Inorganic Bottlebrush and Comb Polymers as a Platform for Supersoft, Solvent-Free Elastomers.

Due to their unique rheological and mechanical properties, bottlebrush polymers are inimitable components of biological and synthetic systems such as cartilage and ultrasoft elastomers. However, while their rheological properties can be precisely controlled through their macromolecular structures, the current chemical spectrum available is limited to a handful of synthetic polymers with aliphatic carbon backbones. Herein we design and synthesize a series of inorganic bottlebrush polymers based on a unique combination of polydimethylsiloxane (PDMS) and polyphosphazene (PPz) chemistry. This non-carbon-based platform allows for simple variation of the significant architectural dimensions of bottlebrush-polymer-based elastomers. Grafting PDMS to PPz and vice versa also allows us to further exploit the unique properties of these polymers combined in a single material. These novel hybrid bottlebrush polymers were cured to give supersoft, solvent-free elastomers. We systematically studied the effect of architectural parameters and chemical functionality on their rheological properties. Besides forming supersoft elastomers, the energy dissipation characteristics of the elastomers were observed to be considerably higher than those for PDMS-based elastomers. Hence this work introduces a robust synthetic platform for solvent-free supersoft elastomers with potential applications as biomimetic damping materials.

Superfluorinated, Highly Water-Soluble Polyphosphazenes as Potential 19F Magnetic Resonance Imaging (MRI) Contrast Agents.

"Hot spot" 19F magnetic resonance imaging (MRI) has garnered significant attention recently for its ability to image various disease markers quantitatively. Unlike conventional gadolinium-based MRI contrast agents, which rely on proton signal modulation, 19F-MRI's direct detection has a unique advantage in vivo, as the human body exhibits a negligible background 19F-signal. However, existing perfluorocarbon (PFC) or PFC-based contrast materials suffer from several limitations, including low longitudinal relaxation rates and relatively low imaging efficiency. Hence, we designed a macromolecular contrast agent featuring a high number of magnetically equivalent 19F-nuclei in a single macromolecule, adequate fluorine nucleus mobility, and excellent water solubility. This design utilizes superfluorinated polyphosphazene (PPz) polymers as the 19F-source; these are modified with sodium mercaptoethanesulfonate (MESNa) to achieve water solubility exceeding 360 mg/mL, which is a similar solubility to that of sodium chloride. We observed substantial signal enhancement in MRI with these novel macromolecular carriers compared to non-enhanced surroundings and aqueous trifluoroacetic acid (TFA) used as a positive control. In conclusion, these novel water-soluble macromolecular carriers represent a promising platform for future MRI contrast agents.

Phosphorus and Silicon-Based Macromolecules as Degradable Biomedical Polymers.

Synthetic polymers are indispensable in biomedical applications because they can be fabricated with consistent and reproducible properties, facile scalability, and customizable functionality to perform diverse tasks. However, currently available synthetic polymers have limitations, most notably when timely biodegradation is required. Despite there being, in principle, an entire periodic table to choose from, with the obvious exception of silicones, nearly all known synthetic polymers are combinations of carbon, nitrogen, and oxygen in the main chain. Expanding this to main-group heteroatoms can open the way to novel material properties. Herein the authors report on research to incorporate the chemically versatile and abundant silicon and phosphorus into polymers to induce cleavability into the polymer main chain. Less stable polymers, which degrade in a timely manner in mild biological environments, have considerable potential in biomedical applications. Herein the basic chemistry behind these materials is described and some recent studies into their medical applications are highlighted.

Amino Acid-Based Polyphosphorodiamidates with Hydrolytically Labile Bonds for Degradation-Tuned Photopolymers.

Photochemical additive manufacturing technologies can produce complex geometries in short production times and thus have considerable potential as a tool to fabricate medical devices such as individualized patient-specific implants, prosthetics and tissue engineering scaffolds. However, most photopolymer resins degrade only slowly under the mild conditions required for many biomedical applications. Herein we report a novel platform consisting of amino acid-based polyphosphorodiamidate (APdA) monomers with hydrolytically cleavable bonds. The substituent on the α-amino acid can be used as a handle for facile control of hydrolysis rates of the monomers into their endogenous components, namely phosphate and the corresponding amino acid. Furthermore, monomer hydrolysis is considerably accelerated at lower pH values. The monomers underwent thiol-yne photopolymerization and could be 3D structured via multiphoton lithography. Copolymerization with commonly used hydrophobic thiols demonstrates not only their ability to regulate the ambient degradation rate of thiol-yne polyester photopolymer resins, but also desirable surface erosion behavior. Such degradation profiles, in the appropriate time frames, in suitably mild conditions, combined with their low cytotoxicity and 3D printability, render these novel photomonomers of significant interest for a wide range of biomaterial applications.

