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DC Bead is designed for the embolization of liver malignancies combined with local sustained chemotherapy delivery. It was first demonstrated around a decade ago that irinotecan could be loaded into DC Bead and used in a transarterially directed procedure to treat colorectal liver metastases, commonly referred to as drug-eluting bead with irinotecan (DEBIRI). Despite numerous reports of its safe and effective use in treating colorectal liver metastases patients, there remains a perceived fundamental paradox as to how this treatment works. This review of the mechanism of action of DEBIRI provides a rationale for why intra-arterial delivery of this prodrug from an embolic bead provides for enhanced tumor selectivity, sparing the normal liver while reducing adverse side effects associated with the irinotecan therapy.

Objective: Uncontrolled rapid release of drugs can reduce their therapeutic efficacy and cause undesirable toxicity; however, controlled release from reservoir materials helps overcome this issue. The aims of this study were to determine the release profiles of ketoprofen and spironolactone from a pH-responsive self-assembling DPA-MPC-DPA triblock copolymer gel and elucidate underlying physiochemical properties., Methods: Drug release profiles from DPA 50 -MPC 250 -DPA 50 gel (pH 7.5), over 32 h (37 °C), were determined using UV-Vis spectroscopy. Nanoparticle size was measured by dynamic light scattering (DLS) and critical micelle concentration (CMC) by pyrene fluorescence. Polymer gel viscosity was examined via rheology, nanoparticle morphology investigated using scanning transmission electron microscopy (STEM) and the gel matrix observed using cryo-scanning electron microscopy (Cryo-SEM)., Key Findings: DPA 50 -MPC 250 -DPA 50 copolymer (15% w/v) formed a free-standing gel (pH 7.5) that controlled drug release relative to free drugs. The copolymer possessed a low CMC, nanoparticle size increased with copolymer concentration, and DLS data were consistent with STEM. The gel displayed thermostable viscosity at physiological temperatures, and the gel matrix was a nanostructured aggregation of smaller nanoparticles., Conclusions: The DPA 50 -MPC 250 -DPA 50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone., (© 2017 Royal Pharmaceutical Society.)

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., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

An improved method for evaluating drug release behaviour of drug-eluting embolization beads (DEBs) was developed utilizing an open-loop flow-through system, in which the beads were packed into an occlusive mass within the system and extracted with a flowing elution medium over time. Glass beads were introduced into the beads mass in order to ensure laminar flow, reduce dead volume and improve reproducibility by compensating for swelling phenomena. The effects of glass bead ratio, elution medium flow rate and ion concentration, DEB size and drug concentration and drug type (doxorubicin and irinotecan) were evaluated using DEB composed of a sulfonate-modified polyvinyl alcohol hydrogel (DC Bead™) as the test article. The rate and amount of drug elution from the packed beads was affected by flow rate, the bead size and initial loading dose. The raw data from the concentration profile analysis provided valuable information to reveal the drug elution behaviour akin to the pharmacokinetic data observed for embolized beads (yielding in vitro Cmax and tmax data) which was complementary to the normal cumulative data obtained. A good correlation with historical reported in vivo data validated the usefulness of the method for predicting in vivo drug elution behaviour., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Due mainly to their poor stability and short plasma half-life, peptides are usually administered by injection, often several times daily. Injectable sustained-release formulations of peptides based on biodegradable polymer microparticles or implants early demonstrated the power of drug delivery technologies to enhance patient adherence and convenience, and increase safety and efficacy. Injectable sustained-release formulations are likely to remain a significant part of new peptide products. However, a new generation of technologies that enable solvent-free formulations and manufacturing processes, injection through narrow gauge needles and ready-to-use presentations will be increasingly used. In addition, the tremendous developments in noninvasive routes of delivery are likely to result in more and more peptides being delivered by the oral, transdermal, nasal or inhalation routes.

Drug-eluting beads (DEBs) are embolising devices in clinical use for the treatment of liver cancer by transarterial chemoembolisation. In this study, release kinetics of doxorubicin (DOX) and irinotecan (IRI) were investigated by experimental evaluations and mathematical modeling, based on Langmuir isotherm and two phenomenological models (Boyd/Bhaskar) developed to determine the actual mechanisms controlling drug release rate. The model was validated through release studies, in particular by assessing how drug loading, ionic strength of the release medium and device swelling during release influence drug release kinetics. Results demonstrated that IRI is released much faster than DOX, and that DEB volume strongly depends upon drug loading and fractional release. This effect was properly taken into account in developing the mathematical model. Experimental results were well fit by numerical simulations, and two different rate-controlling mechanisms were found to govern DOX and IRI delivery.

