Vandetanib-eluting radiopaque beads for chemoembolization: physicochemical evaluation and biological activity of vandetanib in hypoxia.

Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents.

Predicting pharmacokinetic behaviour of drug release from drug-eluting embolization beads using in vitro elution methods.

Drug-eluting Embolic Bead - Transarterial Chemoembolisation (DEB-TACE) is a minimally invasive embolising treatment for liver tumours that allows local release of chemotherapeutic drugs via ion exchange, following delivery into hepatic arterial vasculature. Thus far, no single in vitro model has been able to accurately predict the complete kinetics of drug release from DEB, due to heterogeneity of rate-controlling mechanisms throughout the process of DEB delivery. In this study, we describe two in vitro models capable of distinguishing between early phase and late phase drug release by mimicking in vivo features of each phase. First, a vascular flow system (VFS) was used to simulate the early phase by delivering DEB into a silicon vascular cast under high pulsatile flow. This yielded a burst release profile of drugs from DEB which related to the dose adjusted Cmax observed in pharmacokinetic plasma profiles from a preclinical swine model. Second, an open loop flow-through cell system was used to model late phase drug release by packing beads in a column with an ultra-low flow rate. DEB loaded with doxorubicin, irinotecan and vandetanib showed differential drug release rates due to their varying chemical properties and unique drug-bead interactions. Using more representative in vitro models to map discrete phases of DEB drug release will provide a better capability to predict the pharmacokinetics of developmental formulations, which has implications for treatment safety and efficacy.

Possible mineral contributions to the diet and health of wild chimpanzees in three East African forests.

We present new data on the ingestion of minerals from termite mound soil by East African chimpanzees (Pan troglodytes schweinfurthii) living in the Budongo Forest Reserve, Uganda, the Gombe National Park and the Mahale Mountains National Park, Tanzania. Termite mound soil is here shown to be a rich source of minerals, containing high concentrations of iron and aluminum. Termite mound soil is not, however, a source of sodium. The concentrations of iron and aluminum are the highest yet found in any of the mineral sources consumed. Levels of manganese and copper, though not so high as for iron and aluminum, are also higher than in other dietary sources. We focus on the contribution of termite mound soil to other known sources of mineral elements consumed by these apes, and compare the mineral content of termite soil with that of control forest soil, decaying wood, clay, and the normal plant-based chimpanzee diet at Budongo. Samples obtained from Mahale Mountains National Park and Gombe National Park, both in Tanzania, show similar mineral distribution across sources. We suggest three distinct but related mechanisms by which minerals may come to be concentrated in the above-mentioned sources, serving as potentially important sources of essential minerals in the chimpanzee diet.

Hypoxia as a target for drug combination therapy of liver cancer.

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression of hypoxia-induced HIF-1α in response to these treatments. A pilot study was carried out to evaluate the antitumour effects of these drug combinations delivered from drug-eluting beads in vivo using an ectopic xenograft murine model of HCC. A therapeutic doxorubicin concentration that inhibits the viability of normoxic and hypoxic HepG2 cells and above which hypoxic cells are chemoresistant was identified, together with the lowest effective dose of rapamycin against normoxic and hypoxic HepG2 cells. It was shown that combinations of rapamycin and doxorubicin are more effective than doxorubicin alone. Western Blotting indicated that both doxorubicin and rapamycin inhibit hypoxia-induced accumulation of HIF-1α. Combination treatments were more effective in vivo than either treatment alone. mTOR inhibition can improve outcomes of doxorubicin treatment in HCC.

Towards Hypoxia-responsive Drug-eluting Embolization Beads.

Drug release from chemoembolization microspheres stimulated by the presence of a chemically reducing environment may provide benefits for targeting drug resistant and metastatic hypoxic tumours. A water-soluble disulfide-based bifunctional cross-linker bis(acryloyl)-(l)-cystine (BALC) was synthesised, characterised and incorporated into a modified poly(vinyl) alcohol (PVA) hydrogel beads at varying concentrations using reverse suspension polymerisation. The beads were characterised to confirm the amount of cross-linker within each formulation and its effects on the bead properties. Elemental and UV/visible spectroscopic analysis confirmed the incorporation of BALC within the beads and sizing studies showed that in the presence of a reducing agent, all bead formulations increased in mean diameter. The BALC beads could be loaded with doxorubicin hydrochloride and amounts in excess of 300mg of drug per mL of hydrated beads could be achieved but required conversion of the carboxylic acid groups of the BALC to their sodium carboxylate salt forms. Elution of doxorubicin from the beads demonstrated a controlled release via ionic exchange. Some formulations exhibited an increase in size and release of drug in the presence of a reducing agent, and therefore demonstrated the ability to respond to an in vitro reducing environment.

