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Purpose: To evaluate the use of resonant acoustic mixing (RAM) technology for homogenous blending of a morphologically challenging model API in low-dose concentrations (<0.1% w/w), and assess the potential for blend uniformity (BU) optimization. Methods: Caffeine (CAF) mixing was carried out using a LabRAM I benchtop mixer. Uniformity was assessed under a range of mixing conditions and sample preparation procedures in order to optimize system performance. The capacity for microscale mixing was evaluated from final parameters for 0.05% and 0.0125% CAF blends. Results: Upon optimization, RAM was able to accurately prepare homogeneous mixtures of <0.1% CAF in dilutions of up to 1 part per 8,000. Results from a 0.05% blend targeting 125 μg CAF dosage amounts revealed an AV score of 8.8 while a 0.0125% w/w blend accurately prepared 25 μg of CAF with 99.3% accuracy (98.7% label claim) and AV of 10.1. Microscale mixing in the 0.05% w/w blend was confirmed from plots of BU data against sample size demonstrating a slope of 0.05 within the range of 250–10 mg sample (125–5 μg CAF). L1 BU criteria only failed at the level of 2 μg CAF, despite target precision to 26 nanograms (98.7% label claim). Conclusions: This study presents the first instance of a homogenously mixed <0.1% (w/w) blend using RAM technology and demonstrate the suitability for reproducible dosing of single-digit microgram drug amounts. Uniformity is documented for API amounts 60x smaller than a recent report has shown and 10,000x smaller than achieved previously with CAF. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is an aggressive liver cancer with limited effective treatment options. In this study, we selected TLR agonists imiquimod (IMQ), gardiquimod (GARD), GS-9620 and DSR 6434, and a small molecule checkpoint inhibitor, BMS-202, for characterization of drug loading and release from radiopaque embolic beads (DC Bead LUMI) for potential use in image-guided transarterial embolization (TACE) of HCC. The maximum drug loading capacity and amount of drug released over time were determined by high performance liquid chromatography and compared with the commonly used anthracycline, doxorubicin hydrochloride (Dox). Maximum drug loading was 204.54 ± 3.87, 65.28 ± 3.09, 65.95 ± 6.96, 65.97 ± 1.54, and 148.05 ± 2.24 mg of drug per milliliter of DC Bead LUMI for Dox, GARD, DSR 6434, IMQ, and BMS-202, respectively. Fast loading and subsequent rapid release in saline were observed for IMQ, GARD, and DSR 6434. These drugs could also be partially removed from the beads by repeated washing with de-ionized water suggesting weak interaction with the beads. Aggregation of IMQ was observed in water and saline. GS-9620 partially decomposed in the solubilizing solution, so loading and release were not characterized. Compared to TLR agonists, slower loading and release were observed for Dox and BMS-202. Potential factors influencing drug loading into and release from DC Bead LUMI including steric hinderance, hydrophobicity, drug pKa, and the electrostatic nature of the beads are discussed. The maximum loading capacity of BMS-202 and Dox in DC Bead LUMI exceeded the maximum theoretical loading capacity of the beads expected from ionic interaction alone suggesting additional drug-bead or drug-drug interactions may play a role. Slightly more release was observed for BMS-202 at early time points followed by a slower release compared to Dox. Further study of these drug-bead combinations is warranted in search of new tools for locoregional delivery of immune-modulating agents for treatment of HCC via drug-eluting bead chemoembolization. [ABSTRACT FROM AUTHOR]