Lipiodol-based transarterial chemoembolization (TACE) has been performed for over 3 decades for the treatment of solid tumors and describes the infusion of chemotherapeutic agents followed by embolization with particles. TACE is an effective treatment for inoperable hepatic tumors, especially hypervascular tumors such as hepatocellular carcinoma. Recently, drug eluting beads (DEBs), in which a uniform embolic material is loaded with a drug and delivered in a single image-guided step, have been developed to reduce the variability in a TACE procedure. DEB-TACE results in localization of drug to targeted tumors while minimizing systemic exposure to chemotherapeutics. Once localized in the tissue, drug is eluted from the DEB in a controlled manner and penetrates hundreds of microns of tissue from the DEB surface. Necrosis is evident surrounding a DEB in tissue days to months after therapy; however, the contribution of drug and ischemia is currently unknown. Future advances in DEB technology may include image-ability, DEB size tailored to tumor anatomy and drug combinations., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: Chemotherapeutic drug-eluting beads (DEBs) are microspheres that are in clinical use for intraarterial chemoembolisation of liver cancer. Here we report on the biocompatibility and anti-tumour efficacy of DEBs after intratumoral application in a rat BT4Ca glioma model., Methods and Results: Doxorubicin and irinotecan-eluting DEBs were suspended in a Ca(2+)-free aqueous alginate solution that provides a sol-gel transition when injected into the Ca(2+) rich brain tissue. In this way the DEBs are immobilised at the implantation site. Forced elution studies in vitro using a USP-4 flow-through apparatus demonstrated that the alginate excipient helped to reduce the burst effect and rate the elution from the beads. From the in vivo evaluation, doxorubicin DEBs demonstrated a significant local toxicity, while irinotecan-loaded DEBs showed good local tissue compatibility. Doxorubicin at higher concentrations and irinotecan-loaded DEBs were found to decrease tumour volume, increase survival time and decrease the Ki67 proliferation index of the tumour. Doxorubicin was shown by fluorescent microscopy to diffuse into the peritumoral tissue, but also penetrates along white matter tracts, to more distant areas., Discussion: We conclude that the alginate suspension of irinotecan DEBs can be considered safe and effective in a clinical setting.

Introduction: As an essential complement to chemically crosslinked hydrogels, drug delivery systems based on physical hydrogels with self-assembled nanostructures are gaining increasing attention, owing to potential advantages of reduced toxicity, convenience of in situ gel formation, stimuli-responsiveness, reversible sol-gel transition, and improved drug loading and delivery profiles., Areas Covered: In this review, drug delivery systems based on physical hydrogels are discussed according to their self-assembled nanostructures, such as micelles, layer-by-layer constructs, supramolecular inclusion complexes, polyelectrolyte complexes and crystalline structures. The driving forces of the self-assembly include hydrophobic interaction, hydrogen bonding, electrostatic interaction, π-π stacking and weak van der Waals forces. Stimuli-responsive properties of physical hydrogels, including thermo- and pH-sensitivity, are considered with particular focus on self-assembled nanostructures., Expert Opinion: Fabricating self-assembled nanostructures in drug delivery hydrogels, via physical interactions between polymer-polymer and polymer-drug, requires accurately controlled macro- or small molecular architecture and a comprehensive knowledge of the physicochemical properties of the therapeutics. A variety of nanostructures within hydrogels, with which payloads may interact, provide useful means to stabilize the drug form and control its release kinetics.