Degradable Bottlebrush Polypeptides and the Impact of their Architecture on Cell Uptake, Pharmacokinetics, and Biodistribution In Vivo.

Bottlebrush polymers are highly promising as unimolecular nanomedicines due to their unique control over the critical parameters of size, shape and chemical function. However, since they are prepared from biopersistent carbon backbones, most known bottlebrush polymers are non-degradable and thus unsuitable for systemic therapeutic administration. Herein, we report the design and synthesis of novel poly(organo)phosphazene-g-poly(α-glutamate) (PPz-g-PGA) bottlebrush polymers with exceptional control over their structure and molecular dimensions (Dh ≈ 15-50 nm). These single macromolecules show outstanding aqueous solubility, ultra-high multivalency and biodegradability, making them ideal as nanomedicines. While well-established in polymer therapeutics, it has hitherto not been possible to prepare defined single macromolecules of PGA in these nanosized dimensions. A direct correlation was observed between the macromolecular dimensions of the bottlebrush polymers and their intracellular uptake in CT26 colon cancer cells. Furthermore, the bottlebrush macromolecular structure visibly enhanced the pharmacokinetics by reducing renal clearance and extending plasma half-lives. Real-time analysis of the biodistribution dynamics showed architecture-driven organ distribution and enhanced tumor accumulation. This work, therefore, introduces a robust, controlled synthesis route to bottlebrush polypeptides, overcoming limitations of current polymer-based nanomedicines and, in doing so, offers valuable insights into the influence of architecture on the in vivo performance of nanomedicines.

Hetero and homo α,ω-chain-end functionalized polyphosphazenes.

The control of chain-ends is fundamental in modern macromolecular chemistry for directed one-to-one bioconjugation and the synthesis of advanced architectures such as block copolymers or bottlebrush polymers and the preparation of advanced soft materials. Polyphosphazenes are of growing importance as elastomers, biodegradable materials and in biomedical drug delivery due to their synthetic versatility. While controlled polymerization methods have been known for some time, controlling both chain-ends with high fidelity has proven difficult. We demonstrate a robust synthetic route to hetero and homo α,ω-chain-end functionalized polyphosphazenes via end-capping with easily accessible, functionalized triphenylphosphine-based phosphoranimines. A versatile thiol-ene "click"-reaction approach then allows for subsequent conversion of the end-capped polymers with various functional groups. Finally, we demonstrate the utility of this system to prepare gels based on homo α,ω-chain-end functionalized polyphosphazenes. This development will enhance their progress in various applications, particularly in soft materials and as degradable polymers.

Hollow Silica Microparticles Based on Amphiphilic Polyphosphazenes.

Hollow microparticles are important materials, offering a larger surface area and lower density than their solid counterparts. Furthermore, their inner void space can be exploited for the encapsulation and release of guest species in a variety of applications. Herein, we present phosphazene-based silica hollow microparticles prepared via a surfactant-free sol-gel process through self-assembly of the alkoxysilyl-containing polymer in water-ethanol solution. Solely, a silane-derived polyphosphazene was used as the precursor for the microparticle formation, without additional classical silica sources. These novel hollow silica-based microparticles were prepared without surfactant, using a designed amphiphilic polyphosphazene for the particle formation made by two components, a hydrophilic unit consisting of 3-mercaptopropyl(trimethoxysilane), and a hydrophobic unit (dodecanethiol) attached to the double bonds from the poly(allylamine)phosphazene backbone via a thiol-ene photoreaction. Due to these two functionalities, a "vesicle"-like self-assembled structure was formed in the reaction medium, which could be then utilized for the microparticle preparation. The influence of NaOH during the synthesis was shown to affect the size and the wall thickness of the microparticles. This effect may enhance the possibilities to tailor such microparticles for drug delivery purposes or for future controlled release of other substances, such as drugs, fragrances, or anticorrosive pigments.

