Lignin is an abundant biopolymer that is mainly burned for energy production today. However, using it as a polyfunctional macromolecular building block would be desirable. Herein, Kraft lignin was modified through esterification of its hydroxyl groups with methacrylic anhydride. Then lignin nanocarriers with different morphologies (solid nanoparticles, core–shell structures, porous nanoparticles) were produced by a combination of miniemulsion polymerization and a solvent evaporation process. A UV-active cargo is used as a drug model to investigate the release behavior of the lignin nanocarriers depending on their morphology. To prove the enzymatic response of the lignin nanocarriers, we tested the enzyme laccase as a trigger to release the encapsulated cargo. Furthermore, porous lignin nanoparticles with high surface area were produced by carbonization. The carbon material has a high potential as an adsorbent, which was studied by adsorption tests with methylene blue. These biodegradable nanocarriers based on the polyfunctional bioresource lignin may find useful application as novel drug delivery vehicle in agriculture or as carbon materials for water purification.Keywords: drug-delivery; laccase; lignin; miniemulsion; nanocarrier;

Thermoresponsive materials are currently discussed for applications, e.g., in drug delivery or sensor systems. While homopolymers exhibit a certain LCST, copolymers allow adjusting the cloud points depending on the comonomer ratio. We report on degradable poly(phosphester) (PPE) copolymers exhibiting LCSTs, which can be further tuned by reversible postmodification. A library of copolymers with different cloud points is obtained from a single “precursor polymer”. A novel furfuryl-carrying cyclic phosphate was designed, and different PPE copolymers were prepared via ring-opening polymerization with adjustable furan contents (up to 25 mol % were targeted and achieved) and molecular weights up to 40 000 g/mol (Đ < 1.25). Modification was achieved by a Diels–Alder reaction with maleimides of different hydrophilicity to further alter the solubility profile of the polymers. While the postmodification is thermally reversible, the biodegradable PPE backbone remains unaffected. This first report on the Diels–Alder postmodification of PPEs to adjust LCST behavior further underlines the versatility of this polymer class and might be used in future drug delivery and temperature-responsive devices.

Numerous catechol-containing polymers, including biodegradable polymers, are currently heavily discussed for modern biomaterials. However, there is no report combining poly(phosphoester)s (PPEs) with catechols. Adhesive PPEs have been prepared via acyclic diene metathesis polymerization. A novel acetal-protected catechol phosphate monomer was homo- and copolymerized with phosphoester comonomers with molecular weights up to 42000 g/mol. Quantitative release of the catechols was achieved by careful hydrolysis of the acetal groups without backbone degradation. Degradation of the PPEs under basic conditions revealed complete and statistical degradation of the phosphotri- to phosphodiesters. In addition, a phosphodiester monomer with an adhesive P–OH group and no protective group chemistry was used to compare the binding to metal oxides with the multicatechol-PPEs. All PPEs can stabilize magnetite particles (NPs) in polar solvents, for example, methanol, due to the binding of the phosphoester groups in the backbone to the particles. ITC measurements reveal that multicatechol PPEs exhibit a higher binding affinity to magnetite NPs compared to PPEs bearing phosphodi- or phosphotriesters as repeating units. In addition, the catechol-containing PPEs were used to generate organo- and hydrogels by oxidative cross-linking, due to cohesive properties of catechol groups. This unique combination of two natural adhesive motives, catechols and phosphates, will allow the design of novel future gels for tissue engineering applications or novel degradable adhesives.

Ruthenocenyl glycidyl ether (rcGE) is a novel monomer for the anionic polymerization and copolymerization with ethylene oxide to water-soluble, thermo-, and redox-responsive organometallic poly(ethylene glycol)s (PEGs). The polymers exhibit adjustable molecular weights, comonomer ratios, and narrow molecular weight distributions (typically Mw/Mn < 1.2). Real-time 1H NMR copolymerization kinetics prove random incorporation of rcGE into the polyether backbone in analogy to its ferrocene analog. The rcGE-co-EO copolymers are water-soluble with a lower critical solution temperature, depending on the rcGE content. Terpolymerization of ferrocenyl glycidyl ether, ethylene oxide, and rcGE produces the first random PEG derivatives with multiple redox response. Ruthenocenyl glycidyl ether broadens the field of organometallics, especially ruthenium-containing polymers, and these copolymers might find applications in catalysis, as redox-active surfactants, or as staining reagents in electron microscopy.

Temperature-induced self-assembly of block copolymers allows the formation of smart nanodimensional structures. Mostly, nondegradable lower critical solution temperature (LCST) segments are applied to prepare such dynamic aggregates. However, degradable upper critical phase separation (UCST) block copolymers that would allow the swelling or disassembly at elevated temperatures with eventual backbone hydrolysis have not been reported to date. We present the first well-defined degradable poly(phosphonate)s with adjustable UCST. The organocatalytic anionic ring-opening copolymerization of 2-alkyl-2-oxo-1,3,2-dioxaphospholanes provided functional polymers with excellent control over molecular weight and copolymer composition. The prepolymers were turned into thermoresponsive polymers by thiol–ene modification to introduce pendant carboxylic acids. By this means, non cell-toxic, degradable polymers exhibiting UCST behavior in water between 43 and 71 °C were produced. Block copolymers with PEG as a nonresponsive water-soluble block can self-assemble into well-defined polymersomes with narrow size distribution. Depending on the responsive block, these structures either swell or disassemble completely upon an increased temperature.