Purpose: In the treatment of uterine fibroid embolization related pain, the use of embolics loaded with non-steroidal anti-inflammatory drugs (NSAID) relies on an efficient delivery and impregnation of the embolized tissue. Immuno-labelling and spectroscopic techniques have demonstrated the release of ibuprofen from drug eluting beads (Wassef et al., 2008; Namur et al., 2009) but failed to demonstrate diffusion of the drug beyond the vascular wall (VW). We investigated whether ibuprofen diffused beyond the VW in surrounding tissues (ST), by tracking its biological effects through the modulation of expression of two main inflammatory cytokines., Materials and Methods: Uterine arteries of 6 sheep were embolized with ibuprofen loaded beads (IBU-BB) or non-loaded beads (BB) and sacrificed at one week. On frozen tissue slices, VWs of occluded arteries were isolated from ST using laser capture microdissection. RNA was extracted from VW and ST samples. Gene expression of IL6 and TNFα genes was measured by quantitative real-time PCR (qPCR)., Results: IL6 expression was significantly increased in IBU-BB compared to BB group both in VW (VW: fold-change (FC)=4.9, p=0.0009) and ST (ST: FC=8.7, p=0.0003). In IBU-BB, IL6 was significantly more expressed in VW than in ST (FC=4.4; p=0.0009). TNFα expression was not significantly different between IBU-BB and BB groups., Conclusion: Using qPCR+microdissection was useful to evaluate the spread of the biological effects of drug-loaded systems which attest of the tissular release. This approach can be considered when other drug detection techniques are unsuccessful or difficult to achieve. IL6 can be used as a marker of ibuprofen released by drug eluting beads in uterus. Gradient of expression of IL6 suggests diffusion of ibuprofen across the VW into the ST., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Proteins constitute an increasing proportion of the drugs in development. The barriers to their entry into the blood stream and rapid clearance means that they often have to be injected several times a day, affecting patient compliance. This paper reviews the major technologies enabling the development of injectable sustained-release products and formulation strategies to maintain protein integrity and modify release rates. Whilst many injectable sustained-release products are on the market, these are all delivering small molecular weight drugs and peptides. This is due to the manufacturing processes that denature and degrade the proteins upon encapsulation and release into the body. Formulation strategies are discussed and a number of new technologies reviewed that are able to overcome the issues with conventional manufacturing processes. The reliance of many processes on organic solvents has prevented their application to the development of injectable sustained release protein products. The development of entirely solvent free and aqueous methods of manufacture of these products has meant that numerous sustained-release protein products are close to reaching the market.

Despite some progress in therapy, the prognosis of patients with malignant gliomas remains poor. Local delivery of cytostatics to the tumour has been proven to be an efficacious therapeutic approach but which nevertheless needs further improvements. Drug Eluting Beads (DEB), have been developed as drug delivery embolisation systems for use in trans-arterial chemoembolisation. We tested in a rat model of malignant glioma, whether DEB, loaded with doxorubicin or irinotecan, may be used for local treatment of brain tumours. Unloaded and drug loaded DEB were implanted into the brains of healthy and tumour bearing BD IX rats followed by histological investigations and survival assessment. Intracerebral implantation of unloaded DEB caused no significant local tissue damage, whilst both doxorubicin and irinotecan DEB improved survival time significantly. However, a significant local toxicity was found after the implantation of doxorubicin DEB but not with irinotecan DEB. We concluded that irinotecan appears to be superior in terms of the risk-benefit ratio and that DEB may be used for local treatment of brain tumours.

The distribution of the active lactone and the inactive carboxylate forms of irinotecan released from drug eluting beads composed of a sulfonate-modified PVA hydrogel was studied in order to ascertain the interaction between irinotecan, a water-soluble derivative of anti-cancer drug camptothecin, and the sulfonate groups in beads. Under a neutral condition of pH 7.0, it was demonstrated that the lactone form preferentially binds with sulfonate groups in the hydrogel beads through charge-charge interaction, and the equilibrium of the two forms shifts in favour of the lactone. In terms of stability, the drug-sulfonate interaction results in the retention of the active lactone form within the hydrogel beads. Kinetic experiments indicated that in PBS, the rate constants of lactone hydrolysis and carboxylate lactonization were 3.10 (+/-0.33)x10(-3) min(-1) and 1.36 (+/-0.04)x10(-3) min(-1), respectively. The modelling and elution experiments of the distribution of the lactone and carboxylate during irinotecan delivery by different methods, such as bolus injection, infusion and bead delivery, showed that both infusion and embolic bead delivery provided the lactone form with prolonged half-life. In addition, drug eluting beads have the characteristics of targeted delivery and low toxicity and the advantage of storage of the active form of irinotecan by polyanion stabilisation for use in local therapy of metastatic colorectal cancer to the liver.

Supercritical CO(2) has the potential to be an excellent environment within which controlled release polymers and dry composites may be formed. The low temperature and dry conditions within the fluid offer obvious advantages in the processing of water, solvent or heat labile molecules. The low viscosity and high diffusivity of scCO(2) offer the possibility of novel processing routes for polymer drug composites, but there are still technical challenges to overcome. Moreover, the low solubility of most drug molecules in scCO(2) presents both challenges and advantages. This review explores the current methods that use high pressure and scCO(2) for the production of drug delivery systems and the more specialized application of the fluid in the formation of highly porous tissue engineering scaffolds.

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.