Sclerotherapy is among the least invasive and most commonly utilised treatment options for varicose veins. Nonetheless, it does not cure varicosities permanently and recurrence rates are of up to 64%. Although sclerosing foams have been extensively characterised with respect to their bench-top properties, such as bubble size distribution and half-life, little is known about their flow behaviour within the venous environment during treatment. Additionally, current methods of foam characterisation do not recapitulate the end-point administration conditions, hindering optimisation of therapeutic efficacy. Here, a therapeutically relevant apparatus has been used to obtain a clinically relevant rheological model of sclerosing foams. This model was then correlated with a therapeutically applicable parameter—i.e., the capability of foams to displace blood within a vein. A pipe viscometry apparatus was employed to obtain a rheological model of 1% polidocanol foams across shear rates of 6 s−1 to 400 s−1. Two different foam formulation techniques (double syringe system and Tessari) and three liquid-to-gas ratios (1:3, 1:4 and 1:5) were investigated. A power-law model was employed on the rheological data to obtain the apparent viscosity of foams. In a separate experiment, a finite volume of foam was injected into a PTFE tube to displace a blood surrogate solution (0.2% w/v carboxymethyl cellulose). The displaced blood surrogate was collected, weighed, and correlated with foam's apparent viscosity. Results showed a decreasing displacement efficacy with foam dryness and injection flowrate. Furthermore, an asymptotic model was formulated that may be used to predict the extent of blood displacement for a given foam formulation and volume. The developed model could guide clinicians in their selection of a foam formulation that exhibits the greatest blood displacement efficacy. [ABSTRACT FROM AUTHOR]

To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE). A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with four-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging. RO beads were contoured using automated thresholding, and feasibility of matching between the simulated radiotherapy planning dataset (AVE-IP image from 4D data) and CBCT scans assessed. Additional kV, MV, helical CT and CBCT images of RO beads were obtained using an in-house phantom. Stability of RO bead position was assessed by comparing 4D-CT imaging to CT scans taken 6–20 days following TACE. Eight patients were treated and 4D-CT and CBCT images acquired. RO beads were visible on 4D-CT and CBCT images in all cases and matching successfully performed. Differences in centre of mass of RO beads between CBCT and simulated radiotherapy planning scans (AVE-IP dataset) were 2.0 mm mediolaterally, 1.7 mm anteroposteriorally and 3.5 mm craniocaudally. RO beads in the phantom were visible on all imaging modalities assessed. RO bead position remained stable up to 29 days post TACE. RO beads are visible on IGRT imaging modalities, showing minimal artefact. They can be used for on-set matching with CBCT and remain stable over time. The role of RO beads as fiducial markers for stereotactic liver radiotherapy is feasible and warrants further exploration as a combination therapy approach. [ABSTRACT FROM AUTHOR]

Achieving efficacious systemic levels of orally administered peptides is incredibly challenging due to the significant barriers to their bioavailability—their stability in the gastrointestinal tract and challenge of transepithelial transit, and variable pharmacokinetics. Even so, as the generally preferred route of administration, significant research effort in academic and industrial settings has focused on enabling the systemic absorption of orally delivered peptides. Despite several decades of research, few have ever reached the market. The recent approval of Rybelsus® (oral semaglutide) by the FDA [1], the EMA [2], and the Pmda [3] represents a significant landmark in the delivery of therapeutic peptides and is the culmination of more than 30 years research and development of the drug delivery technology enabling the product—Emisphere's Eligen™ technology—and an outstanding commitment to scientific, technical, and clinical innovation by Novo Nordisk. Following years of fundamental and applied research, an innovative clinical strategy led to the aptly named PIONEER clinical programme. This included ten Phase 3 clinical trials that demonstrated the tablet formulation to be as effective as the already approved injectable form of the drug, and more effective than competitor products in terms of its blood glucose lowering effects and weight loss. Not only is this a potentially life changing medicine for diabetic patients, it holds tremendous commercial potential for Novo Nordisk, with some analysts predicting the product to reach $5 billion in peak revenues [3]. In this "Inspirational Note," we summarize some of the public domain work that led to the achievement of this significant milestone and provide commentary on its potential future impact. [ABSTRACT FROM AUTHOR]

Current therapy for hypervascular cancers, e.g., hepatocellular carcinoma, includes occlusion of the tumor blood supply by arterial infusion of embolic microspheres (beads) suspended in iodine-based contrast under fluoroscopic guidance. Available radiopaque, imageable beads use iodine as the radiopacifier and cannot be differentiated from contrast. This study aimed to synthesize and characterize imageable beads using bismuth as the radiopacifier that could be distinguished from iodine contrast based upon the difference in the binding energy of k-shell electrons (k-edge). Radiodense bismuth beads were successfully synthesized some with uniform bismuth distribution across the beads. The beads were spherical and could be infused through clinical microcatheters. The bismuth beads could be imaged with clinical dual-energy computed tomography (CT), where iodine-based contrast could be distinguished from the microspheres. The ability to separate iodine from bismuth may enhance the diagnostic information acquired on follow-up CT, identifying the distribution of the embolic beads separately from the contrast. Furthermore, with sequential use of iodine- and bismuth-based beads, the two radiopaque beads could be spatially distinguished on imaging, which may enable the development of dual drug delivery and dual tracking. [ABSTRACT FROM AUTHOR]