Phosphoryl choline derivatives are important compounds for drug development. Also other phosphoesters have received increased demand in recent years. Many of such compounds rely 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) as an intermediate. COP is available in a two-step reaction from the cyclic adduct of phosphorus chloride and ethylene glycol after oxidation. Although commercially available, in-house synthesis of COP is often required due to pricing, purity, and delivery issues. Air is a convenient and economical oxidizing agent, yet not used for synthesis of COP. While slow consumption of the P(III)-precursor 2-chloro-1,3,2-dioxaphospholane with molecular oxygen from a gas bottle, high amounts of unreacted oxygen are lavished and even may cause an explosion. Oxygen from air is a reasonable and safer alternative. Additionally, catalytic amounts of cobalt(II)chloride increase the reaction kinetics remarkably. The results presented allow a controlled and fast access to a variety of phosphoesters by optimized reaction conditions of COP and its derivatives.Download high-res image (174KB)Download full-size image

“A living race” – polymerization kinetics of anionic polymerizations depends strongly on the solvent polarity and reactivity of the growing chain end. Both the carb- and oxyanionic polymerization is under control at the university lab and on the industrial level, however, no information for the aza-anionic polymerization of aziridines has been reported systematically. This work studies the polymerization of two activated aziridines (2-methyl-N-mesylaziridine (MsMAz) and 2-methyl-N-tosylaziridine (TsMAz)) by real-time 1H NMR spectroscopy. This technique allows monitoring the consumption of the monomer precisely during the polymerization under different conditions (temperature, solvent, initiator and counter-ion variation). From the experimental data, propagation rate constants (kp) were calculated and analyzed. The polymerization of MsMAz was monitored at different temperatures (20, 50, and 100 °C). The increase of temperature increases the speed of polymerization, but keeps the living behavior. Furthermore, the influence of different solvents on the polymerization speed was examined, proving solvating solvents such as DMSO and DMF as the fastest solvents. Two different initiators, the potassium salts of N,N′-(1,4-phenylenebis(methylene))dimethanesulfonamide (BnBis(NHMs)), the first bifunctional initiator for the AROP of aziridines, and of N-benzyl-sulfonamide (BnNHMs) were compared. The variation of the counter ions Li+, Na+, K+, and Cs+ (generated from the respective bis(trimethylsilyl)amide salts) proved successful polymerization of both monomers with all counter ions. Slight variations have been detected in the order: Cs+ > Li+ > Na+ > K+, which is in strong contrast for the AROP of epoxides, shows a strong gegenion-dependent kinetic profile. This allows the use of commercially available initiators, such as BuLi for the synthesis of PAz. With these results in hand, the azaanionic polymerization can be used as a valuable tool in the family of anionic polymerization for the preparation of structurally diverse polysulfonamides and polyamines under a broad variety of conditions, while maintaining the living behavior.

The thermal properties of halogen-free flame retardant poly(phosphoester)s from acyclic diene metathesis polycondensation have been optimized by a systematic post-modification using 1,2,4-triazoline-3,5-dione derivatives. The straightforward modification not only increased their glass transition temperatures significantly but also improved the thermal stability with respect to their char yields.

The encapsulation of sensitive drugs into nanocarriers retaining their bioactivity and achieving selective release is a challenging topic in current drug delivery design. Established protocols rely on metal-catalyzed or unspecific reactions to build the (mostly synthetic) vehicles which may inhibit the drug's function. Triggered by light, the mild tetrazole–ene cycloaddition enables us to prepare protein nanocarriers (PNCs) preserving at the same time the bioactivity of the sensitive antitumor and antiviral cargo Resiquimod (R848). This catalyst-free reaction was designed to take place at the interface of aqueous nanodroplets in miniemulsion to produce core–shell PNCs with over 90% encapsulation efficiency and no unwanted drug release over storage for several months. Albumins used herein are major constituents of blood and thus ideal biodegradable natural polymers for the production of such nanocarriers. These protein carriers were taken up by dendritic cells and the intracellular drug release by enzymatic degradation of the protein shell material was proven. Together with the thorough colloidal analysis of the PNCs, their stability in human blood plasma and the detailed protein corona composition, these results underline the high potential of such naturally derived drug delivery vehicles.

•Copolymerization of three 2-alkyl-2-oxo-1,3,2-dioxaphospholanes to random polyphosphonates.•Characterization of terpolymer properties and polymerization kinetics.•Thiol-ene pendant-group modification to introduce zwitterionic groups.•LCST-behavior of PPE terpolymers and coacervate formation at elevated temperature.Coacervates are partially hydrated, colloidal polymer droplets in water held together by hydrophobic interactions and are considered promising candidates for drug delivery applications. We present the first coacervates made from temperature-induced phase separation of aqueous poly(phosphoester) terpolymer solutions. Such coacervates are interesting for drug carrier applications as they are non-toxic, fully biodegradable and form spontaneously upon heating above a threshold temperature (lower critical solution temperature, LCST). The investigated poly(ethylene alkyl phosphonate) terpolymers are synthesized via the organocatalytic anionic ring-opening polymerization of cyclic phosphonate monomers. This way polymers with high control over molecular weight, terpolymer composition (and hence physical and chemical properties) and rather narrow molecular weight distributions (Р< 1.30) are produced. The terpolymers bear functional pendant groups for further modifications and have a finely tunable balance of hydrophilic and hydrophobic side-chains randomly distributed over the whole chain, as proven by 31P NMR polymerization kinetics. These functional terpolymers spontaneously phase separate into a polymer rich coacervate phase in water upon heating above the LCST, providing an elegant method to prepare degradable and non-toxic carrier system.Download high-res image (169KB)Download full-size image