We have recently achieved efficient cytosolic delivery by using pH-sensitive poly(2-(methacryloyloxy)ethylphosphorylcholine)-co-poly(2-(diisopropylamino)ethylmethacrylate) (PMPC-PDPA) diblock copolymers that self-assemble to form vesicles, known as polymersomes, in aqueous solution. It is particularly noteworthy that these diblock copolymers form stable polymersomes at physiological pH but rapidly dissociate below pH 6 to give molecularly-dissolved copolymer chains (unimers). These PMPC-PDPA polymersomes are used to encapsulate nucleic acids for efficient intracellular delivery. Confocal laser scanning microscopy and fluorescence flow cytometry are used to quantify cellular uptake and to study the kinetics of this process. Finally, we examine how PMPC-PDPA polymersomes affect the viability of primary human cells (human dermal fibroblasts (HDF)), paying particular regard to whether inflammatory responses are triggered.

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.

Drug eluting beads that release irinotecan in a controlled manner may be useful for application in the chemoembolization of colorectal cancer metastases to the liver. In this study, irinotecan drug eluting beads were prepared with loadings up to 50 mg drug/mL hydrated beads. Drug loading was via an ion-exchange mechanism with sulfonate binding sites in the bead. Release in vitro was shown to be sustained and dependent upon the presence of ions in the elution medium, drug loading and bead size. Drug elution in PBS was controlled by solute diffusion within the beads and gave rise to values for the diffusion coefficient, D, of between 2.4x10(-9) and 1.4x10(-7) cm(2)s(-1). The beads were shown to decrease in size (by a maximum 25-30%), and concomitantly their modulus of compression increased (from approximately 27 kPa to a maximum of about 49 kPa), with increasing drug loading. This did not however, influence their ability to be suspended homogeneously in contrast agent or delivered through a microcatheter. Following porcine hepatic artery embolization, maximum plasma levels were 70-75% lower for both irinotecan and SN-38 compared to intraarterial bolus administration, with peak levels observed at 2 and 5 min after completion of the embolization procedure. The in vivo data were shown to correlate well with the in vitro release measured using a T-apparatus model of embolization.

Purpose: The purpose of this investigation is to present the in vitro characterization and detailed drug-loading procedure for DC Bead, a microsphere product that can be loaded with chemotherapeutic agents for embolization., Materials and Methods: DC Bead is an embolic microsphere product that is capable of being loaded with anthracycline drugs such as doxorubicin just before administration in a transarterial chemoembolization (TACE) procedure. Beads can be loaded from solutions prepared from doxorubicin powder or the doxorubicin HCl formulation. In this evaluation, bead sizes were measured by optical microscopy with video imaging. Gravimetric analysis demonstrated the effect of drug loading on bead water content, and its consequent impact on bead compressibility was determined. The subsequent deliverability of the beads was assessed by mixing the beads with contrast medium and saline solution and passing the beads through an appropriately sized microcatheter. A T-cell apparatus was used to monitor the in vitro elution of the drug from the beads over a period of 24 hours in various elution media., Results: DC Bead spheres could be easily loaded with doxorubicin to a recommended level of 25 mg/mL of hydrated beads by immersion of the beads in the drug solution for 10-120 minutes depending on microsphere size. Other commercial embolic microspheres were shown not to load doxorubicin to the same extent or release it in the same fashion and were considered unsuitable for local drug delivery. Maximum theoretic capacity for DC Bead was approximately 45 mg/mL. Increase in doxorubicin loading resulted in a concomitant decrease in water content and consequential increase in bead resistance to compression force. Drug loading also resulted in a decrease in the average size of the beads, which was dependent on bead size and drug dose. This did not impact bead delivery at any drug loading level to a maximum of 37.5 mg/mL. Beads 100-700 microm in size could be delivered through 2.7-F microcatheters, whereas the 700-900-microm range required 3-F catheters. Modeling of the kinetics of drug elution from the beads in vitro at a loading dose of 25 mg/mL yielded calculated half-lives of 150 hours for the 100-300-microm range to a maximum of 1,730 hours for the 700-900-microm size range, which was dependent on the ionic strength of the elution medium. For comparison, there was a rapid loss of drug from an unstable Lipiodol emulsion with a half-life of approximately 1 hour., Conclusions: DC Bead can be loaded with doxorubicin to provide an accurate dosage of drug per unit volume of beads. Drug elution is dependent on ion exchange with the surrounding environment and is controlled and sustained, unlike the rapid separation of the drug from Lipiodol. Drug loading has no impact on the handling and deliverability of the beads, making them suitable for superselective TACE.

