cyclic polymers feature enhanced mechanical strength while simultaneously incorporating more solvent with respect to networks formed from their linear analogues with identical molar mass and chemical composition. The translation of topology effects by cyclic polymers into the properties of polymer networks provides hydrogels that ideally do not include defects, such as dangling chain ends, and display unprecedented physicochemical characteristics. [ABSTRACT FROM AUTHOR]

Personalized cancer vaccines targeting specific neoantigens have been envisioned as one of the most promising approaches in cancer immunotherapy. However, the physicochemical variability of the identified neoantigens limits their efficacy as well as vaccine manufacturing in a uniform format. Herein, we developed a uniform nanovaccine platform based on poly(2-oxazoline)s (POx) to chemically conjugate neoantigen peptides, regardless of their physicochemical properties. This vaccine system could self-assemble into nanoparticles with uniform size (around 50 nm) and improve antigen accumulation as well as infiltration in the lymph node to increase antigen presentation. In vivo vaccination using this system conjugated with three predicted peptide neoantigen peptides from the MC38 tumor cell line induced 100% robust CD8 + T cell responses and superior tumor clearance compared to free peptides. This POx-based vaccine carrier represents a generalizable approach to increase the availability and efficacy of screened neoantigen peptides for a personalized cancer vaccine.

Poly(ethylene glycol) (PEG) is a hydrophilic polymer ubiquitously used in both medical and nonmedical goods. Recent debate surrounding the observed stimulation of immune responses against PEG has spurred the development of materials that may be suitable replacements for this common polymeric component. The underlying view is that these alternative materials with comparable physicochemical properties can overcome the unfavorable and unpredictable effects of antibody-mediated clearance by being chemically, and therefore antigenically, distinct from PEG. However, this hypothesis has not been thoroughly tested in any defined manner, and the immune response observed against PEG has not been rigorously investigated within the context of these emerging materials. Consequently, it remains unclear whether immunity-mediated discrimination between polymeric entities even occurs in vivo and, if this is the case, how it may be exploited. In this study, we utilize positron emission tomography-computed tomography molecular imaging in mice immunized to develop specific antibody responses to PEG and an alternative polymer in order to visualize and quantify the influence of antipolymer antibodies on the biodistribution of synthetic polymers in vivo as a function of immunization status. Under the conditions of this experiment, mice could be primed to exhibit both innate and adaptive immunity to all of the polymer systems to which they were exposed. We demonstrate that alternating between chemically disparate polymers is a viable approach to extend their efficacy when antipolymer humoral immune responses arise.

Amphiphilic polymers represent one of the main class of stabilizers for non-lamellar lyotropic liquid crystalline nanoparticles, being essential for their formation and stability. In the present study, poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO- b -PCL) block copolymers and poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) gradient copolymers were incorporated as stabilizers in liquid crystalline nanoparticles prepared from glyceryl monooleate. The polymers were chosen according to their high biocompatibility and promising stealth properties, in order to develop safe and efficient drug delivery nanosystems. The physicochemical characteristics and fractal dimension of the resultant nanosystems were obtained from light scattering techniques, while their micropolarity and microfluidity from fluorescence spectroscopy. The effect of temperature, serum proteins and ionic strength on the physicochemical behavior was monitored. Their morphology was assessed by cryo-TEM, while their thermal behavior by microcalorimetry and high-resolution ultrasound spectroscopy. Their properties were dependent on the stabilizer chemistry and topology (block/gradient copolymer) and its concentration. Subsequently, resveratrol, as model hydrophobic drug, was loaded into the nanosystems, the entrapment efficiency was calculated and in vitro release studies were carried out, highlighting how the different stabilizer can differentiate the drug release profile. In conclusion, the proposed copolymers broaden the toolbox of polymeric stabilizers for the development of liquid crystalline nanoparticles intended for drug delivery applications. [ABSTRACT FROM AUTHOR]