An important and usually the only function of most surfactants in heterophase systems is stabilizing one phase in another, for example, droplets or particles in water. Surfactants with additional chemical or physical handles are promising in controlling the colloidal properties by external stimuli. The redox stimulus is an attractive feature; however, to date only a few ionic redox-responsive surfactants have been reported. Herein, the first nonionic and noncytotoxic ferrocene-containing block copolymers are prepared, carrying a hydrophilic poly(ethylene glycol) (PEG) chain and multiple ferrocenes in the hydrophobic segment. These amphiphiles were studied as redox-sensitive surfactants that destabilize particles as obtained in miniemulsion polymerization. Because of the nonionic nature of such PEG-based copolymers, they can stabilize nanoparticles even after the addition of ions, whereas particles stabilized with ionic surfactants would be destabilized by the addition of salt. The redox-active surfactants were prepared by the anionic ring-opening polymerization of ferrocenyl glycidyl ether, with PEG monomethyl ether as the macroinitiator. The resultant block copolymers with molecular weights (Mn) between 3600 and 8600 g mol–1 and narrow molecular weight distributions (Mw/Mn = 1.04–1.10) were investigated via 1H nuclear magnetic resonance and diffusion ordered spectroscopy, size exclusion chromatography, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Furthermore, the block copolymers were used as building blocks for redox-responsive micelles and as redox-responsive surfactants in radical polymerization in miniemulsion to stabilize model polystyrene nanoparticles. Oxidation of iron to the ferrocenium species converted the amphiphilic block copolymers into double hydrophilic macromolecules, which led to the destabilization of the nanoparticles. This destabilization of nanoparticle dispersions may be useful for the formation of coatings and the recovery of surfactants.

Nature on planet earth is dominated by poly(phosphoester)s (PPEs). They structure and determine life in the form of deoxy- and ribonucleic acid (DNA & RNA), and, as pyrophosphates, they store chemical energy in organisms. Polymer chemistry, however, is dominated by the non-degradable polyolefins and degradable polycarboxylic esters (PCEs) produced on a large scale today. Recent work has illustrated the potential of PPEs for future applications beyond flame-retardancy, the main application of PPEs today, and provided a coherent vision to implement this classic biopolymer in modern applications that demand biocompatibility and degradability as well as the possibility to adjust the properties to individual needs. This comprehensive review summarizes synthetic protocols to PPEs, their applications in biomedicine, e.g., as biodegradable drug carrier or in tissue engineering, and their flame retardant properties. We highlight recent developments that may make phosphorus-based polymers attractive materials for various future applications.

Reactions and polymerizations at the interface of two immiscible liquids are reviewed. The confinement of two reactants at the interface to form a new product can be advantageous in terms of improved reaction kinetics, higher yields, and selectivity. The presence of the liquid–liquid interface can accelerate the reaction, or a phase-transfer catalyst is employed to draw the reaction in one phase of choice. Furthermore, the use of immiscible systems, e.g., in emulsions, offers an easy means of efficient product separation and heat dissipation. A general overview on low molecular weight organic chemistry is given, and the applications of heterophase polymerization, occurring at or in proximity of the interface, (mostly) in emulsions are presented. This strategy can be used for the efficient production of nano- and microcarriers for various applications.

The ring-opening polymerization of N-tosyl aziridines, in the presence of 1,3-bis(isopropyl)-4,5(dimethyl)imidazol-2-ylidene as an organocatalyst and an N-tosyl secondary amine as initiator mimicking the growing chain, provides the first metal-free route to well defined poly(aziridine)s (PAz) and related PAz-based block copolymers.

Poly(phosphoester)s (PPEs) are interesting degradable multi-functional polymers. Here, we present the first synthesis of poly(phosphoramidate)s (PPAs) via acyclic diene metathesis (ADMET) polycondensation with amidate linkages in side chains. In contrast to conventional polyamides, the P–N-bond in phosphoramidates is more labile than the corresponding esters. Unsaturated PPAs were compared with structural analogues of PPEs: two novel α,ω-dienes, i.e. bis-(undecen-10-yl)-n-butyl-phosphoramidate (1) and bis-(undecen-10-yl)-n-butyl-phosphate (2) have been polymerized by Grubbs-type catalysts to polymers with molecular weights up to ca. 20000 g mol−1. After hydrogenation polyethylene-like structures were obtained with the phosphoramidate or -ester representing a precisely placed defect. PPAs were compared to their PPE analogues with respect to their thermal behavior and stability by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), showing similar crystallization behavior for the saturated materials, but significant differences for unsaturated PPA vs. PPE. This synthesis of PPAs via ADMET polymerization offers an interesting approach to various PPAs. The hydrolytically labile pendant phosphoramidate further offers the possibility for the development of hydrolytically degradable materials or as processable intermediates for poly(phosphodiester)s which often show limited solubility.

Handling the insoluble POM: the preparation of nanoparticles based on hyperbranched-linear-hyperbranched ABA triblock copolymers with variable hydrophilicity and composed of short hyperbranched polyglycerol (hbPG) as the A-blocks and linear poly(oxymethylene) (POM) as a B-block is described. The POM-hbPG-nanoparticles with diameters in the range of 190 to 250 nm were generated in a convenient process, combining the solvent evaporation process with the miniemulsion technique, a water borne handling for POM-copolymers. Furthermore, the film formation properties of the nanoparticles were investigated by deposition on silicon and subsequent sintering, which leads to films with a thickness in the μm-range that were investigated via SEM. The surface properties of these films were investigated via static contact angle measurements at the liquid/vapor interface. The contact angle decreases from 67° for the polymer film based on POM with two hydroxyl end groups to 29° for POM-copolymers with 16 hydroxyl groups, confirming the influence of the polymer structure and size of the hbPG block on the surface properties. In summary, this work presents a possibility for a facile handling and film formation of the insoluble POM, opening new applications, e.g., in coatings.

2-Cyclohexyl-2-oxo-1,3,2-dioxaphospholane (cyHexPPn), a new monomer for the anionic ring-opening polymerization to poly(ethylene alkyl phosphonate)s is presented. The organo-catalyzed polymerization produces homopolymers with excellent control over molecular weight and narrow molecular weight distributions. The homopolymer was found to exhibit a glass transition at 15 °C, which is 60 °C higher compared to all previously reported poly(ethylene n-alkyl phosphonate)s. Copolymerization with the water-soluble 2-isopropyl-2-oxo-1,3,2-dioxaphospholane (iPrPPn) resulted in water-soluble, well-defined copolymers. The copolymer composition matched the theoretical value in all cases and Tg showed a linear correlation with the amount of (iPrPPn) incorporated. The copolymer was found to exhibit low cell-toxicity towards sensitive murine macrophage-like cells (RAW264.7).