Major challenges associated with nano-sized drug delivery systems include removal from systemic circulation by phagocytic cells and controlling appropriate drug release at target sites. 2-methacryloyloxyethyl phosphorylcholine (MPC) has been copolymerised in turn with two pH responsive comonomers (2-(diethylamino)ethyl methacrylate (DEA) and 2-(diisopropylamino)ethyl methacrylate (DPA), to develop novel biocompatible drug delivery vehicles. Micelles were prepared from a series of copolymers with varying block compositions and their colloidal stability and dimensions were assessed over a range of solution pH using photon correlation spectroscopy. The drug loading capacities of these micelles were evaluated using Orange OT dye as a model compound. The cytotoxicity of the micelles was assessed using an in vitro assay. The MPC-DEA diblock copolymers formed micelles at around pH 8 and longer DEA block lengths allowed higher drug loadings. However, these micelles were not stable at physiological pH. In contrast, MPC-DPA diblock copolymers formed micelles of circa 30 nm diameter at physiological pH. In vitro assays indicated that these MPC-DPA diblock copolymers had negligible cytotoxicities. Thus novel non-toxic biocompatible micelles of appropriate size and good colloidal stability with pH-modulated drug uptake and release can be readily produced using MPC-DPA diblock copolymers.

Phospholipid-like polymers based on 2-methacryloyloxyethyl phosphorylcholine containing varying amounts of the cationically charged monomer choline methacrylate (CMA) from 0 to 30 wt% have been prepared. Substrates coated with these materials were shown to bind significantly lower amounts of specific proteins compared to the uncoated control. ELISA assays demonstrated that fibrinogen did not bind appreciably to coatings containing 0-30% CMA, whereas albumin binding was seen to increase significantly as the CMA content of the coating increased. Platelet activation assays, measurement of plasma coagulation time and whole blood contact scanning electron micrography demonstrated that the haemocompatibility of the coatings was shown to be unaffected by the CMA component. The CMA polymer coatings have been shown to absorb/adsorb many different drug compounds covering a wide range of molecular weights and release these in a controlled fashion. The range of cationic polymers assessed can interact with the net negative charge found in many large therapeutic biomolecules, such as DNA fragments used in gene therapy, that may be of interest in the preventative treatment of conditions such as restenosis. Coronary stents coated with 6% or 20% CMA-containing polymers have been shown to load and release this type of genetic material irrespective of molecular weight of the biomolecule. Ex vivo and in vivo studies have shown that these compounds can be delivered to the stented section of the vessel with very low quantities delivered outside the vessel target area.

This review describes the historical development of an imageable spherical embolic agent and focuses on work performed in collaboration between Biocompatibles UK Ltd (a BTG International group company) and the NIH to demonstrate radiopaque bead utility and bring a commercial offering to market that meets a clinical need. Various chemistries have been investigated and multiple prototypes evaluated in search of an optimized product with the right balance of handling and imaging properties. Herein, we describe the steps taken in the development of DC Bead LUMI™, the first commercially available radiopaque drug-eluting bead, ultimately leading to the first human experience of this novel embolic agent in the treatment of liver tumors. [ABSTRACT FROM AUTHOR]

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 for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 μM compared to 28.1 and 19.2 μM 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, 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. [ABSTRACT FROM AUTHOR]

Abstract: Supercritical CO2 has the potential to be an excellent environment within which controlled release polymers and dry composites may be formed. The low temperature and dry conditions within the fluid offer obvious advantages in the processing of water, solvent or heat labile molecules. The low viscosity and high diffusivity of scCO2 offer the possibility of novel processing routes for polymer drug composites, but there are still technical challenges to overcome. Moreover, the low solubility of most drug molecules in scCO2 presents both challenges and advantages. This review explores the current methods that use high pressure and scCO2 for the production of drug delivery systems and the more specialized application of the fluid in the formation of highly porous tissue engineering scaffolds. [Copyright &y& Elsevier]