Reversible Speed Regulation of Self-Propelled Janus Micromotors via Thermoresponsive Bottle-Brush Polymers.

Invited for the cover of this issue is the group of Ian Teasdale and Yolanda Salinas at the Johannes Kepler University Linz. The image depicts the self-propelled Janus micromotors reported in this work. Read the full text of the article at 10.1002/chem.202004792.

Reversible Speed Regulation of Self-Propelled Janus Micromotors via Thermoresponsive Bottle-Brush Polymers.

This work reports a reversible braking system for micromotors that can be controlled by small temperature changes (≈5 °C). To achieve this, gated-mesoporous organosilica microparticles are internally loaded with metal catalysts (to form the motor) and the exterior (partially) grafted with thermosensitive bottle-brush polyphosphazenes to form Janus particles. When placed in an aqueous solution of H2 O2 (the fuel), rapid forward propulsion of the motors ensues due to decomposition of the fuel. Conformational changes of the polymers at defined temperatures regulate the bubble formation rate and thus act as brakes with considerable deceleration/acceleration observed. As the components can be easily varied, this represents a versatile, modular platform for the exogenous velocity control of micromotors.

Hybrid Porous Microparticles Based on a Single Organosilica Cyclophosphazene Precursor.

Porous organosilica microparticles consisting of silane-derived cyclophosphazene bridges were synthesized by a surfactant-mediated sol-gel process. Starting from the substitution of hexachlorocyclotriphosphazene with allylamine, two different precursors were obtained by anchoring three or six alkoxysilane units, via a thiol-ene photoaddition reaction. In both cases, spherical, microparticles (size average of ca. 1000 nm) with large pores were obtained, confirmed by both, scanning and transmission electron microscopy. Particles synthesized using the partially functionalized precursor containing free vinyl groups were further functionalized with a thiol-containing molecule. While most other reported mesoporous organosilica particles are essentially hybrids with tetraethyl orthosilicate (TEOS), a unique feature of these particles is that structural control is achieved by exclusively using organosilane precursors. This allows an increase in the proportion of the co-components and could springboard these novel phosphorus-containing organosilica microparticles for different areas of technology.

Visible Light Photocleavable Ruthenium-Based Molecular Gates to Reversibly Control Release from Mesoporous Silica Nanoparticles.

Herein we present hybrid mesoporous silica nanomaterials (MSN) with visible light-sensitive ruthenium complexes acting as gates. Two different [Ru(bpy)2L1L2]2+ complexes were investigated by grafting [Ru(bpy)2(4AMP)2](PF6)2 (RC1) and [Ru(bpy)2(PPh3)Cl]Cl (RC2) via two or one ligands onto the surface of mesoporous silica nanoparticles (MSNs), to give MSN1-RC1 and MSN2-RC2, respectively. The pores were previously loaded with a common dye, safranin O, and release studies were conducted. The number and position of the ligands were shown to influence the photocages behavior and thus the release of the cargo. Release studies from MSN1-RC1 in acetonitrile showed that in the dark the amount of dye released was minimal after 300 min, whereas a significant increase was measured upon visible light irradiation (ca. 90%). While successful as a photochemically-controlled gated system, RC1 was restricted to organic solvents since it required cleavage of two ligands in order to be cleaved from the surface, and in water only one is cleaved. Release studies from the second nanomaterial MSN2-RC2, where the complex RC2 was bound to the MSN via only one ligand, showed stability under darkness and in aqueous solution up to 180 min and, rapid release of the dye when irradiated with visible light. Furthermore, this system was demonstrated to be reversible, since, upon heating to 80 °C, the system could effectively re-close the pores and re-open it again upon visible light irradiation. This work, thus, demonstrates the potential reversible gate mechanism of the ruthenium-gated nanomaterials upon visible light irradiation, and could be envisioned as a future design of photochemically-driven drug delivery nanosystems or on/off switches for nanorelease systems.

Main-Chain Phosphorus-Containing Polymers for Therapeutic Applications.