Acetal-protected and sulfonamide-activated aziridines (Az) have been prepared and polymerized by living anionic polymerization with molecular weight dispersities in most cases below Đ < 1.2 and controlled molecular weights. Three new monomers have been prepared varying in the length of the pendant chain. The resulting double protected polymers can be selectively deprotected in order to release the polyamine or the polyol structures. Detailed structural characterization was performed for all polymers, and chain extension proves their living polymerization behavior and the formation of block copolymers. Thermal analysis can be used in order to follow the deprotection steps. These new protected monomers broaden the scope of the azaanionic polymerization of aziridines and may find useful applications as well-defined functional poly(ethylene imine) derivatives.

•In situ and fast synthesis of magnetic nanoparticles on chitosan by sonochemistry.•All samples presented superparamagnetic behavior.•Hybrid nanocomposite available for use as modified electrodes.Chitosan-based magnetite nanocomposites were synthesized using a versatile ultrasound assisted in situ method involving one quick step. This synthetic route approach results in the formation of spheroidal nanoparticles (Fe3O4) with average diameter between 10 and 24 nm, which were found to be superparamagnetic with saturation magnetization (Ms) ranges from 32–57 emu g−1, depending on the concentration. The incorporation of Fe3O4 into chitosan matrix was also confirmed by FTIR and TG techniques. This hybrid nanocomposite has the potential application as electrochemical sensors, since the electrochemical signal was excepitionally stable. In addition, the in situ strategy proposed in this work allowed us to synthesize the nanocomposite system in a short time, around 2 min of time-consuming, showing great potential to replace convencional methods. Herein, the procedure will permit a further diversity of applications into nanocomposite materials engineering.

Pharmacokinetic properties determine the efficacy of protein therapeutics. The covalent attachment of poly(ethylene glycol) (PEG) extends the half-life of such biologicals to maintain a therapeutically effective concentration over a prolonged period of time and improves administration and compliance. A major obstacle of these polymer–protein conjugates is the chemical stability of the PEG preventing its metabolism and leading to side effects. Instead, we propose the PPEylation, that is, the conjugation of degradable poly(phosphoester)s (PPE) to proteins, in order to generate fully biodegradable polymer–protein conjugates. The structure of the PPEylated protein conjugates was verified with mass spectrometry and size exclusion chromatography. They were compared to structural analogues, except classical, PEGylated proteins, and exhibit comparable bioactivity, but avoiding any nondegradable polymer in the conjugate. We proved the degradation of the protective polymer shell surrounding the conjugate in aqueous environments at physiological conditions by online triple detection size exclusion chromatography and gel electrophoresis. We believe that this research will provide an attractive alternative for future drug design with implications for the clinical use of biologicals.

Redox-responsive poly(ferrocenylsilane) (PFS) is used to construct nanocontainers that can be loaded with hydrophobic cargo by a miniemulsion approach. The resulting structures comprise a solid shell surrounding a liquid oil core and have diameters of approximately 470 nm with a shell thickness of ca. 29 nm. The electrochemical behavior of the ferrocene group is investigated using cyclic voltammetry. Electrochemical oxidation and the thereby caused change of container morphology are shown. Hydrophobic molecules (Nile Red and 2-propylpyiridine) are loaded into the nanocontainers and can be released upon oxidation of the shell material. The oxidation is achieved chemically by the addition of hydrogen peroxide or by the enzymatic oxidation of glucose to release 2-propylpyridine over a period of time.

In-chain poly(phosphonate)s have been prepared via acyclic diene metathesis polymerization of three different monomers. Novel unsaturated phosphonate monomers with asymmetric structure have been developed. The monomers are accessible via a three-step synthesis that can be easily scaled up. This is the first report on poly(phosphonate)s by olefin metathesis where the stable carbon–phosphorus linkage is localized in the polymer backbone. This changes the nature of the degradation products compared to other poly(phosphoester)s. Polymers with molecular weights up to 31 000 g mol–1 can be achieved and have been characterized in detail NMR spectroscopy, size exclusion chromatography, thermogravimetry, and differential scanning calorimetry. They have been also compared to structural analogues polyphosphates with respect to crystallization (SAXS, WAXS) and their rheological behavior. Also, solution grown crystals were analyzed rendering some of the herein reported poly(phosphonate)s as interesting defect poly(ethylene)-like structures.

The specific targeting of either tumor cells or immune cells in vivo by carefully designed and appropriately surface-functionalized nanocarriers may become an effective therapeutic treatment for a variety of diseases. Carbohydrates, which are prominent biomolecules, have shown their outstanding ability in balancing the biocompatibility, stability, biodegradability, and functionality of nanocarriers. The recent applications of sugar (mono/oligosaccharides and/or polysaccharides) for the development of nanomedicines are summarized in this review, including the application of carbohydrates for the surface-functionalization of various nanocarriers and for the construction of the nanocarrier itself. Current problems and challenges are also addressed.

Triple-stimuli-responsive PEG-based materials are prepared by living anionic ring-opening copolymerization of ethylene oxide and vinyl ferrocenyl glycidyl ether and subsequent thiol–ene postpolymerization modification with cysteamine. The hydrophilicity of these materials can be tuned by three stimuli: (i) temperature (depending on the comonomer ratio), (ii) oxidation state of iron centers in the ferrocene moieties, and (iii) pH-value (through amino groups), both in aqueous solution and at the interface after covalent attachment to a glass surface. In such materials, the cloud point temperatures are adjustable in solution by changing oxidation state and/or pH. On the surface, the contact angle increases with increasing pH and temperature and after oxidation, making these smart surfaces interesting for catalytic applications. Also, their redox response can be switched by temperature and pH, making this material useful for catalysis and electrochemistry applications. Exemplarily, the temperature-dependent catalysis of the chemiluminescence of luminol (a typical blood analysis tool in forensics) was investigated with these polymers.Keywords: ferrocene; polyether; redox-active polymer; smart surface; stimuli responsive;

A novel, general protocol for a polymer-mediated Horner–Wadsworth–Emmons (HWE) reaction is reported. The polyvalent polymeric reagent was prepared via acyclic diene metathesis (ADMET) polymerization. Homo- and copolymers of reactive poly(phosphonate)s with molecular weights up to 40000 g·mol−1 and molecular weight dispersities Đ < 2 were successfully synthesized. Subsequent application of these polymers in the HWE reaction to prepare a library of aromatic α,β-unsaturated ketones (chalcons) has proven to be an efficient synthetic pathway to minimize purification efforts, as the polymeric side-product can be removed by simple precipitation. In this paper we also demonstrate for the first time the preparation of a linear polyphosphate from a polyalkylphosphonate.