Isothermal titration calorimetry (ITC) was utilised to investigate suitability of the technique to determine the stoichiometry and thermodynamics of the interactions that occur between a commonly used chemotherapeutic drug, namely doxorubicin, and a polymer bead-based drug delivery embolisation system (DC Bead™). Six temperatures were selected for drug–polymer titrations (293–313 K) and in all cases an initially exothermic signal reverted to an endothermic response upon the saturation of the beads with drug. From these experiments, and subsequent calculations, the molar ratio of drug to SO 3 − (polymer) was found to be 0.4:1 at all temperatures studied. Enthalpic data was calculated from the raw ITC data with an average enthalpy of drug-polymer binding of – 14.8 kJ mol −1 at 293 K through to – 19.4 kJ mol −1 at 313 K implying the process is enthalpically-driven yet only affected by an increase in experimental temperature to a limited extent whereby an increase in experimental temperature results in a small increase in the negativity in change in enthalpy recorded. The application of ITC in this study (with its unique ability to monitor real-time interactions and facilitate stoichiometric calculations) resolves the lack of knowledge regarding the thermodynamics of this specific drug-polymer interaction. This study confirms that ITC is not only useful for this specific system, but also highlights the potential use of ITC for more general studies in this area. [ABSTRACT FROM AUTHOR]

Abstract: The absorption enhancing efficiency of CriticalSorb™ for human growth hormone (MW 22kDa) was investigated in the conscious rat model. The principle absorption enhancing component of CriticalSorb™, Solutol® HS15, comprises polyglycol mono- and di-esters of 12-hydroxystearic acid combined with free polyethylene glycol. When administering hGH nasally in rats with increasing concentrations of Solutol® HS15, it was found that for a 10%w/v solution formulation a bioavailability of 49% was obtained in the first 2h after administration. Furthermore it was shown that the most effective ratio of Solutol® HS15 to hGH was 4:1 on a mg to mg basis. Histopathology studies in rats after 5days repeated nasal administration showed that Solutol® HS15 had no toxic effect on the nasal mucosa. These results have been confirmed in a 6month repeat nasal toxicity study in rats. It can be concluded that the principle absorption enhancing component of CriticalSorb™ – Solutol® HS15 – is a potent and non- toxic nasal absorption enhancer that warrants further development. [Copyright &y& Elsevier]

Inhalation of nanoparticles for pulmonary drug delivery offers the potential to harness nanomedicine formulations of emerging therapeutics, such as curcumin, for treatment of lung cancer. Biocompatible nanoparticles composed of poly(2-methacryloyloxyethyl phosphorylcholine)- b -poly(2-(diisopropylamino)ethyl methacrylate) (MPC-DPA) have been shown to be suitable nanocarriers for drugs, whilst N -trimethyl chitosan chloride (TMC) coating of nanoparticles has been reported to further enhance their cellular delivery efficacy; the combination of the two has not been previously investigated. Development of effective systems requires the predictable, controllable, and reproducible ability to prepare nanosystems possessing particle sizes, and drug loading capacities, appropriate for successful airway travel, lung tissue penetration, and tumor suppression. Although a number of MPC-DPA based nanosystems have been described, a complete understanding of parameters controlling nanoparticle formation, size, and morphology has not been reported; in particular the effects of differing solvents phases remains unclear. In this current study a matrix of 31 solvent combinations were examined to provide novel data pertaining to the formation of MPC-DPA nanoparticles, and in doing so afforded the selection of systems with particle sizes appropriate for pulmonary delivery applications to be loaded with curcumin, and coated with TMC. This paper presents the first report of novel data detailing the successful preparation, characterisation, and optimisation of MPC-DPA nanoparticles of circa 150–180 nm diameter, with low polydispersity, and a curcumin loading range of circa 2.5–115 μM, tunable by preparation parameters, with and without TMC coating, and thus considered suitable candidates for inhalation drug delivery applications. [ABSTRACT FROM AUTHOR]

The instability of human growth hormone (hGH) to temperature and interfaces makes its formulation into injectable, sustained-release drug delivery systems challenging. A novel method of encapsulating hGH in polymeric microparticles has been developed using supercritical CO2(scCO2) technology, but there is limited understanding of the stability of hGH within this system. The aim of this study was to evaluate the stability of hGH in scCO2 processing. The integrity of the protein was assessed following exposure to scCO2 using a range of different analytical techniques. Mass spectrometry showed that no peptide cleavage occurred as a result of processing or exposure to scCO2. Size-exclusion chromatography detected formation of aggregates at high temperatures, but not as a result of the encapsulation process. Reverse-phase chromatography demonstrated that the production of deamidation products occurred as a function of temperature, but only at temperatures higher than those used for the encapsulation process. Circular dichroism and infrared spectroscopy demonstrated that the use of scCO2 was not detrimental to the secondary molecular structure of hGH. Together, these results show that the structural integrity of hGH is unaffected by scCO2 processing and that hGH can be successfully encapsulated in polymer microparticles using this technique. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:56-67, 2012 [ABSTRACT FROM AUTHOR]