[Display omitted] • First study of the fouling behaviour of water-soluble poly(2,4-dialkyl-2-oxazoline)s. • Poly(2,4-dimethyl-2-oxazoline)s (PdMeOx) of different handedness, alongside racemic PdMeOx are prepared with high end-group fidelity. • PdMeOx is revealed as low-fouling polymer. • Chirality of PdMeOx influences protein corona formation. Low-fouling polymers play a crucial role in the development of therapeutic nanoparticles (NPs), which are commonly described as nanomedicines. These hydrophilic polymers are typically designed to favourably alter the protein corona that forms around a NP by reducing the binding of opsonins, resulting in reduced immune recognition and clearance. The polymer specific proteome of the corona is mainly dictated by the physicochemical properties of the polymer and several parameters such as hydrophilicity and charge have been explored to regulate its composition. To date, there has been little attention given to the influence of the chirality of the hydrophilic polymer on the composition of the corona. Water-soluble poly(2,4-dialkyl-2-oxazoline)s (PdOx) are a unique synthetic polymer class to explore the effect of chirality as they can be rendered optically active if enantiopure monomers are used for their synthesis. Herein we prepared two water-soluble poly(2,4-dimethyl-2-oxazoline)s (PdMeOx) of different handedness, alongside racemic PdMeOx and the well-established low-fouling structural isomer poly(2-ethyl-2-oxazoline) (PEtOx). All polymers were equipped with sulphur-containing xanthate moieties with high end-group fidelity, which enabled anchoring to gold nanoparticles (AuNPs) as a useful handle for evaluation of the polymer-specific fouling. It was revealed that a hard corona formed after exposing the coated AuNP to human plasma proteins as investigated by dynamic light scattering, SDS-PAGE and PierceTM bicinchoninic acid protein assay (BCA) revealing a similar protein adsorption between PEtOx and all three PdMeOx. Moreover, a detailed proteomics study using liquid chromatography coupled to mass spectrometry (LC–MS/MS) was performed and analysed by label-free quantitation (LFQ). Overall, the PdMeOx systems showed similar human plasma protein corona profiles compared to the PEtOx control. However, between the R- and S-PdMeOx enantiomers differences in protein population abundances were observed, suggesting the propensity for specific interaction of chiral PdOx with different elements of the proteome. Overall, the present study introduces PdMeOx as a chiral, low fouling polymer system, which can reduce protein fouling in a similar magnitude to the PEtOx control. Importantly, we provide a first insight into how changes in the chirality of PdMeOx can influence the components of the protein corona, which will inform the future design of PdOx nanotherapeutics. [ABSTRACT FROM AUTHOR]