Unusual behaviour induced by phase separation in hydrogel microspheres.

Hydrogel microspheres with the capability to interact with charged species such as various drugs by ion-exchange processes are useful in a variety of biomedical applications. Such systems have been developed to allow active loading of the microsphere with chemotherapeutic agents in the hospital pharmacy for subsequent locoregional therapy of tumours in the liver by drug-eluting bead chemoembolization (DEB-TACE). A variety of microspherical embolisation systems have been described, all based upon hydrogels bearing anionic functionalities to allow interaction with cationically charged drugs. We have recently prepared a series of microspheres bearing cationic functionality and have observed some unusual behaviour induced by phase-separation that occurs during the synthesis of the microspheres. The phase-separation results in the core of the microsphere being enriched in cationic polymer component compared to the outer polyvinyl alcohol (PVA)-based phase. For certain formulations, subsequent swelling in water results in the PVA-rich skins separating from the charged cores. Ion-exchange interactions with model compounds bearing multi-anionic groups create differential contraction of the charged core relative to the skin, resulting in an unusual "golf-ball" appearance to the surface of the microspheres. STATEMENT OF SIGNIFICANCE: The authors believe that the unusual behaviour of the microspheres reported in this paper is the first observation of its kind resulting from phase-separation during synthesis. This could have novel applications in drug delivery for systems that can respond by shedding their skin or altering the surface area to volume ratio upon loading a drug.

Preparation and characterisation of vandetanib-eluting radiopaque beads for locoregional treatment of hepatic malignancies.

Since their introduction around a decade ago, embolic drug-eluting beads (DEBs) have become a well-established treatment option for the locoregional transarterial treatment of hepatic malignancies. Despite this success, the therapy is seen to be limited by the choice of drug and more effective options are therefore being sought. These include the small molecule multi-tyrosine kinase inhibitors (MTKi), which exert an anti-angiogenic and anti-proliferative effect that could be highly beneficial in combating some of the unwanted downstream consequences of embolization. Vandetanib is an MTKi which acts against such targets as vascular endothelial growth factor receptor (VEGFR) and epithelial growth factor receptor (EGFR) and has demonstrated modest activity against hepatocellular carcinoma (HCC), albeit with some dose-limiting cardiac toxicity. This makes this compound an interesting candidate for DEB-based locoregional delivery. In this study we describe the preparation and characterisation of vandetanib DEBs made from DC Bead™ and its radiopaque counterpart, DC Bead LUMI™. Drug loading was shown to be dependent upon the pH of the drug loading solution, as vandetanib has multiple sites for protonation, with the bead platform also having a fundamental influence due to differences in binding capacities and bead shrinkage effects. Fourier transform infrared (FTIR) spectroscopy and energy dispersive X-ray (EDX) Spectroscopy confirmed drug interaction is by ionic interaction, and in the case of the radiopaque DEB, the drug is distributed uniformly inside the bead and contributes slightly to the overall radiopacity by virtue of a bromine atom on the vandetanib structure. Drug release from both bead platforms is controlled and sustained, with a slightly slower rate of release from the radiopaque bead due to its more hydrophobic nature. Vandetanib DEBs therefore have suitable characteristics for intra-arterial delivery and site-specific sustained release of drug into liver tumours.

Synthesis and characterisation of cationic quaternary ammonium-modified polyvinyl alcohol hydrogel beads as a drug delivery embolisation system.