Varicose veins are chronic venous defects that affect >20% of the population in developed countries. Among potential treatments, sclerotherapy is one of the most commonly used. It involves endovenous injection of a surfactant solution (or foam) in varicose veins, inducing damage to the endothelial layer and subsequent vessel sclerosis. Treatments have proven to be effective in the short‐term, however recurrence is reported at rates of up to 64% 5‐year post‐treatment. Thus, once diagnosed with varicosities there is a high probability of a permanently reduced quality of life. Recently, foam sclerotherapy has become increasingly popular over its liquid counterpart, since foams can treat larger and longer varicosities more effectively, they can be imaged using ultrasound, and require lower amounts of sclerosing agent. In order to minimize recurrence rates however, an investigation of current treatment methods should lead to more effective and long‐lasting effects. The literature is populated with studies aimed at characterizing the fundamental physics of aqueous foams; nevertheless, there is a significant need for appropriate product development platforms. Despite successfully capturing the microstructural evolution of aqueous foams, the complexity of current models renders them inadequate for pharmaceutical development. This review article will focus on the physics of foams and the attempts at optimizing them for sclerotherapy. This takes the form of a discussion of the most recent numerical and experimental models, as well as an overview of clinically relevant parameters. This holistic approach could contribute to better foam characterization methods that patients may eventually derive long term benefit from. [ABSTRACT FROM AUTHOR]

Purpose: Topotecan is a camptothecin analogue with potential advantages over irinotecan for transarterial chemoembolization (TACE) of hepatic colorectal metastases including greater anti-neoplastic activity without enzymatic activation. The purpose of this study was to assess safety and tolerability of topotecan-loaded radiopaque microspheres (ROMTOP) administered by TACE in a rabbit model and to compare the in vitro elution of topotecan from microspheres to irinotecan.Materials and Methods: Topotecan was loaded into radiopaque microspheres (70-150 µm, DC Bead LUMI™, Biocompatibles UK Ltd-Boston Scientific Corporation) to the maximum capacity of 80 mg/mL of microspheres. Six healthy New Zealand White rabbits underwent hepatic TACE with ROMTOP under fluoroscopic guidance until angiographic stasis. Assessment of toxicities included regular liver function tests and complete blood counts until euthanasia 28 days post-TACE. In vitro topotecan elution from the microspheres was assessed using an open-loop flow-through system and compared to irinotecan.Results: The mean bead volume and topotecan dose delivered were 0.086 mL (0.076-0.105 mL) and 1.99 mg/kg (1.51-2.55 mg/kg), respectively. Aspartate aminotransferase and alanine aminotransferase were elevated post-embolization but resolved within 2 weeks. One rabbit died two days after TACE with pyloric duodenal perforation observed at necropsy, potentially due to non-target embolization. In vitro elution of topotecan from ROMTOP was complete in 10 h compared to 3 h for irinotecan-loaded microspheres.Conclusion: Selective embolization with ROMTOP was tolerated at a dose of 2 mg/kg (24 mg/m2) in rabbits. In vitro topotecan elution from microspheres was more prolonged compared to irinotecan. [ABSTRACT FROM AUTHOR]