When polymer mixtures become increasingly complex, the conventional analysis techniques become insufficient for complete characterization. Mass spectrometric techniques can satisfy this increasing demand for detailed sample characterization. Even though isobaric polymers are indistinguishable using simple mass spectrometry (MS) analyses, more advanced techniques such as tandem MS (MS/MS) or ion mobility (IM) can be used. Here, we report proof of concept for characterizing isomeric polymers, namely poly(2-n-propyl-2-oxazoline) (Pn-PrOx) and poly(2-isopropyl-2-oxazoline) (Pi-PrOx), using MS/MS and IM-MS. Pi-PrOx ions lose in intensity at higher accelerating voltages than Pn-PrOx ions during collision-induced dissociation (CID) MS/MS experiments. A Pn/i-PrOx mixture could also be titrated using survival yield calculations of either precursor ions or cation ejection species. IM-MS yielded shape differences in the degree of polymerization (DP) regions showing the structural rearrangements. Combined MS techniques are thus able to identify and deconvolute the molar mass distributions of the two isomers in a mixture. Finally, the MS/MS and IM-MS behaviors are compared for interpretation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hydrophilic PEtOx shows higher cyclization efficiency in water compared to amphiphilic copolymers of EtOx and BuOx. • Cyclization yield of both, amphiphilic and hydrophilic polymers, is highly dependent on polymer concentration in solution. • Cyclization yield of amphiphilic copolymers decreases significantly at reaction temperatures close to the T CP. • Yield of monocyclic hydrophilic PEtOx remains stable, independent of temperature. The steadily increasing interest in cyclic polymers has led to a plethora of proposed applications, particularly as biomaterials. However, the large-scale synthesis of cyclic polymers remains one of the greatest challenges in the field. One reason for this is the poorly understood role of the polymer structure on the cyclization efficiency, leading to synthesis protocols that must be optimized on a case-by-case basis without consideration for the chemical nature of the polymer. Recently, we found through a combination of laboratory experiments and molecular dynamics simulations that the polymer backbone flexibility has a major influence on the cyclization efficiency of poly(cyclic imino ether)s. Concurrently, we identified that a more flexible polymer backbone was also better solvated in the given organic solvent. To deconvolute the importance of the polymer backbone flexibility and solvation, in this study a variety of α-alkyne, ω-azide terminated (co)polymers of 2-ethyl-2-oxazoline and 2– n -butyl-2-oxazoline with different amphiphilicities, but the same polymer backbone, have been synthesized and subjected to copper-catalysed azide-alkyne cycloaddition (CuAAC) reactions in water. In agreement with our previous studies, it was observed that an increase in polymer chain hydrophobicity, and hence a decrease in solvation, leads to a significant decrease in cyclization efficiency. To further understand the effect of different CuAAC reaction conditions on the reaction outcome, different polymer concentrations and reaction temperatures were screened. This study highlights the importance of polymer amphiphilicity, and more generally solvation, in CuAAC protocols aimed towards the synthesis of cyclic polymers. [ABSTRACT FROM AUTHOR]

Water-soluble polymers are still the most popular carrier for the preparation of amorphous solid dispersions (ASDs). The advantage of this type of carrier is the fast drug release upon dissolution of the water-soluble polymer and thus the initial high degree of supersaturation of the poorly soluble drug. Nevertheless, the risk for precipitation due to fast drug release is a phenomenon that is frequently observed. In this work, we present an alternative carrier system for ASDs where a water-soluble and water-insoluble carrier are combined to delay the drug release and thus prevent this onset of precipitation. Poly(2-alkyl-2-oxazoline)s were selected as a polymer platform since the solution properties of this polymer class depend on the length of the alkyl sidechain. Poly(2-ethyl-2-oxazoline) (PEtOx) behaves as a water-soluble polymer at body temperature, while poly(2-n-propyl-2-oxazoline) (PPrOx) and poly(2-sec-butyl-2-oxazoline) (PsecBuOx) are insoluble at body temperature. Since little was known about the polymer’s miscibility behaviour and especially on how the presence of a poorly-water soluble drug impacted their miscibility, a preformulation study was performed. Formulations were investigated with X-ray powder diffraction, differential scanning calorimetry (DSC) and solid-state nuclear magnetic resonance spectroscopy. PEtOx/PPrOx appeared to form an immiscible blend based on DSC and this was even more pronounced after heating. The six drugs that were tested in this work did not show any preference for one of the two phases. PEtOx/PsecBuOx on the other hand appeared to be miscible forming a homogeneous blend between the two polymers and the drugs.

Abstract Controlled release of spices has always been an important subject in the fragrance and flavor industry. In this work, a kind of amphiphilic poly(2-oxazoline)s with pendant Schiff base residues in the hydrophobic segment was designed and synthesized as a potential delivery system for the pH-sensitive release of aldehyde/ketone fragrances in applications of functional perfumery. The aldehyde contents of 0.65–1.74 mmol/g were reached for polymer-fragrance conjugates. Upon direct dissolution in water, polymers self-assembled into micelle-type aggregates with hydrodynamic diameters ranging from 55 to 250 nm. The release kinetic experiments showed that the aroma-carrying nanoparticles exhibited improved stability toward hydrolysis compared to the corresponding non-micellar system. At acidic pH, the imine linkages in the polymers were gradually hydrolyzed and an increasing amount of the aldehyde was released over time. Furthermore, the pseudopeptide pro-fragrances displayed a high affinity to the cotton surface due to the presence of tertiary amide backbones and protonated amino groups in the polymeric matrices. [ABSTRACT FROM AUTHOR]