Water-soluble copolymers of ferrocenyl glycidyl ether (fcGE) and glycidol were prepared via anionic ring-opening multibranching polymerization (ROMBP). The resulting hyperbranched materials with molecular weights (Mn) of 3500 to 12300 g mol−1 and relatively narrow molecular weight distributions (Mw/Mn = 1.40–1.69) exhibit both temperature- as well as redox-responsive behavior, which was studied via turbidity measurements. The cloud point temperatures (Tc) were adjusted between 45 and 60 °C through variation of the fcGE comonomer content. Additionally, these Tcs can be increased by the addition of an oxidizing agent. The extent of oxidation of the materials was quantified by Mößbauer spectroscopy and can be correlated to the change in the Tcs. Furthermore, the copolymers were investigated via1H and inverse gated (IG) 13C NMR spectroscopy, size exclusion chromatography (SEC), MALDI-ToF mass spectroscopy and differential scanning calorimetry (DSC). The reversible oxidation of the fc moities is demonstrated by cyclic voltammetry.

The first orthogonal ferrocene monomer, vinyl ferrocenyl glycidyl ether (VfcGE), for both anionic and radical polymerization – without the need of a protection group – is presented. Anionic ring-opening copolymerization of VfcGE and ethylene oxide (EO) generates stimuli-responsive, multifunctional poly[(vinyl ferrocenyl glycidyl ether)-co-(ethylene oxide)] (P[VfcGE-co-EO]) copolymers (molecular weights of ca. 7500 g mol−1 and low molecular weight dispersities (Đ ≤ 1.14)). The amount of the equimolar ferrocenyl and vinyl groups are controlled by the comonomer ratio up to 15.4 mol% VfcGE. The pendant vinyl groups of P[VfcGE-co-EO] were post-modified with 3-mercaptopropionic acid via thiol–ene chemistry. The EO copolymers exhibit temperature-, redox-, and pH-responsive behavior in water depending on the polymers’ microstructure. Free radical polymerization of VfcGE leads to polyalkylene:(vinyl ferrocenyl glycidyl ether) with pendant epoxide side chains at each ferrocene unit. The resulting polymer was used to generate redox-responsive protein nanoparticles with bovine serum albumin (BSA) by nucleophilic ring-opening of the pendant epoxides.

A novel cyclic phosphate monomer, 2-(2-(benzyloxy)ethoxy)-1,3,2-dioxaphospholane-2-oxide (BnEEP), was developed to generate poly(phosphoester)s containing protected pendant hydroxyl groups by anionic ring-opening polymerization. The hydroxyl-groups were released by a mild catalytic hydrogenation leaving the polymer backbone intact. In addition, the number of pendant hydroxyl groups was varied by copolymerization of BnEEP with ethyl ethylene phosphate (EEP). Furthermore, copolymers of BnEEP with an acetal protected cyclic phosphate, 2-(2,2-dimethyl-1,3-dioxolan-4-yl-methoxy)-2-oxo-1,3,2-dioxaphospholane (GEP), were prepared in order to establish a selective deprotection of the acetal or the benzyl protective groups by acidic hydrolysis or catalytic hydrogenation respectively. No degradation of the polyester backbone was detected under the reported conditions. The novel monomer allows adjustment of the chemical and physical properties of the poly(phosphoester)s and gives access to various side chain functionalities.

Poly(alkyl ethylene phosphonate)s with different alkyl side chains exhibit significant differences in their degradation behavior. Three novel 2-alkyl-2-oxo-1,3,2-dioxaphospholanes, cyclic monomers for the ring-opening polymerization (ROP) toward poly(alkyl alkylene phosphonate)s, were synthesized by robust two- or three-step protocols in reasonable yields and high purity. The polymerization was promoted by the organocatalysts 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and proceeded with high control over molecular weight and narrow molecular weight distributions (Đ < 1.2) up to full conversion. These polymers with methyl, ethyl, and isopropyl side chains are perfectly soluble in water (up to 25 mg mL–1) without a temperature-dependent phase separation. They showed no toxicity against HeLa cells after 24 h of incubation at any tested concentration. Polymers with butyl side chains exhibit decreased solubility and concentration-dependent cloud point temperatures and show toxicity against HeLa cells at concentrations above 25 μg mL–1. The polymers showed no acetylcholinesterase inhibition. All polymers exhibited significantly different degradation times under both neutral as well as basic conditions (variation of the alkyl side chain allowed stabilities from 8 h up to 6 days).

Telechelic poly(phosphoester)s have been prepared via acyclic diene metathesis polymerization with varying molecular weights and end group functionalization. Telechelic alcohols, acids, epoxides, thioesters and bromides with tailorable molecular weights between 3000 and ca. 30,000 g/mol have been prepared and characterized in detail. A high end-group functionality (>99 %) was found in all cases.