The in vitro and in vivo handling and performance characteristics of a small caliber radiopaque embolic microsphere, 40–90 μm DC Bead LUMI™ (LUMI40‐90), were studied. Microsphere drug loading and elution and effects on size, suspension, and microcatheter delivery were evaluated using established in vitro methodologies. In vivo evaluations of vascular penetration (rabbit renal artery embolization), long‐term biocompatibility and X‐ray imaging properties, pharmacokinetics and local tissue effects of both doxorubicin (Dox) and irinotecan (Iri) loaded microspheres (swine hepatic artery embolization) were conducted. Compared to 70–150 μm DC Bead LUMI (LUMI70‐150), LUMI40‐90 averaged 70 μm versus 100 μm, which was unchanged upon drug loading. Handling, suspension, and microsphere delivery studies were successfully performed. Dox loading was faster (20 min) and Iri equivalent (<10 min) while drug elution rates were similar. Contrast suspension times were longer with no delivery complications. Vascular penetration was statistically greater (rabbit) with no unexpected adverse safety findings (swine). Microspheres ± drug were visible under X‐ray imaging (CT) at 90 days. Peak plasma drug levels and area under the curve were greater for LUMI40‐90 compared to LUMI70‐150 but comparable to 70–150 μm DC BeadM1™ (DC70‐150). Local tissue effects showed extensive hepatic necrosis for Dox, whereas Iri displayed lower toxicity with more pronounced lobar fibrosis. LUMI40‐90 remains suspended for longer and have greater vessel penetration compared to the other DC Bead LUMI sizes and are similarly highly biocompatible with long‐term visibility under X‐ray imaging. Drug loading is equivalent or faster with pharmacokinetics similar to DC70‐150 for both Dox and Iri. [ABSTRACT FROM AUTHOR]

Liquid formulations have a well-established role in therapeutic embolisation of blood vessels with the widespread use of cyanoacrylate glues, precipitating polymer suspensions, sclerosing agents and viscous emulsions of oil and chemotherapeutic agents. There is currently an emerging market for next generation liquid embolics which aim to address some of the short-comings of the currently used products. These next generation systems use varying chemistries in their approach to formulate new systems including polymerising, precipitating and phase-transitioning mechanisms to form solidified masses in situ within the vasculature. Some of these emerging technologies have been developed to possess improved imaging properties such as inherent radiopacity, rather than relying on having to mixing with radiopaque materials such as tantalum powder and reduction of X-ray imaging artefacts (streaking). Others offer solvent-free formulations which gel on contact with blood thereby allowing precise control over gel formation during the embolisation process without the use of potentially toxic solvents. In this review, we discuss the role of liquid agents in therapeutic embolisation and the potential of emerging technologies under development for use in the next generation of embolics. [ABSTRACT FROM AUTHOR]

Yttrium‐doped glasses have been utilized for biomedical applications such as radiotherapy, especially for liver cancer treatment. In this paper, the crystallization behavior of phosphate‐based glasses doped with yttrium (in the system 45P2O5–(30 − x) Na2O–25CaO–xY2O3—where x = 0, 1, 3 and 5) have been investigated via Differential Scanning Calorimetry (DSC) using nonisothermal technique at different heating rates (5°C, 10°C, 15°C and 20°C/min). The glass compositions were characterized via EDX, XRD, Density and Molar volume analysis. The Moynihan and Kissinger methods were used for the determination of glass transition activation energy (Eg) which decreased from 192 to 118 kJ/mol (Moynihan) and 183 to 113 kJ/mol (Kissinger) with increasing yttrium oxide content. Incorporation of 0 to 5 mol% Y2O3 revealed an approximate decrease of 71 kJ/mol (Ozawa and Augis) for onset crystallization (Ex) and 26 kJ/mol (Kissinger) for crystallization peak activation energies (Ec). Avrami index (n) value analyzed via Matusita–Sakka equation suggested a one‐dimensional crystal growth for the glasses investigated. SEM analysis explored the crystalline morphologies and revealed one‐dimensional needle‐like crystals. Overall, it was found that these glass formulations remained amorphous with up to 5 mol% Y2O3 addition with further increases in Y2O3 content resulting in significant crystallization. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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]

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 DPA50- MPC250- DPA50 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 DPA50- MPC250- DPA50 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 DPA50- MPC250- DPA50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone. [ABSTRACT FROM AUTHOR]

