Ian Teasdale

Porous polymer monoliths for small molecule separations: advancements and limitations

Porous polymer monoliths are considered to be one of the major breakthroughs in separation science. These materials are well known to be best suited for the separation of large molecules, specifically proteins, an observation most often explained by convective mass transfer and the absence of small pores in the polymer scaffold. However, this conception is not sufficient to explain the performance of small molecules. This review focuses in particular on the preparation of (macro)porous polymer monoliths by simple free-radical processes and the key events in their formation. There is special focus on the fluid transport properties in the heterogeneous macropore space (flow dispersion) and on the transport of small molecules in the swollen, and sometimes permanently porous, globule-scale polymer matrix. For small molecule applications in liquid chromatography, it is consistently found in the literature that the major limit for the application of macroporous polymer monoliths lies not in the optimization of surface area and/or modification of the material and microscopic morphological properties only, but in the improvement of mass transfer properties. In this review we discuss the effect of resistance to mass transfer arising from the nanoscale gel porosity. Gel porosity induces stagnant mass transfer zones in chromatographic processes, which hamper mass transfer efficiency and have a detrimental effect on macroscopic chromatographic dispersion under equilibrium (isocratic) elution conditions. The inherent inhomogeneity of polymer networks derived from free-radical cross-linking polymerization, and hence the absence of a rigid (meso)porous pore space, represents a major challenge for the preparation of efficient polymeric materials for the separation of small molecules.

Polyphosphazenes: Multifunctional, Biodegradable Vehicles for Drug and Gene Delivery

Poly[(organo)phosphazenes] are a unique class of extremely versatile polymers with a range of applications including tissue engineering and drug delivery, as hydrogels, shape memory polymers and as stimuli responsive materials. This review aims to divulge the basic principles of designing polyphosphazenes for drug and gene delivery and portray the huge potential of these extremely versatile materials for such applications. Polyphosphazenes offer a number of distinct advantages as carriers for bioconjugates; alongside their completely degradable backbone, to non-toxic degradation products, they possess an inherently and uniquely high functionality and, thanks to recent advances in their polymer chemistry, can be prepared with controlled molecular weights and narrow polydispersities, as well as self-assembled supra-molecular structures. Importantly, the rate of degradation/hydrolysis of the polymers can be carefully tuned to suit the desired application. In this review we detail the recent developments in the chemistry of polyphosphazenes, relevant to drug and gene delivery and describe recent investigations into their application in this field.

Water-Soluble, Biocompatible Polyphosphazenes with Controllable and pH-Promoted Degradation Behavior

The synthesis of a series of novel, water-soluble poly(organophosphazenes) prepared via living cationic polymerization is presented. The degradation profiles of the polyphosphazenes prepared are analyzed by GPC, 31P NMR spectroscopy, and UV–Vis spectroscopy in aqueous media and show tunable degradation rates ranging from days to months, adjusted by subtle changes to the chemical structure of the polyphosphazene. Furthermore, it is observed that these polymers demonstrate a pH-promoted hydrolytic degradation behavior, with a remarkably faster rate of degradation at lower pH values. These degradable, water soluble polymers with controlled molecular weights and structures could be of significant interest for use in aqueous biomedical applications, such as polymer therapeutics, in which biological clearance is a requirement and in this context cell viability tests are described which show the non-toxic nature of the polymers as well as their degradation intermediates and products.

Multifunctional and biodegradable polyphosphazenes for use as macromolecular anti-cancer drug carriers

Using a living cationic polymerisation procedure we synthesised a series of multi-armed poly(organo)phosphazenes with controlled molecular weights and excellent aqueous solubility. The synthetic flexibility of polyphosphazenes was exploited in order to incorporate an acid-sensitive hydrazide linker to the polymer backbone, as well as tumour-targeting folic acid groups. We were then able to attach hydrophobic anti-cancer drug molecules via the pH labile linker and studied its pH-triggered release kinetics from the polymeric carrier. Although stable for short periods (several days) in an aqueous environment, the polymers were shown to degrade over longer periods (weeks) under simulated physiological conditions. Furthermore, the rate of degradation could be tailored through careful selection of substituents. These biodegradable, multi-functional polyphosphazenes represent promising candidates for use as macromolecular carriers for the tumour-targeted delivery of anti-cancer drugs.

Chain-end-functionalized polyphosphazenes via a one-pot phosphine-mediated living polymerization.