The energy stored in the triplet states of organic molecules, capable of energy transfer via an emissive process (phosphorescence) or a nonemissive process (triplet–triplet transfer), is actively dissipated in the presence of molecular oxygen. The reason is that photoexcited singlet oxygen is highly reactive, so the photoactive molecules in the system are quickly oxidized. Oxidation leads to further loss of efficiency and various undesirable side effects. In this work we have developed a structurally diverse library of hyperbranched unsaturated poly(phosphoester)s that allow efficient scavenging of singlet oxygen, but do not react with molecular oxygen in the ground state, i.e., triplet state. The triplet–triplet annihilation photon upconversion was chosen as a highly oxygen-sensitive process as proof for a long-term protection against singlet oxygen quenching, with comparable efficiencies of the photon upconversion under ambient conditions as in an oxygen-free environment in several unsaturated polyphosphates. The experimental results are further correlated to NMR spectroscopy and theoretical calculations evidencing the importance of the phosphate center. These results open a technological window toward efficient solar cells but also for sustainable solar upconversion devices, harvesting a broad-band sunlight excitation spectrum.

While it has been shown that phosphates can target molecules and nanocarriers to bone we herein demonstrate the preparation of polyphosphate nanoparticles loaded with paclitaxel using a simple miniemulsion/solvent-evaporation technique as a model for chemotherapeutic delivery. Polyphosphates exhibit much higher structural versatility, relying on the pentavalence of the phosphorus center compared to conventional polyesters. This versatility allows for the development of new degradable polymeric carriers with inherent bone adhesion ability by the interaction of the nanoparticles with a calcium phosphate material used for bone regeneration. The novel polyphosphate nanoparticles were investigated in detail with respect to their size distribution, zeta-potential, thermal and morphological properties and were further proven to be efficiently loaded with a hydrophobic drug (up to 15 wt%). The in vitro cytotoxicity was assessed against human cancer cell lines (HeLa and Saos-2), and the paclitaxel-loaded nanoparticles showed a similar cytotoxicity profile similar to the commercially available formulation Taxomedac® and the pure paclitaxel for loading ratios of 10 wt% but additionally proved efficient adhesion on calcium phosphate granules allowing drug delivery to bone. This first report demonstrates that polyphosphate nanoparticles are promising materials for the development of systemic or local bone cancer treatment, even by direct application or by formation of composites with calcium phosphate cements.

The interface as a “screw clamp”: the copper-free 1,3-dipolar azide–alkyne cycloaddition at the interface of nanodroplets in miniemulsions was studied in detail by NMR spectroscopic methods. The reaction at the oil–water interface proved to exhibit higher rate constants, increased molecular weights and high regioregularity compared to the reaction in solution.

The first synthesis of hollow nanocapsules with an aqueous core via olefin cross metathesis is presented. The reaction was tailored such that it proceeds selectively at the oil–water interface of aqueous nanodroplets in an inverse miniemulsion. The cross metathesis takes place between an acrylated polysaccharide and unsaturated organophosphates under mild conditions. This general protocol allows the synthesis of biocompatible and polyfunctional nanocapsules via the bioorthogonal olefin metathesis, thus generating a highly versatile methodology for the design of future materials for biomedical applications but also for materials science. Functionalization of the nanocapsules was demonstrated with fluorescent labels, which can be attached to the pendant phosphoester either within the cross-linker, exploiting the versatility of the phosphorus chemistry, or via coupling to the capsules’ surface.

A small difference brings high control: In poly(phosphonate)s a stable carbon–phosphorus linkage attaches a side chain to a degradable poly(phosphoester)-backbone. A novel cyclic phosphonate monomer was developed to generate water-soluble aliphatic poly(ethylene methylphospho-nate)s. The monomer is accessible via a robust three-step protocol that can be easily scaled-up. Polymerization was initiated by a primary alcohol, mediated by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in less than 2 h at 0 °C. The molecular weight distributions were monomodal and very narrow (below 1.1) in all cases and molecular weights up to about 20000 g/mol have been prepared, proving the living nature of this polymerization. The resulting polymers were characterized in detail via NMR spectroscopy, size exclusion chromatography, and differential scanning calorimetry. Also, the reaction kinetics have been evaluated for several monomer/initiator ratios and found to guarantee a living behavior in all cases superior to other poly(phosphate)s reported earlier. The polymers are all highly water-soluble without a lower critical solution temperature and are nontoxic against HeLa cells.

The functional group distribution along the polymer backbone resulting from the living anionic copolymerization of styrene (S) and para-but-3-enyl styrene (pBuS) was investigated in cyclohexane at room temperature. A variety of copolymers with different comonomer contents x(S) = 0–0.84 have been synthesized with molecular weight dispersities Mw/Mn ≤1.12. All polymers have been characterized in detail by 1H NMR spectroscopy, size exclusion chromatography (SEC), and differential scanning calorimetry (DSC). A detailed understanding of the monomer sequence distribution during the copolymerization was achieved by real-time 1H NMR spectroscopy. This technique permits us to determine the changing monomer concentration of each monomer in stock throughout the reaction. Consequently, monomer incorporation and thus the probability of incorporation can be determined at any time of the copolymerization, and a precise determination of the functional group density along the polymer chain is possible. To demonstrate accessibility of the olefin side chains of the copolymer for transformations, quantitative thiol–ene addition of a cysteine derivative has been studied.

The abundant biomaterial lignin was used to prepare hollow nanocapsules by interfacial polyaddition in inverse miniemulsions. These cross-linked lignin nanocontainers can be loaded with hydrophilic substances which can be released by an enzymatic trigger from natural plant extracts revealing them as potential nanocontainers for agricultural applications.

Ferrocenyl glycidyl ether (fcGE) and allyl glycidyl ether (AGE) are copolymerized via living anionic ring-opening polymerization to generate polyfunctional copolymers with molecular weights up to 40 300 g/mol and low molecular weight dispersities (Mw/Mn < 1.18). Copolymerizations were carried out in bulk at 100 °C and unexpectedly found to proceed without any isomerization of the allyl double bonds. The copolymerization behavior of fcGE and AGE was monitored by in situ quantitative 13C NMR kinetic measurements in bulk, evidencing the formation of random copolymers under these conditions, showing no gradient of comonomer incorporation. The redox-active behavior of the copolymers and homopolymers of fcGE was studied by cyclic voltammetry (CV). In order to demonstrate possible postmodification reactions, the random copolymers were modified with N-acetyl-l-cysteine methyl ester via a thiol–ene addition. All polymers have furthermore been characterized by 1H NMR spectroscopy, DOSY 1H NMR spectroscopy, size exclusion chromatography (SEC), and MALDI-ToF mass spectrometry.