Abstract: The possibility to impart surface properties to any polymeric substrate using a fast, reproducible, and industrially friendly procedure, without the need for surface pretreatment, is highly sought after. This is in particular true in the frame of antibacterial surfaces to hinder the threat of biofilm formation. In this study, the potential of aryl‐azide polymers for photofunctionalization and the importance of the polymer structure for an efficient grafting are demonstrated. The strategy is illustrated with a UV‐reactive hydrophilic poly(2‐oxazoline) based copolymer, which can be photografted onto any polymer substrate that contains carbon–hydrogen bonds to introduce antifouling properties. Through detailed characterization it is demonstrated that the controlled spatial distribution of the UV‐reactive aryl‐azide moieties within the poly(2‐oxazline) structure, in the form of pseudogradient copolymers, ensures higher grafting efficacy than other copolymer structures including block copolymers. Furthermore, it is found that the photografting results in a covalently bound layer, which is thermally stable and causes a significant antiadherence effect and biofilm reduction against Escherichia coli and Staphylococcus epidermidis strains while remaining noncytotoxic against mouse fibroblasts. [ABSTRACT FROM AUTHOR]

ABSTRACT: Hydrogen bonding is widely present and plays a significant role in material science and supramolecular chemistry. This work reports a straightforward strategy for the preparation of polymeric nanoparticles from neutral poly(2‐oxazoline)s (POx) and tannic acid (TA) driven by their intermolecular hydrogen bonding. Dynamic light scattering (DLS) and scanning electron microscope (SEM) measurements showed that POx bearing different substituents, that is, methyl, ethyl and n‐propyl in the 2‐position all could assemble with TA into stable nanoparticles in water or ethanol. The diameter of the assembled nanoparticles could be manipulated by varying parameters such as molecular weight of POx, concentration and ratio of POx, and TA. Interestingly, POx/TA nanoparticles exhibited upper critical solution temperature (UCST)‐type thermoresponsive properties in ethanol or water depending on the molecular weight and substituent in the 2‐position of POx. Increasing or decreasing the temperature at the transition point resulted in the reversible transformation between assembled nanoparticles and disassembled poly(2‐n‐propyl‐2‐oxazoline) (PnPrOx) and TA. In view of the tailored size of the stable nanoparticles and the biocompatibilities of POx and TA, the prepared thermoresponsive nanoparticles are promising candidates as carriers for medicine toward related biomedical applications. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1520–1527 [ABSTRACT FROM AUTHOR]

Polymeric porous adsorbents are reported for removal of explosives, namely picric acid, 1,3,5-trinitro-1,3,5-triazinane (RDX), and pentaerythritol tetranitrate (PETN) and their subsequent quantification using direct analysis with ambient plasma mass spectrometry. The adsorbents are obtained by functionalization of short-chain poly(2-oxazoline)s with methyl ester side chains using 4-(aminomethyl)pyridine with a degree of functionalization equal to 0, 5, 10, and 20%. The subsequent step consist of cross-linking using a high internal phase emulsion procedure by further side-chain amidation with diethylenetriamine as crosslinker. Picric acid, RDX, and PETN were chosen as the model compounds as they belong to three different groups of explosives, in particular nitroaromatics, nitroamines, and nitrate esters, respectively. The adsorption isotherms, kinetics, as well as the influence of pH and temperature on the adsorption process was investigated. The porous adsorbents showed the highest maximum adsorption capacity towards picric acid, reaching 334 mg g−1, while PETN (80 mg g−1) and RDX (17.4 mg g−1) were less efficiently adsorbed. Subsequent quantification of the adsorbed explosives is performed by a specially designed ambient mass spectrometry setup equipped with a thermal heater. The obtained limits of detection were found to be 20-times improved compared to direct analysis of analyte solutions. The effectiveness of the proposed analytical setup is confirmed by successful quantification of the explosives in river water samples. The research clearly shows that functional porous adsorbents coupled directly with ambient mass spectrometry can be used for rapid quantification of explosives, which can be, e.g., used for tracking illegal manufacturing sites of these compounds. [Display omitted] • Porous adsorbents were obtained using functional poly(2-oxazoline)s • The materials were used for adsorption of picric acid, RDX, and PETN • The highest adsorption capacity was obtained for picric acid, reaching 334 mg g−1 • Quantification was performed using ambient plasma mass spectrometry • This analytical procedure allowed to significantly improve limits of detection [ABSTRACT FROM AUTHOR]