A simple polymerization of trichlorophosphoranimine (Cl3P = N−SiMe3) mediated by functionalized triphenylphosphines is presented. In situ initiator formation and the subsequent polymerization progress are investigated by 31P NMR spectroscopy, demonstrating a living cationic polymerization mechanism. The polymer chain lengths and molecular weights of the resulting substituted poly(organo)phosphazenes are further studied by 1H NMR spectroscopy and size exclusion chromatography. This strategy facilitates the preparation of polyphosphazenes with controlled molecular weights and specific functional groups at the α-chain end. Such well-defined, mono-end-functionalized polymers have great potential use in bioconjugation, surface modification, and as building blocks for complex macromolecular constructs.

Degradable Glycine-Based Photo-Polymerizable Polyphosphazenes for Use as Scaffolds for Tissue Regeneration

Photo-polymerizable scaffolds are designed and prepared via short chain poly(organo)phosphazene building blocks bearing glycine allylester moieties. The polyphosphazene was combined with a trifunctional thiol and divinylester in various ratios, followed by thiol-ene photo-polymerization to obtain porous matrices. Degradation studies under aqueous conditions showed increasing rates in correlation with the polyphosphazene content. Preliminary cell studies show the non-cytotoxic nature of the polymers and their degradation products, as well as the cell adhesion and proliferation of adipose-derived stem cells.

Branched Polyphosphazenes with Controlled Dimensions

Using living cationic polymerization, a series of polyphosphazenes is prepared with precisely controlled molecular weights and narrow polydispersities. As well as varying chain length through the use of a living polymerization, amine-capped polyalkylene oxide (Jeffamine) side chains with varied lengths are grafted to the polymer backbone to give a series of polymers with varied dimensions. Dynamic light scattering and size exclusion chromatography are used to confirm the preparation of polymers with a variety of controlled dimensions and thus hydrodynamic volumes. Furthermore, it is demonstrated how the number of arms per repeat unit, and thus the density of branching, can also be further increased from two to four through using a one-pot thiolactone conversion of the Jeffamines, followed by thiol-yne addition to the polyphosphazene backbone. These densely branched, molecular brush-type polymers on a biodegradable polyphosphazene backbone all show excellent aqueous solubility and have potential in drug-delivery applications.

Metallo‐Supramolecular Gels that are Photocleavable with Visible and Near‐Infrared Irradiation

Abstract A photolabile ruthenium‐based complex, [Ru(bpy)2(4AMP)2](PF6)2, (4AMP=4‐(aminomethyl)pyridine) is incorporated into polyurea organo‐ and hydrogels via the reactive amine moieties on the photocleavable 4AMP ligands. While showing long‐term stability in the dark, cleavage of the pyridine–ruthenium bond upon irradiation with visible or near‐infrared irradiation (in a two‐photon process) leads to rapid de‐gelation of the supramolecular gels, thus enabling spatiotemporal micropatterning by photomasking or pulsed NIR‐laser irradiation

Photoreactive, water-soluble conjugates of hypericin with polyphosphazenes

The naturally occurring drug hypericin has invoked much interest in a wide variety of biomedical applications as an antiviral, antibacterial, or antitumor agent, as well as its use as a photosensitizer for photodynamic therapy. However, hypericin suffers from notoriously poor solubility, in particular in aqueous solution, a requirement for many biomedical applications. Using state-of-the-art living polymerization techniques, conjugates of hypericin with biodegradable polyphosphazenes were prepared which show significantly enhanced solubility in ethanol and water compared with the parent compound. Herein, we report the synthesis and structural characterization of these novel polymer–drug conjugates as well as initial testing of their photoreactivity.Graphical Abstract

Stimuli-Responsive Capsules Prepared from Regenerated Silk Fibroin Microspheres

Microcapsules are synthesized via the self-assembly of silk-fibroin microspheres with polycaprolactone in a colliodosome preparation procedure. The microsphere building blocks with controlled diameter are prepared from the naturally occurring biopolymer, silk fibroin, and then act as stabilizers for oil-in-water (O/W) emulsion and organized themselves on the surface of chloroform droplets to form the capsules. The concentration of the protein-based microspheres and the binding polycacrolactone is used to tailor the size, as well as the permeability of the resultant capsules. Furthermore, microencapsulation of fluorescently labeled macromolecules (20-2000 KDa) is demonstrated. The permeability of the capsules is observed to be stimuli responsive, making it possible to incorporate a pH-triggered payload release from the capsules. The relatively simple preparation of capsules with controlled dimensions and tunable permeability, alongside the biocompatibility and biodegradability of both polymer components makes these promising materials for potential use in smart drug-delivery systems.