To extend the platform of clinically utilised chemoembolic agents based on ion-exchange systems to support the delivery of anionic drugs, a series of PVA-based beads was produced with different levels of (3-acrylamidopropyl)trimethylammonium chloride (APTA) in their formulation. The beads were characterised to confirm composition and the effect of formulation variation on physical properties was assessed. Suspension polymerisation was shown to successfully produce uniformly spherical copolymer beads with APTA content up to 60 wt%. Equilibrium water content and resistance to compression both increased with increasing APTA content in the formulation. Confocal laser scanning microscopy was used with model drugs to demonstrate that by increasing APTA content, compounds between the molecular weight range 70-250 kDa could permeate the microsphere structures. Interaction with anionic drugs was modelled using multivalent dyes. Dyes with multi-binding sites had increased interaction with the polymer, slowing the release and also demonstrating a reduced rate of elution from beads with higher charge density. The model drug release studies demonstrate that these systems can be engineered for different potential anionic drugs for local therapeutic delivery in the clinic.

Mineral Acquisition from Clay by Budongo Forest Chimpanzees.

Chimpanzees of the Sonso community, Budongo Forest, Uganda were observed eating clay and drinking clay-water from waterholes. We show that clay, clay-rich water, and clay obtained with leaf sponges, provide a range of minerals in different concentrations. The presence of aluminium in the clay consumed indicates that it takes the form of kaolinite. We discuss the contribution of clay geophagy to the mineral intake of the Sonso chimpanzees and show that clay eaten using leaf sponges is particularly rich in minerals. We show that termite mound soil, also regularly consumed, is rich in minerals. We discuss the frequency of clay and termite soil geophagy in the context of the disappearance from Budongo Forest of a formerly rich source of minerals, the decaying pith of Raphia farinifera palms.

Nanoprecipitation of polymeric nanoparticle micelles based on 2-methacryloyloxyethyl phosphorylcholine (MPC) with 2-(diisopropylamino)ethyl methacrylate (DPA), for intracellular delivery applications.

Biodistribution of nanoparticle-based intracellular delivery systems is mediated primarily by particle size and physicochemical properties. As such, overcoming the rapid removal of these by the reticuloendothelial system remains a significant challenge. To date, a number of copolymer nanoparticle systems based on 2-methacryloyloxyethyl phosphorylcholine (MPC) with 2-(diisopropylamino)ethyl methacrylate (DPA), displaying biomimetic and pH responsive properties, have been published, however these have been predominately polymersome based, whilst micelle systems have remained relatively unexplored. This study utilised nanoprecipitation to investigate the effects of solvent and buffer choice upon micelle size and polydispersity, and found using methanol produced monodisperse micelles of circa 70 nm diameter, whilst ethanol produced polydisperse systems with nanoparticles of circa 128 nm diameter. The choice of aqueous buffer, dialysis of the systems, extended storage, and exposure to a wide temperature range (5-70 °C) had no significant effect on micelle size, and the systems were highly resistant to dilution, indicating excellent colloidal stability. Optimisation of the nanoprecipitation process, post precipitation, was investigated, and model drugs successfully loaded whilst maintaining system stability. Subsequent in vitro studies suggested that the micelles were of negligible cellular toxicity, and an apparent cellular uptake was observed via confocal laser scanning microscopy. This paper presents the first report of an optimised nanoprecipitation methodology for the formation of MPC-DPA nanoparticle micelles, and in doing so achieved monodisperse systems with the size and physicochemical characteristics seen as desirable for long circulating therapeutic delivery vehicles.

Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies.

Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivo using a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicin/rapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicin/rapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours.

Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer.

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40-45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC(50) for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 microM compared to 28.1 and 19.2 microM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml(-1), like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3-6.6 mg were shown to be well-tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83-1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2-0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity.

Characterisation of physico-mechanical properties and degradation potential of calcium alginate beads for use in embolisation.

High molecular weight alginate beads with 59% mannuronic acid content or 68% guluronic acid were prepared using a droplet generator and crosslinked in calcium chloride. The alginate beads were compared to current embolisation microspheres for compressibility and monitored over 12 weeks for size and weight change at 37 degrees C in low volumes of ringers solutions. A sheep uterine model was used to analyse bead degradation and inflammatory response over 12 weeks. Both the in vitro and in vivo data show good delivery, with a compressibility similar to current embolic beads. In vitro, swelling was noted almost immediately and after 12 weeks the first signs of degradation were noted. No difference was noted in vivo. This study has shown that high molecular weight alginate gel beads were well tolerated by the body, but beads associated with induced thrombi were susceptible to inflammatory cell infiltration. The beads were shown to be easy to handle and were still observable after 3 months in vivo. The beads were robust enough to be delivered through a 2.7 Fr microcatheter. This study has demonstrated that high molecular weight, high purity alginate bead can be considered as semi-permanent embolisation beads, with the potential to bioresorb over time.