Background. Mesenchymal stem cells (MSCs) and glucagon-like peptide-1 (GLP-1) are being tested as treatment strategies for myocardial infarction (MI); however, their mechanisms in the heart are not fully understood. Methods. We examined the effects of MSCs, either native, or engineered to secrete a GLP-1 fusion protein (MSCs ± GLP-1), on human cardiomyocyte apoptosis in vitro. The effect on cardiac remodeling when encapsulated in alginate beads (CellBeads-MSC and CellBeads-MSC + GLP-1) was also evaluated in a pig MI model, whereby pigs were treated with Empty Beads, CellBeads-MSC, or CellBeads-MSC + GLP-1 and sacrificed at one or four weeks following MI. Results. MSC + GLP-1 conditioned media demonstrated antiapoptotic effects on ischaemic human cardiomyocytes in vitro. In vivo, qRT-PCR revealed large changes in the expression of several genes involved in extracellular matrix remodeling, which were altered following MSC ± GLP treatment. After four weeks, infarcted areas were imaged using atomic force microscopy, demonstrating significant alterations between groups in the structure of collagen fibrils and resulting scar. Conclusions. These data demonstrate that MSCs ± GLP-1 exhibit modulatory effects on healing post-MI, affecting both apoptosis and collagen scar formation. These data support the premise that both MSCs and GLP-1 could be beneficial in MI treatment. [ABSTRACT FROM AUTHOR]

Purpose: To describe first clinical experience with a directly image-able, inherently radio-opaque microspherical embolic agent for transarterial embolization of liver tumors.Methodology: LC Bead LUMI™ is a new product based upon sulfonate-modified polyvinyl alcohol hydrogel microbeads with covalently bound iodine (~260 mg I/ml). 70-150 μ LC Bead LUMI™ iodinated microbeads were injected selectively via a 2.8 Fr microcatheter to near complete flow stasis into hepatic arteries in three patients with hepatocellular carcinoma, carcinoid, or neuroendocrine tumor. A custom imaging platform tuned for LC LUMI™ microbead conspicuity using a cone beam CT (CBCT)/angiographic C-arm system (Allura Clarity FD20, Philips) was used along with CBCT embolization treatment planning software (EmboGuide, Philips).Results: LC Bead LUMI™ image-able microbeads were easily delivered and monitored during the procedure using fluoroscopy, single-shot radiography (SSD), digital subtraction angiography (DSA), dual-phase enhanced and unenhanced CBCT, and unenhanced conventional CT obtained 48 h after the procedure. Intra-procedural imaging demonstrated tumor at risk for potential under-treatment, defined as paucity of image-able microbeads within a portion of the tumor which was confirmed at 48 h CT imaging. Fusion of pre- and post-embolization CBCT identified vessels without beads that corresponded to enhancing tumor tissue in the same location on follow-up imaging (48 h post).Conclusion: LC Bead LUMI™ image-able microbeads provide real-time feedback and geographic localization of treatment in real time during treatment. The distribution and density of image-able beads within a tumor need further evaluation as an additional endpoint for embolization. [ABSTRACT FROM AUTHOR]