[Display omitted] • Optimisation of the CROP reaction parameters allowed to reach a living character. • A family of poly(2-oxazoline)s with controlled molecular weight was synthesized. • Obtained poly(2-oxazoline)s showed liquid crystalline behaviour. • Under thermal treatment, these copolymers self-assemble into columnar structures. The polymerization of dendronized monomers is an attractive option to synthesize liquid crystalline columnar polymers with side chain dendrons. Following this approach, we report for the first time in the present study the synthesis of a family of side chain liquid crystalline (SCLC) poly(2-oxazoline)s, poly(2-(3,4,5-tris(4-dodecyloxybenzyloxy)phenyl)-2-oxazoline) (PTOx) from its oxazoline monomer precursor, 2-(3,4,5-tris(4-dodecyloxybenzyloxy)phenyl)-4,5-dihydro-1,3-oxazole) (TAPOx), by cationic ring-opening polymerization (CROP). The optimisation of the reaction parameters (temperature, type of initiator, terminating agent, solvent and monomer concentration), combined with the nature of the CROP allowed us to obtain high molecular weight SCLC poly(2-oxazoline)s. NMR investigations were consistent with the targeted molecular weights of the synthesized PTOx and the living nature of TAPOx polymerization. Regarding the mesomorphic characterization, all synthesized acyl-substituted poly(ethyleneimine)s exhibited liquid crystalline mesophases in a broad temperature range. XRD studies demonstrated that these dendronized poly(2-oxazoline)s self-assemble into columnar structures. Mesomorphic and thermal properties suggest that these family of poly(2-oxazoline)s could be excellent candidates to build up membranes for proton transport applications. [ABSTRACT FROM AUTHOR]

Buckminster fullerene (C60)′s main hurdle to enter the field of biomedicine is its low bioavailability, which results from its extremely low water solubility. A well-known approach to increase the water solubility of C60 is by complexation with γ-cyclodextrins. However, the formed complexes are not stable in time as they rapidly aggregate and eventually precipitate due to attractive intermolecular forces, a common problem in inclusion complexes of cyclodextrins. In this study we attempt to overcome the attractive intermolecular forces between the complexes by designing custom γ-cyclodextrin (γCD)-based supramolecular hosts for C60 that inhibit the aggregation found in native γCD-C60 complexes. The approach entails the introduction of either repulsive electrostatic forces or increased steric hindrance to prevent aggregation, thus enhancing the biomedical application potential of C60. These modifications have led to new sub-100 nm nanostructures that show long-term stability in solution. [ABSTRACT FROM AUTHOR]