Decaying Raphia farinifera palm trees provide a source of sodium for wild chimpanzees in the Budongo Forest, Uganda.

For some years, chimpanzees have been observed eating the pith of decaying palm trees of Raphia farinifera in the Budongo Forest, Uganda. The reasons for doing this have until now been unknown. An analysis of the pith for mineral content showed high levels of sodium to be present in the samples. By contrast, lower levels were found in bark of other tree species, and also in leaf and fruit samples eaten by chimpanzees. The differences between the Raphia samples and the non-Raphia samples were highly significant (p<0.001). It is concluded that Raphia provides a rich and possibly essential source of sodium for the Budongo chimpanzees. Comparison of a chewed sample (wadge) of Raphia pith with a sample from the tree showed a clear reduction in sodium content in the chewed sample. Black and white colobus monkeys in Budongo Forest also feed on the pith of Raphia. At present, the survival of Raphia palms in Budongo Forest is threatened by the use of this tree by local tobacco farmers.

The in vitro corneal biocompatibility of hydroxyapatite-coated carbon mesh.

The purpose of this study was to consider the use of a hydroxyapatite (HA) coated porous carbon matrix as a synthetic dental laminate substitute in osteo-odonto-keratoprosthetic (OOKP) design. 3 types of carbon meshes were coated with HA by sonoelectrochemical deposition. The materials were characterised by scanning electron microscopy (SEM) and HA deposition was characterised by elemental analysis and X-ray diffractometry (XRD). In vitro assays were carried out to quantify the effects of HA coating on human keratocyte adhesion. Cellular cytokine production was used to assess inflammatory potential. HA coating significantly increased keratocyte adhesion to the carbon matrix (p<0.01). The materials did not induce excessive cytokine production by the adherent keratocytes. In addition, the matrices themselves adsorbed significant levels of the cytokine IL-8 (p<0.05). The results indicate that HA coated carbon matrices provide a suitable environment to enhance in-growth of corneal cells without inducing further inflammation. The materials may also suppress excessive inflammation by adsorption of the cytokine IL-8 into the porous, internal carbon structure.

Inflammatory cytokine removal by an activated carbon device in a flowing system.

A prototype in-line filtration/adsorption device has been developed using novel synthetic pyrolysed carbon monoliths with controlled mesoporous domains of 2-50nm. Porosity was characterized by SEM and porosimetry. Removal of inflammatory cytokines TNF, IL-6, IL-1beta and IL-8 was assessed by filtering cytokine spiked human plasma through the walls of the carbon modules under pressure. The effect of carbon filtration on plasma clotting response and total plasma protein concentration was also assessed. Significant removal of the cytokines IL-6, IL-1beta and IL-8 was observed. Initially marked TNF removal diminished over time. The coagulation studies indicated that the carbon device does not exacerbate the propensity of blood plasma to clot. The total plasma protein concentration remained constant. The device offers a broader approach to the treatment of systemic inflammatory response syndrome (SIRS) by the removal of inflammatory mediators central to its progression.

Doxorubicin eluting beads-2: methods for evaluating drug elution and in-vitro:in-vivo correlation.