Reactive poly(phosphoester)s (PPEs) have been prepared via the acyclic diene metathesis polymerization of the monomers di(buten-3-yl) chlorophosphate and di(undecen-10-yl) chlorophosphate. Molecular weights can be adjusted from 3000 to ca. 50 000 g/mol and have been prepared and characterized in detail. This is the first report on olefin metathesis polymerization of highly electrophilic phosphochlorides, which were postmodified with different nucleophiles, i.e., alcohols, amines, and water, thus allowing the synthesis of side chain polyphosphoamidates, poly(phosphoester)s, and free acids from the same starting polymer. High side-chain functionality was found in all cases.

Olefin metathesis step-growth (acyclic diene metathesis (ADMET)) and chain-growth (ring-opening metathesis) polymerization was used to prepare linear poly(phosphonate)s with variable hydrophilicity. The first phosphonate monomer, i.e., di(undec-10-en-1-yl) methylphosphonate, for ADMET polymerization was developed, and potentially degradable and biocompatible, unsaturated poly(phosphonate)s were prepared with molecular weights up to 23 000 g mol–1 with molecular weight dispersities Đ < 2. These polymers were studied with respect to their interaction with a calcium phosphate bone substitute material from an aqueous nanoparticle dispersion that was prepared by a solvent evaporation miniemulsion protocol. Ring-opening metathesis polymerization (ROMP) was employed to synthesize more hydrophilic amorphous polyphosphonates from a novel seven-membered cyclic phosphonate monomer, i.e., 2-methyl-4,7-dihydro-1,3,2-dioxaphosphepine 2-oxide, as well as hydrophobic crystalline copolymers with cis-cyclooctene. ROMP yielded polymers with molecular weights up to 6000 g mol–1 (homopolymer) and 47 000 g mol–1 (copolymers). Poly(phosphonate)s are potentially hydrolytically degradable materials and therefore promising materials for biomedical applications.

Squaric acid diesters can be applied as reagents to couple two amino-functional compounds. Consecutive coupling of two amines allows the synthesis of asymmetric squaric acid bisamides with either low molecular weight compounds but also biomolecules or polymers. The key feature of the squaric acid diester mediated coupling is the reduced reactivity of the resulting ester-amide after the first amidation step of the diester. This allows the sequential amidation and generation of asymmetric squaramides with high selectivity and in high yields. This article gives an overview of the well-established squaric acid diester mediated coupling reactions for glycoconjugates and presents recent advances that aim to expand this very versatile reaction protocol to the modification of peptides and proteins.

It is demonstrated how acyclic diene metathesis polymerization (ADMET) provides an efficient strategy for the labeling of polyolefins. The versatility of phosphorus chemistry allows designing substituted BODIPY monomers or chain stoppers for the synthesis of precise labeled (degradable) polyphosphoesters.

Copolymers with varying compositions of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EEP) and 2-ethoxy-4-methyl-2-oxo-1,3,2-dioxaphospholane (EMEP) have been synthesized via 1,5,7-triazabicyclo[4.4.0]dec-5-ene-catalyzed anionic ring-opening polymerization. The molecular weights and comonomer ratios were well controlled and polymers with reasonable molecular weight distributions (<1.5) were obtained in all cases. The copolymers were investigated by 1H and 31P NMR spectroscopies to determine the underlying microstructure via detailed dyad analysis. The copolymers were found to be nontoxic to HeLa cells. Furthermore, the obtained copolymers of EEP and EMEP show thermoresponsive properties, i.e., exhibit a lower critical solution temperature (LCST).

For the first time, ring-opening metathesis polymerization of novel 7-membered cyclic phosphate monomers and their copolymerization with cyclooctene is presented. The monomers were investigated with respect to their metathesis behavior with different Grubbs catalysts and it was found that the Grubbs third generation catalyst gives the best results resulting in polymers with a molecular weight of up to 5000 g mol−1. Also copolymers with cyclooctene (up to a molecular weight of ca. 50000 g mol−1) were synthesized and the monomer ratios were varied. The degree of polymerization could be controlled and the polydispersity index was usually below two. Acidic hydrolysis of the copolymer showed a complete shift of the molecular weight distribution to higher elution times in SEC, indicating a random incorporation into the poly(cyclooctene) backbone of the phosphate monomers and the possible degradation of the phosphate bonds along the backbone. Further, potentially degradable nanoparticles were prepared by a solvent evaporation miniemulsion technique.

Epoxide termination and functionalization of living poly(ferrocenyldimethylsilane) (PFDMS) is introduced by precapping the living PFDMS with a 4/2 molar mixture of 1,1-diphenylethylene and 1,1-dimethylsilacyclobutane acting as a “carbanion pump” system. Subsequent addition of allyl glycidyl ether (AGE) leads to quantitatively functionalized PFDMS–AGE polymers with molecular weights between 1500 and 15 400 g mol–1 and polydispersity indices ≤1.10, carrying one hydroxyl group and an additional allylic double bond. PFDMS–AGE was then applied as a macroinitiator for the living anionic ring-opening polymerization of ethylene oxide (EO) to generate amphiphilic and water-soluble poly(ferrocenyldimethylsilane-b-ethylene oxide) block copolymers with a low polydispersity index. All polymers have been characterized by 1H NMR spectroscopy, DOSY 1H NMR spectroscopy, size exclusion chromatography (SEC), and MALDI-ToF mass spectrometry. In addition, for the characterization of the morphology of the PFDMS-b-PEO block copolymers transmission electron microscopy (TEM) was performed in methanol, confirming the formation of cylindrical micelles with an organometallic core and polyether corona.