Polymers in which phosphorus is an integral part of the main chain, including polyphosphazenes and polyphosphoesters, have been widely investigated in recent years for their potential in a number of therapeutic applications. Phosphorus, as the central feature of these polymers, endears the chemical functionalization, and in some cases (bio)degradability, to facilitate their use in such therapeutic formulations. Recent advances in the synthetic polymer chemistry have allowed for controlled synthesis methods in order to prepare the complex macromolecular structures required, alongside the control and reproducibility desired for such medical applications. While the main polymer families described herein, polyphosphazenes and polyphosphoesters and their analogues, as well as phosphorus-based dendrimers, have hitherto predominantly been investigated in isolation from one another, this review aims to highlight and bring together some of this research. In doing so, the focus is placed on the essential, and often mutual, design features and structure-property relationships that allow the preparation of such functional materials. The first part of the review details the relevant features of phosphorus-containing polymers in respect to their use in therapeutic applications, while the second part highlights some recent and innovative applications, offering insights into the most state-of-the-art research on phosphorus-based polymers in a therapeutic context.

Dual stimuli-responsive polyphosphazene-based molecular gates for controlled drug delivery in lung cancer cells.

A switchable silane derived stimuli-responsive bottle-brush polyphosphazene (PPz) was prepared and attached to the surface of mesoporous silica nanoparticles (MSNs). The hybrid polymer with PEG-like Jeffamine® M-2005 side-arms undergo conformational changes in response to both pH and temperature due to its amphiphilic substituents and protonatable main-chain, hence were investigated as a gatekeeper. Safranin O as control fluorophore or the anticancer drug camptothecin (CPT) were encapsulated in the PPz-coated MSNs. At temperatures below the lower critical solution temperature (LCST), the swollen conformation of PPz efficiently blocked the cargo within the pores. However, above the LCST, the PPz collapsed, allowing release of the payload. Additionally, protonation of the polymer backbone at lower pH values was observed to enhance opening of the pores from the surface of the MSNs and therefore the release of the dye. In vitro studies demonstrated the ability of these nanoparticles loaded with the drug camptothecin to be endocytosed in both models of tumor (A549) and healthy epithelial (BEAS-2B) lung cells. Their accumulation and the release of the chemotherapeutic drug, co-localized within lysosomes, was faster and higher for tumor than for healthy cells, further, the biocompatibility of PPz-gated nanosystem without drug was demonstrated. Tailored dual responsive polyphosphazenes thus represent novel and promising candidates in the construction of future gated mesoporous silica nanocarriers designs for lung cancer-directed treatment.

Mesoporous Silica Micromotors with a Reversible Temperature Regulated On-Off Polyphosphazene Switch.

The incorporation of an extraneous on-off braking system is necessary for the effective motion control of the next generation of micrometer-sized motors. Here, the design and synthesis of micromotors is reported based on mesoporous silica particles containing bipyridine groups, introduced by cocondensation, for entrapping catalytic cobalt(II) ions within the mesochannels, and functionalized on the surface with silane-derived temperature responsive bottle-brush polyphosphazene. Switching the polymers in a narrow temperature window of 25-30 °C between the swollen and collapsed state, allows the access for the fuel H2 O2 contained in the dispersion medium to cobalt(II) bipyridinato catalyst sites. The decomposition of hydrogen peroxide is monitored by optical microscopy, and effectively operated by reversibly closing or opening the pores by the grafted gate-like polyphosphazene, to control on demand the oxygen bubble generation. This design represents one of the few examples using temperature as a trigger for the reversible on-off external switching of mesoporous silica micromotors.

Activatable Hybrid Polyphosphazene-AuNP Nanoprobe for ROS Detection by Bimodal PA/CT Imaging.

Overproduction of reactive oxygen species (ROS) is often related to inflammation or cancer and can cause tissue damage. Probes that have been previously reported to image ROS typically rely on imaging techniques that have low depth penetration in tissue, thus limiting their use to superficial disease sites. We report herein a novel formulation of hybrid nanogels loaded with gold nanoparticles (AuNP) to produce contrast for computed tomography (CT) and photoacoustics (PA), both being deep-tissue imaging techniques. The polyphosphazene polymer has been designed to selectively degrade upon ROS exposure, which triggers a switch-off of the PA signal by AuNP disassembly. This ROS-triggered degradation of the nanoprobes leads to a significant decrease in the PA contrast, thus allowing ratiometric ROS imaging by comparing the PA to CT signal. Furthermore, ROS imaging using these nanoprobes was applied to an in vitro model of inflammation, that is, LPS-stimulated macrophages, where ROS-triggered disassembly of the nanoprobe was confirmed via reduction of the PA signal. In summary, these hybrid nanoprobes are a novel responsive imaging agent that have the potential to image ROS overproduction by comparing PA to CT contrast.