DC Bead is a sulfonate-modified, PVA-based microspherical embolisation agent approved for the treatment of hypervascular tumours and arterio-venous malformations. The beads have previously been shown to actively sequester oppositely charged drugs, such as doxorubicin hydrochloride (dox) by an ion-exchange mechanism. In order to characterise the release kinetics and predict the in vivo behaviour of drug eluting beads (DEB), two elution methods were utilised. The first, an application of the USP dissolution method Type II - Apparatus, enables study of the complete elution of loaded DC Bead in less than 4 h, allowing relatively rapid comparison to be made between different products and formulations. Release data obtained using this method were fitted to first order kinetics (R (2) > 0.998) and the elution constants shown to increase with the total surface area of the beads exposed to the elution medium. Diffusion coefficients were calculated adopting the Fickian diffusion model, which predicted slow elution rates under physiological conditions. The second method involved the use of a T-Apparatus where the drug experiences an element of diffusion through a static environment. This method was developed to resemble the in vivo situation in embolisation procedures more closely. Slow release of dox from DC Bead with half-lives over 1,500 h were predicted for all size ranges using a slow release model. A strong linear relationship was found between the release data from T-Apparatus and pharmacokinetic data obtained from patients treated with DC Bead loaded with dox in transarterial chemoembolisation (TACE) procedures. These data indicated a Level A in vitro-in vivo correlation (IVIVC) for the first 24 h post embolisation. Both systems developed were automated and good reproducibility was obtained for all samples, demonstrating the usefulness of these elution techniques for product development and comparative testing.

Polymeric hydrogels for novel contact lens-based ophthalmic drug delivery systems: a review.

Only about 5% of drugs administrated by eye drops are bioavailable, and currently eye drops account for more than 90% of all ophthalmic formulations. The bioavailability of ophthalmic drugs can be improved by a soft contact lens-based ophthalmic drug delivery system. Several polymeric hydrogels have been investigated for soft contact lens-based ophthalmic drug delivery systems: (i) polymeric hydrogels for conventional contact lens to absorb and release ophthalmic drugs; (ii) polymeric hydrogels for piggyback contact lens combining with a drug plate or drug solution; (iii) surface-modified polymeric hydrogels to immobilize drugs on the surface of contact lenses; (iv) polymeric hydrogels for inclusion of drugs in a colloidal structure dispersed in the lens; (v) ion ligand-containing polymeric hydrogels; (vi) molecularly imprinted polymeric hydrogels which provide the contact lens with a high affinity and selectivity for a given drug. Polymeric hydrogels for these contact lens-based ophthalmic drug delivery systems, their advantages and drawbacks are critically analyzed in this review.

Doxorubicin eluting beads - 1: effects of drug loading on bead characteristics and drug distribution.

DC Bead is a FDA cleared embolisation device for the treatment of hypervascular tumours and arteriovenous malformations. This product is currently evaluated in a number of centres in Europe as an embolic device for transarterial chemoembolisation (TACE). The beads consist of poly(vinyl alcohol) microspheres modified with sulfonic acid groups and are available at different size ranges varying from 100 to 900 microm in diameter. The beads were shown to actively sequester doxorubicin hydrochloride (dox) from solution in a time dependent upon the dose of the drug and size of the beads. Drug uptake was by an ion-exchange mechanism, and in the absence of other ions in solution, the beads could load a maximum of around 40 mg dox/mL hydrated beads, with >99% of drug being sequestered from the solution. A loading of 25 mg dox/mL beads was recommended as providing a practical therapeutic dose and optimum handling characteristics. There was a decrease in equilibrium water content of the beads with increasing dox loading, which resulted in a decrease in the average diameter of the beads and an increase in the compressive modulus. The deliverability properties, however, were not affected after drug loading. Using a variety of microscopic methods, the drug was shown to be distributed throughout the bead structure, but concentrated in the outer 20 microm surface layer, a feature related to the method of synthesis. This study characterises the properties of DC Bead loaded with dox with respect to important characteristics in embolisation and demonstrates the potential of this drug device combination for the treatment of hypervascular tumours such as hepatocellular carcinoma.

Mesoporous carbide-derived carbon with porosity tuned for efficient adsorption of cytokines.

Porous carbons can be used for the purification of various bio-fluids, including the cleansing blood of inflammatory mediators in conditions such as sepsis or auto-immune diseases. Here we show that the control of pore size in carbons is a key factor to achieving efficient removal of cytokines. In particular, the surface area accessible by the protein governs the rate and effectiveness of the adsorption process. We demonstrate that novel mesoporous carbon materials synthesized from ternary MAX-phase carbides can be optimized for efficient adsorption of large inflammatory proteins. The synthesized carbons, having tunable pore size with a large volume of slit-shaped mesopores, outperformed all other materials or methods in terms of efficiency of TNF-alpha removal and the results are comparable only with highly specific antibody-antigen interactions.