Objective To compare foam bubble size and bubble size distribution, stability, and degradation rate of commercially available polidocanol endovenous microfoam (Varithena®) and physician-compounded foams using a number of laboratory tests. Methods Foam properties of polidocanol endovenous microfoam and physician-compounded foams were measured and compared using a glass-plate method and a Sympatec QICPIC image analysis method to measure bubble size and bubble size distribution, Turbiscan™ LAB for foam half time and drainage and a novel biomimetic vein model to measure foam stability. Physician-compounded foams composed of polidocanol and room air, CO2, or mixtures of oxygen and carbon dioxide (O2:CO2) were generated by different methods. Results Polidocanol endovenous microfoam was found to have a narrow bubble size distribution with no large (>500 µm) bubbles. Physician-compounded foams made with the Tessari method had broader bubble size distribution and large bubbles, which have an impact on foam stability. Polidocanol endovenous microfoam had a lower degradation rate than any physician-compounded foams, including foams made using room air (p < 0.035). The same result was obtained at different liquid to gas ratios (1:4 and 1:7) for physician-compounded foams. In all tests performed, CO2 foams were the least stable and different O2:CO2 mixtures had intermediate performance. In the biomimetic vein model, polidocanol endovenous microfoam had the slowest degradation rate and longest calculated dwell time, which represents the length of time the foam is in contact with the vein, almost twice that of physician-compounded foams using room air and eight times better than physician-compounded foams prepared using equivalent gas mixes. Conclusion Bubble size, bubble size distribution and stability of various sclerosing foam formulations show that polidocanol endovenous microfoam results in better overall performance compared with physician-compounded foams. Polidocanol endovenous microfoam offers better stability and cohesive properties in a biomimetic vein model compared to physician-compounded foams. Polidocanol endovenous microfoam, which is indicated in the United States for treatment of great saphenous vein system incompetence, provides clinicians with a consistent product with enhanced handling properties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Clinical use of DC BeadTM loaded with doxorubicin (DEBDOXTM) or irinotecan (DEBIRITM), for the treatment of primary and secondary tumours of the liver respectively, is showing great promise. Recently there has been a tendency to select smaller bead size ranges to treat tumours in an effort to allow more drug dose to be administered, improve tumoural penetration and resultant drug delivery and tumour coverage. Herein we describe the development and performance characterisation of a new DC Bead size range (DC BeadM1TM, 70–150 lm) capable of an increased bead delivery in the distal vasculature, corresponding to greater tumour coverage and drug dose delivered. Both unloaded and drug loaded DC BeadM1 were shown to have a greater density of distal volume of penetration although the ultimate distal level of penetration was the same as that of the 100–300 lm beads in an in vitro penetration model. Elution of doxorubicin was slower than irinotecan elution, but it was similar when comparing the same drug elution from 70 to 150 lm compared to 100–300 lm beads. Radiopaque versions of 70–150 and 100–300 lm beads were prepared in order to evaluate distribution ex vivo using l-CT and doxorubicin distribution using epifluorescent microscopy. Liver distribution of the radiopaque versions of the beads was shown to be more distal and efficient at filling smaller vessels with the DC BeadM1 and correspondingly more beads were found per vessel histologically with a larger area of drug coverage with the smaller size range. This study indicates that the smaller (70–150 lm) beads should permit an increased dose of drug to be administered to both hypervascular and hypovascular tumours as compared to 100–300 lm beads. [ABSTRACT FROM AUTHOR]

The gram-negative anaerobe Porphyromonas gingivalis colonizes the gingival crevice and is etiologically associated with periodontal disease that can lead to alveolar bone damage and resorption, promoting tooth loss. Although susceptible to antibiotics, P. gingivalis can evade antibiotic killing by residing within gingival keratin-ocytes. This provides a reservoir of organisms mat may recolonize me gingival crevice once antibiotic therapy is complete. Polymersomes are nanosized amphiphilic block copolymer vesicles that can encapsulate drugs. Cells internalize polymersomes by endocytosis into early endosomes, where they are disassembled by me low pH, causing intracellular release of their drug load. In this study, polymersomes were used as vehicles to deliver antibiotics in an attempt to kill intracellular P. gingivalis within monolayers of keratinocytes and organotypic oral mucosal models. Polymersome-encapsulated metronidazole or doxycycline, free metronidazole, or doxycycline, or polymersomes alone as controls, were used, and the number of surviving intracellular P. gingivalis was quantified after host cell lysis. Polymersome-encapsulated metronidazole or doxycycline significantly (P<0.05) reduced the number of intracellular P. gingivalis in both monolayer and organotypic cultures compared to free antibiotic or polymersome alone controls. Polymersomes are effective delivery vehicles for antibiotics that do not normally gain entry to host cells. This approach could be used to treat recurrent periodontitis or other diseases caused by intra-cellular-dwelling organisms. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of doxorubicin stability over time when stored into the DC Bead embolic agent, in various containers, which are used for the delivery of the doxorubicin-loaded beads to the patients for up to 14 days under refrigerated conditions.Methods: The doxorubicin was loaded through the ionic exchange mechanism into the calibrated polyvinyl alcohol-based hydrogel beads (DC Bead), with the loading process carried out either in the original DC Bead glass vials or within a polypropylene plastic syringe. The loaded samples were eluted at given time points and the extracted doxorubicin was analysed by high-performance liquid chromatography for concentration and chromatographic area response purity.Results: The variance on the doxorubicin concentration of the samples stored in the syringes under refrigerated conditions was less than 10% over the 14 days period. The chromatographic purity of doxorubicin eluted from the DC Bead in their primary glass vial packaging was measured at 99.7%. The dissolution test showed that the elution rate and amount recovered from samples stored in vials were statistically similar between Day 0 and Day 14. The chromatographic purity of the doxorubicin loaded into DC Bead in presence of non-ionic contrast medium was >99.0% for 7 days under refrigerated conditions.Conclusions: Doxorubicin-loaded DC Bead® are shown to have adequate physicochemical stability over a period of 14 days when stored in syringes or vials under refrigerated conditions for up to 14 days. The admixtures of doxorubicin-loaded beads with contrast medium are stable for up to 7 days under refrigerated conditions. [ABSTRACT FROM PUBLISHER]