Dynamic Supramolecular Ruthenium-Based Gels Responsive to Visible/NIR Light and Heat.

A simple supramolecular crosslinked gel is reported with a photosensitive ruthenium bipyridine complex functioning as a crosslinker and poly(4-vinylpyridine) (P4VP) as a macromolecular ligand. Irradiation of the organogels in H2 O/MeOH with visible and NIR light (in a multiphoton process) leads to cleavage of pyridine moieties from the ruthenium complex breaking the cross-links and causing degelation and hence solubilization of the P4VP chains. Real-time (RT) photorheology experiments of thin films showed a rapid degelation in several seconds, whereas larger bulk samples could also be photocleaved. Furthermore, the gels could be reformed or healed by simple heating of the system and restoration of the metal-ligand crosslinks. The relatively simple dynamic system with a high sensitivity towards light in the visible and NIR region make them interesting positive photoresists for nano/micropatterning applications, as was demonstrated by writing, erasing, and rewriting of the gels by single- and multiphoton lithography.

Stimuli-Responsive Phosphorus-Based Polymers.

This microreview details recent developments in stimuli-responsive polymers with phosphorus in the main-chain, in particular polyphosphazenes and polyphosphoesters. The presence of phosphorus in the polymers endows unique properties onto the macromolecules, which can be utilized for the preparation of materials capable of physically responding to specific stimuli. Achieving the desired responsiveness has been much facilitated by recent developments in synthetic polymer chemistry, in particular controlled synthesis and backbone functionalization phosphorus-based polymers, in order to achieve the required properties and hence responsiveness of the materials. The development of phosphorus-based polymers which respond to the most important stimuli are discussed, namely, pH, oxidation, reduction, temperature and biological triggers. The polymers are placed in the context not just of each other but also with reference to state-of-the-art organic polymers.

Coumarin-Caged Polyphosphazenes with a Visible-Light Driven On-Demand Degradation.

Polymers that, upon photochemical activation with visible light, undergo rapid degradation to small molecules are described. Through functionalization of a polyphosphazene backbone with pendant coumarin groups sensitive to light, polymers which are stable in the dark could be prepared. Upon irradiation, cleavage of the coumarin moieties exposes carboxylic acid moieties along the polymer backbone. The subsequent macromolecular photoacid is found to catalyze the rapid hydrolytic degradation of the polyphosphazene backbone. Water-soluble and non-water-soluble polymers are reported, which due to their sensitivity toward light in the visible region could be significant as photocleavable materials in biological applications.

Palladium complexes containing imino phenoxide ligands: synthesis, luminescence, and their use as catalysts for the ring-opening polymerization of rac-lactide.

ABSTRACT: The preparation, structural characterization, luminescence, and catalytic activity of three palladium(II) complexes bearing imino phenoxide ligands are reported. The X-ray studies revealed that the complexes are mononuclear with palladium centres coordinated in a square-planar coordination environment. Two of the complexes are emissive in solution at room temperature. The catalytic activities towards the ring-opening polymerization of rac-lactide (rac-LA) were tested. Polymers with moderate molecular weights and relatively broad dispersity (Ð) were obtained. Kinetic studies revealed that the polymerization followed first-order kinetics.

Degradable, Dendritic Polyols on a Branched Polyphosphazene Backbone.

Herein, we present the design, synthesis, and characterization of fully degradable, hybrid, star-branched dendritic polyols. First multiarmed polyphosphazenes were prepared as a star-branched scaffold which upon functionalization produced globular branched hydroxyl-functionalized polymers with over 1700 peripheral functional end groups. These polyols with unique branched architectures could be prepared with controlled molecular weights and relatively narrow dispersities. Furthermore, the polymers are shown to undergo hydrolytic degradation to low molecular weight degradation products, the rate of which could be controlled through postpolymerization functionalization of the phosphazene backbone.