The first ferrocene-containing epoxide monomer, ferrocenyl glycidyl ether (fcGE), is introduced. The monomer has been copolymerized with ethylene oxide (EO). This leads to electroactive, water-soluble, and thermoresponsive poly(ethylene glycol) (PEG) derived copolyethers. Anionic homo- and copolymerization of fcGE with EO was possible. Molecular weights could be varied from 2000 to 10 000 g mol–1, resulting in polymers with narrow molecular weight distribution (Mw/Mn = 1.07–1.20). The ferrocene (fc) content was varied from 3 to 30 mol %, obtaining water-soluble materials up to 10 mol % incorporation of the apolar ferrocenyl comonomer. Despite the steric bulk of fcGE, random copolymers were obtained, as confirmed via detailed 1H NMR kinetic measurements as well as 13C NMR studies of the polymer microstructure, including detailed triad characterization. In addition, the poly(fcGE) homopolymer has been prepared. All water-soluble copolyethers with fc side chains exhibited a lower critical solution temperature (LCST) in the range 7.2–82.2 °C in aqueous solution, depending on the amount of fcGE incorporated. The LCST is further tunable by oxidation/reduction of ferrocene, as demonstrated by cyclic voltammetry. Investigation of the electrochemical properties by cyclovoltammetry revealed that the iron centers can be oxidized reversibly. Further, to evaluate the potential for biomedical application, cell viability tests of the fc-containing PEG copolymers were performed on a human cervical cancer cell line (HeLa), revealing good biocompatibility only in the case of low amounts of fcGE incorporated (below 5%). Significant cytotoxic behavior was observed with fcGE content exceeding 5%. The ferrocene-substituted copolyethers are promising for novel redox sensors and create new options for the field of organometallic (co)polymers in general.

A powerful methodology for the synthesis of unsaturated polyphosphoesters (UPPEs) relying on acyclic diene metathesis (ADMET) polymerization is described. A facile two-step protocol gives fast access to structurally versatile and potentially degradable and biocompatible materials. For the first time this allows to control the microstructure of either backbone and/or side chains of polyphosphoesters. Four different monomers are polymerized under different conditions to yield UPPEs with molecular weights ranging from 7000 up to 50 000 g mol–1 with reasonable polydispersity. The unsaturated and saturated polyphosphoesters are characterized in detail with various techniques. A major benefit of the UPPEs is revealed by differential scanning calorimetry proving the control over thermal properties with tunable melting or glass transition temperatures for the different saturated and unsaturated PPEs which is an important feature for future applications. This unique combination of the benefits of metathesis polymerization and phosphorus chemistry is a highly versatile system for materials in many applications ranging from adhesives to biomaterials.

The interface as a “screw clamp”: the copper-free 1,3-dipolar azide–alkyne cycloaddition at the interface of nanodroplets in miniemulsions was studied in detail by NMR spectroscopic methods. The reaction at the oil–water interface proved to exhibit higher rate constants, increased molecular weights and high regioregularity compared to the reaction in solution.

While it has been shown that phosphates can target molecules and nanocarriers to bone we herein demonstrate the preparation of polyphosphate nanoparticles loaded with paclitaxel using a simple miniemulsion/solvent-evaporation technique as a model for chemotherapeutic delivery. Polyphosphates exhibit much higher structural versatility, relying on the pentavalence of the phosphorus center compared to conventional polyesters. This versatility allows for the development of new degradable polymeric carriers with inherent bone adhesion ability by the interaction of the nanoparticles with a calcium phosphate material used for bone regeneration. The novel polyphosphate nanoparticles were investigated in detail with respect to their size distribution, zeta-potential, thermal and morphological properties and were further proven to be efficiently loaded with a hydrophobic drug (up to 15 wt%). The in vitro cytotoxicity was assessed against human cancer cell lines (HeLa and Saos-2), and the paclitaxel-loaded nanoparticles showed a similar cytotoxicity profile similar to the commercially available formulation Taxomedac® and the pure paclitaxel for loading ratios of 10 wt% but additionally proved efficient adhesion on calcium phosphate granules allowing drug delivery to bone. This first report demonstrates that polyphosphate nanoparticles are promising materials for the development of systemic or local bone cancer treatment, even by direct application or by formation of composites with calcium phosphate cements.

Squaric acid diesters can be applied as reagents to couple two amino-functional compounds. Consecutive coupling of two amines allows the synthesis of asymmetric squaric acid bisamides with either low molecular weight compounds but also biomolecules or polymers. The key feature of the squaric acid diester mediated coupling is the reduced reactivity of the resulting ester-amide after the first amidation step of the diester. This allows the sequential amidation and generation of asymmetric squaramides with high selectivity and in high yields. This article gives an overview of the well-established squaric acid diester mediated coupling reactions for glycoconjugates and presents recent advances that aim to expand this very versatile reaction protocol to the modification of peptides and proteins.

The specific targeting of either tumor cells or immune cells in vivo by carefully designed and appropriately surface-functionalized nanocarriers may become an effective therapeutic treatment for a variety of diseases. Carbohydrates, which are prominent biomolecules, have shown their outstanding ability in balancing the biocompatibility, stability, biodegradability, and functionality of nanocarriers. The recent applications of sugar (mono/oligosaccharides and/or polysaccharides) for the development of nanomedicines are summarized in this review, including the application of carbohydrates for the surface-functionalization of various nanocarriers and for the construction of the nanocarrier itself. Current problems and challenges are also addressed.

The ring-opening polymerization of N-tosyl aziridines, in the presence of 1,3-bis(isopropyl)-4,5(dimethyl)imidazol-2-ylidene as an organocatalyst and an N-tosyl secondary amine as initiator mimicking the growing chain, provides the first metal-free route to well defined poly(aziridine)s (PAz) and related PAz-based block copolymers.