There is an emerging need both in pharmacology and within the biomedical industry to develop new tools to target intracellular mechanisms. The efficient delivery of functionally active proteins within cells is potentially a powerful research strategy, especially through the use of antibodies. In this work, we report on a nanovector for the efficient encapsulation and delivery of antibodies into live cells with no significant loss of cell viability or any deleterious effect on cell metabolic activity. This delivery system is based on poly[2-(methacryl-oytoxy)ethyl phosphorylcholine]-block-[2-(diisopropylamino)ethyl methacrylate] (PMPC-PDPA), a pH-sensitive diblock copolymer that self-assembles to form nanometer-sized vesicles, also known as polymersomes, at physiological pH. Polymersomes can successfully deliver relatively high antibody payloads within different types of live cells. We demonstrate that these antibodies can target their respective epitope showing immunolabeling of γ-tubulin, actin, Golgi protein, and the transcription factor NF-κB in live cells. Finally, we demonstrate that intracellular delivery of antibodies can control specific subcellular events, as well as modulate cell activity and proinflammatory processes. [ABSTRACT FROM AUTHOR]

Ion-exchange microspheres (IEMs) are widely employed in controlled drug delivery of ionic drugs due to their high loading capacity and the possibility to obtain the controlled release of the loaded drug(s) at a specific site. Among IEMs, DC Bead™ are embolic microdevices (100-300 μm diameter) designed for transarterial chemoembolization (TACE) and composed of cross-linked poly(vinyl alcohol) (PVA) hydrogel, bearing anionic sulfonate moieties on the cross-links, and able to bind cationic drugs such as doxorubicin hydrochloride (Dox). Even if DC Bead™ were studied for their release and bulk characteristics, a thorough characterization of these devices is still lacking. In particular, the aim of this work was the determination of bound and free water, Dox distribution within the microdevices and drug-DC Bead™ interactions, in terms of transport features within the device. Compared with previous results, different Dox radial distributions in DC Bead™ were found, and related to bead microsctructure and ion exchange mechanism. Artifacts due to the self-quenching of Dox at high concentration were prevented and the diffusion coefficients of drug-polymer (Dox-ionic sites) evaluated in different sections of the microspheres. Furthermore, DSC results indicated that in the hydrogel either free (bulk) or bound (non-freezable) water could be found, and that no freezing-bound water was present. [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]

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°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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Embolization of blood vessels may result in a variety of side effects which can include pain and inflammation. The objective of this study was to assess the release and effect of ibuprofen (IBU) from Bead Block™ microspheres (BB) loaded with IBU (IBU‐BB) on the foreign body inflammatory reaction in a sheep uterine artery model. Both uterine arteries of 12 hormonally cycled ewes were embolized with 0.5 mL of 500–700 μm BB (n = 6) or IBU‐BB (n = 6). Animals were sacrificed at 1 week (1W) or 3 weeks (3W) (n = 3 each group). The gross examination of the organs was performed and distribution of the beads in the tissue was assessed. Inflammation was estimated histologically by quantitative and semiquantitative classification of inflammatory cells on HES and MGG stains and use of videoanalysis after immunohistolabeling with CD‐antibodies to a variety of inflammatory cells. At 1W, a significant decrease of inflammatory response was observed for IBU‐BB relative to BB in terms of number of lymphocytes and of immunohistochemical staining for CD172a, MHC‐II, CD3, and CD4. At 3W, the inflammatory response for IBU‐BB was similar to that for BB at 1W in terms of cell populations and moderate intensity. There was no or low amounts of staining for CD8 and CD45RA and none for CD21 in all four groups. Immunohistochemical detection of IBU showed that some drug was still present in the beads at 1W but none was detectable at 3W suggesting it had all eluted. These results signify that the inflammatory response is dampened by the action of IBU eluted from the beads and that IBU‐BB can delay postembolization inflammatory reaction. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2008 [ABSTRACT FROM AUTHOR]