Poly(2-oxazoline)s (PAOx) are of increasing importance for a wide range of applications, mostly in the biomedical field. This review describes the synthesis of 2-oxazoline monomers and their cationic ring-opening polymerization, and gives a comprehensive overview of all reported PAOx homopolymers. In the second part of the review, the polymer properties of these PAOx homopolymers with varying side-chain structures are discussed. Altogether, this review intends to serve as an encyclopedia for poly(2-oxazoline)s enabling the straightforward selection of a polymer structure with the desired properties for a certain application. © 2017 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Poly(2-oxazoline)s are regarded as bioinspired polymers due to their structural relation to polypeptides. In this work, a new kind of poly(2-oxazoline)s containing dipeptide segments in the side chains was synthesized through a bottom-up protocol, which involves ring-opening copolymerization of 2-( N -Boc- l -2-pyrrolidinyl)-2-oxazoline (PyOX Boc ) with 2-(3-butenyl)-2-oxazoline (BuOX) followed by deprotection and amide coupling with N -protected L-proline. The resulting vinyl-functionalized polymers were subsequently immobilized onto mercaptopropylated silica bead matrices by means of thio-click chemistry and their potential as the chiral stationary phase (CSP) for high-performance liquid chromatography was preliminarily evaluated with a series of structurally different racemates. The results showed that this class of pseudopeptide CSPs is particularly adapted to the enantiomeric separation of 1,1′-bi-2-naphthol and acyloin compounds (such as benzoin) under normal-phase conditions. Moreover, an increase in the length of polymer main chains is beneficial to the enhancement of both enantioselectivity and resolution ability. The chiral discrimination of analytes by the polymeric selectors stems primarily from hydrogen bonding and π-π interactions as well as steric hindrance. [ABSTRACT FROM AUTHOR]

Amphiphilic block copolymers possess great potential as biomaterials in drug delivery and gene therapy. Herein, pseudopeptidic-type diblock copolymer of poly(2-oxazoline)- block-polypeptoid (POx- b-POI) is presented and synthesized. Poly[2-(3-butenyl)-2-oxazoline]- block-poly(sarcosine) (PBuOx- b-PSar) comprising hydrophobic POx segment bearing alkenyl side chain and hydrophilic POI segment of N-methyl glycine, viz., sarcosine, is prepared by ring-opening polymerization (ROP) through a one-pot and three-step route. Diphenyl phosphate initiates ROP of BuOx, and then the living chain end of PBuOx is quenched by ammonia to obtain PBuOx-ammonium phosphate in situ, the active ammonium group initiates ROP of sarcosine N-carboxy anhydride. PBuOx- b-PSar with controlled molecular weights (4.7-10.8 kg mol−1) and narrow dispersities ( ÐM 1.15-1.21) are characterized by 1H NMR, 13C NMR, and size-exclusion chromatography. Dynamic light scattering and transmission electron microscopy analysis reveal that PBuOx- b-PSar self-assembles into nanostructures of average diameter DH of 37-109 nm in aqueous solution. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test demonstrates the cytocompatibility (relative cell viability > 80%) of the PBuOx- b-PSar. In view of the self-assembly and biocompatibility, the readily prepared diblock copolymers may hopefully be used in biomedical applications. [ABSTRACT FROM AUTHOR]

A variety of hydrophilic diblock and triblock copolymers of AB and ABA type with temperature-sensitive poly(2-isopropyl-2-oxazoline) blocks und pH-sensitive poly(2-carboxyethyl-2-oxazoline) blocks have been synthesized. The temperature- and pH-induced reversible phase transition renders the block copolymers as amphiphilic macromolecules and allows for defined aggregation through self-assembly following the packing parameter of amphiphilic macromolecules. Size, structure and arrangement of the individual block copolymer segments define the temperature and pH values of the transitions as well as the nature of the formed aggregates. DLS measurements were used to determine the transition temperatures at selected pH values in aqueous solution whereas AFM was used to visualize and characterize the formed aggregates adsorbed on Si wafer surfaces. In the case of vesicles formed by the diblock and triblock copolymers, double and monolayer membranes could be verified. The tendency of different states of organization of poly(2-isopropyl-2-oxazoline) blocks from crystalline to amorphous is assumed to be the cause for the different box-like structures determined on Si wafer surfaces. [ABSTRACT FROM AUTHOR]