DC BeadTM 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 μm 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 μm 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. [ABSTRACT FROM AUTHOR]

A drug eluting coronary stent was developed for use in preclinical and clinical trial evaluation. The stent was coated with a phosphorylcholine (PC)‐based polymer coating containing the cell migration inhibitor batimastat. A pharmacokinetic study was conducted in a rabbit iliac model using 14C‐radiolabeled version of the drug; this showed the drug release to be first order with 94% of it being released within 28 days. Unloaded and drug‐loaded stents were implanted in a porcine coronary artery model; a number were explanted at 5 days and scanning electron microscopy was used to show that the presence of the drug did not affect the rate of stent endothelialisation. The remainder of the stents were removed after 6 months and the stents carefully removed from the arterial tissue. Fourier‐transform infrared (FT‐IR) spectroscopy (both attenuated total reflectance and microscopic imaging) was used to show the presence of the PC coating on control unloaded, drug‐loaded and explanted stents, providing evidence that the coating was still present. This was further confirmed by use of atomic force microscopy (AFM) amplitude‐phase, distance (a‐p,d) curves which generated the characteristic traces of the PC coating. Further AFM depth‐profiling techniques found that the thicknesses of the PC coatings on an control unloaded stent was 252±19 nm, on an control batimastat‐loaded stent 906±224 nm and on an explanted stent 405±224 nm. The increase in thickness after the drug‐loading process was a consequence of drug incorporation in the film, and the return to the unloaded dimensions for the explanted sample indicative of elution of the drug from the coating. The drug delivery PC coating was therefore found to be stable following elution of the drug and after 6 months implantation in vivo. [ABSTRACT FROM AUTHOR]

Since the first reports on foam sclerotherapy, multiple studies have been conducted to determine the physical properties and behavior of foams, but relatively little is known about their biological effects on the endothelial cells lining the vessel wall. Moreover, a systematic comparison of the biological performance of foams produced with different methods has not been carried out yet. Herein, a 2D in vitro method was developed to compare efficacy of commercially available polidocanol injectable foam (PEM, Varithena) and physician-compounded foams (PCFs). Endothelial cell attachment upon treatment with foam was quantified as an indicator of therapeutic efficacy, and was correlated with foam physical characteristics and administration conditions. An ex vivo method was also developed to establish the disruption and permeabilisation of the endothelium caused by sclerosing agents. It relied on the quantitation of extravasated bovine serum albumin conjugated to Evans Blue, as an indicator of endothelial permeability. In our series of comparisons, PEM presented a greater overall efficacy compared to PCFs, across the different biological models, which was attributed to its drainage dynamics and gas formulation. This is consistent with earlier studies that indicated superior physical cohesiveness of PEM compared to PCFs. [ABSTRACT FROM AUTHOR]

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55–108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans. [ABSTRACT FROM AUTHOR]

The article “The effect of cationically modified phosphorylcholine polymers on human osteoblasts in vitro and their effect on bone formation in vivo”, written by Jonathan M. Lawton, Mariam Habib, Bingkui Ma, Roger A. Brooks, Serena M. Best, Andrew L. Lewis, Neil Rushton and William Bonfield, was originally published Online First without open access. After publication in volume 28, issue 9, page 144 it was noticed that the copyright was wrong in the PDF version of the article. The copyright of the article should read as “© The Author(s) 2017”. [ABSTRACT FROM AUTHOR]