The potential of poly(2-oxazoline) containing copolymers for drug delivery is discussed in this feature article. Advances in synthetic routes for 2-oxazoline copolymerization and chemical modification of biocompatible poly(2-oxazoline) copolymers allow the control of amphiphilic poly(2-oxazoline) copolymers at the molecular level. Thus macromolecular design dictates self-organization of poly(2-oxazoline) copolymers at the nano-scale into morphologically diverse, functional nanostructures in aqueous solutions, able to respond to changes caused by external stimuli and showing fine-tuned interactions, loading and release properties of encapsulated hydrophobic drugs and biological macromolecules. The latest advances in the use of poly(2-oxazoline) containing copolymers as carriers of hydrophobic drugs, therapeutic proteins/peptides and nucleic acids are presented through representative examples from recent literature. It can be safely concluded that nanocarriers based on poly(2-oxazoline) containing block copolymers show a great potential for applications in the biomedical field in the near future. [ABSTRACT FROM AUTHOR]

[Display omitted] • The combination of CROP and RAFT polymerization was applied to synthesize graft copolymers presenting oligosiloxane and oligoalkyloxazoline side chains with fully tunable composition. • Poly(oxazoline)-based graft copolymers were applied to fabricate PDMS-based antifouling coatings. • Graft copolymers featuring oligoalkyloxazoline side chains emerged as valid alternatives to PEG-based derivatives as surface-active additives to fabricate antibiofouling coatings. • Graft copolymers including oligoalkyloxazoline grafts proved more efficient than their PEG-containing counterparts in inhibiting the settlement and promoting the removal of marine macrofoulers. Poly(ethylene glycol) (PEG)-based graft copolymers have been widely applied for the modification of poly(dimethyl siloxane) (PDMS)-based coatings that resist marine biofouling. In this research, we synthesized oligo(2-alkyl-2-oxazoline) (OAOXA)-based graft copolymer analogues, and subsequently tested their applicability in the formulation of structurally similar coatings, aiming to highlight the influence of polymer composition on biopassive properties. In particular, poly(dimethyl siloxane methacrylate)- co -oligo(2-alkyl-2-oxazoline)methacrylate copolymers were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization, starting from oligo(2-ethyl-2-oxazoline)- and oligo(2-methyl-2-oxazoline)-methacrylate macromonomers (OEOXMA and OMOXMA, respectively). Amphiphilic copolymer films with OAOXA grafts were found to be more hydrophilic with respect to those obtained using PEG analogues. PDMS coatings containing the graft copolymers as surface additives were tested towards the settlement of the macrofouler Ficopomatus enigmaticus and the diatom Navicula salinicola. The biofouling experiments indicated that OAOXA-containing films showed a comparable and in some cases improved performance with respect to their PEG-based counterparts, thus highlighting how OAOXA-based graft copolymers represent a valid alternative to PEG derivatives as surface-active additives to design antibiofouling coatings. [ABSTRACT FROM AUTHOR]

Novel amphiphilic poly(2-oxazoline)s bearing l -prolinamide moieties at the alkyl side-chain termini were designed and synthesized by a bottom-up protocol. These polymers formed micelle-type assemblies with a size of 10–30 nm in water, in which the majority of prolinamide active groups was tucked into the hydrophobic inner core. As a nanoreactor, the micellar systems were successfully applied to the direct asymmetric aldol reaction in aqueous media. The results demonstrated that the polymer-bound prolinamide catalysts show a significant improvement in catalytic efficiency when compared with their monomeric counterpart and non-amphiphilic reference polymer, affording the anti-product with a moderate stereoselectivity in the representative aldol addition of cyclohexanone to p -nitrobenzaldehyde. Additionally, the poly(2-oxazoline) derivatives can also promote effectively the reactions of tetrahydro-4 H -pyran-4-one or cyclopentanone donors to give the corresponding aldol adducts in high yield and with good diastereo- and enantioselectivities. [ABSTRACT FROM AUTHOR]