Response of Carex breviculmis to phosphorus deficiency and drought stress.

Introduction: The drought and phosphorus deficiency have inevitably become environmental issues globally in the future. The analysis of plants functional trait variation and response strategies under the stress of phosphorus deficiency and drought is important to explore their ability to respond to potential ecological stress. Methods: In this study, Carex breviculmis was selected as the research object, and a 14-week pot experiment was conducted in a greenhouse, with two phosphorus treatment (add 0.5mmol/L or 0.05µmol/L phosphorus) and four drought treatment (add 0-5%PEG6000), totaling eight treatments. Biomass allocation characteristics, leaf anatomical characteristics, biochemical parameters, root morphology, chemical element content, and photosynthetic parameters were measured. Results: The results showed that the anatomical characteristics, chemical elements, and photosynthetic parameters of Carex breviculmis responded more significantly to main effect of phosphorus deficiency. Stomatal width, leaf phosphorus content and maximum net photosynthetic rate decreased by 11.38%, 59.39%, 38.18% significantly (p<0.05), while the change in biomass was not significant (p>0.05). Biomass allocation characteristics and root morphology responded more significantly to main effect of drought. Severe drought significantly decreased leaf fresh weight by 61% and increased root shoot ratio by 223.3% compared to the control group (p<0.05). The combined effect of severe drought and phosphorus deficiency produced the highest leaf N/P ratio (291.1% of the control) and MDA concentration (243.6% of the control). Correlation analysis and redundancy analysis showed that the contributions of phosphorus and drought to functional trait variation were similar. Lower epidermal cell thickness was positively correlated with maximum net photosynthetic rate, leaf phosphorus, chlorophyll ab, and leaf fresh weight (p<0.05). Discussion: In terms of response strategy, Carex breviculmis was affected at the microscopic level under phosphorus deficiency stress, but could maintain the aboveground and underground biomass well through a series of mechanisms. When affected by drought, it adopted the strategy of reducing leaf yield and improving root efficiency to maintain life activities. Carex breviculmis could maintain its traits well under low phosphorus and moderate drought, or better conditions. So it may have good ecological service potential in corresponding areas if promoted. This study also provided a reference for plant response to combined drought and phosphorus deficiency stresses.

P2X7 receptor promotes migration and invasion of non-small cell lung cancer A549 cells through the PI3K/Akt pathways.

It has been demonstrated that the ATP-gated ion channel P2X7 receptor is involved in tumor progression and plays an important role in regulating tumor cell growth, invasion, migration and angiogenesis. However, P2X7 receptors have been relatively poorly studied in non-small cell lung cancer (NSCLC) cells. Therefore, the aim of this study was to investigate the effects of P2X7 receptor on A549 cells (NSCLC cell line) migration and invasion and to reveal the molecular mechanisms mediated by it. We detected the expression and function of P2X7 receptor in A549 cells. The effects and mechanisms of P2X7 receptor on A549 cells migration, invasion, and epithelial-mesenchymal transition were detected in vitro and in vivo. The results showed P2X7 receptor expressed by A549 cells had ion channel and macropore formation function. In addition, activation of P2X7 receptor by adenosine triphosphate (ATP) or 2'(3')-O-(4-Benzoylbenzoyl)-adenosine-5'-triphosphate (BzATP) promoted Epithelial-mesenchymal transition (EMT), migration and invasion of A549 cells, which was attenuated by treatment of cells with P2X7 receptor antagonist A438079 and Oxidized ATP. Furthermore, activation of P2X7 receptor increased phosphorylated protein kinase B (p-Akt) levels, and the phosphatidylinositol-tris-phosphate kinase 3 (PI3K)/protein kinase B (Akt) inhibitor LY294002 blocked migration and invasion of A549 cells induced by ATP or BzATP. At the same time, in vivo results showed that P2X7 receptor could also promote EMT and PI3K/Akt expression in transplanted tumors. Our study indicated that P2X7 receptor promotes A549 cells migration and invasion through the PI3K/Akt signaling pathway, suggesting that P2X7 receptor may be a potential therapeutic target for NSCLC.

Research Progress in the Relationship Between P2X7R and Cervical Cancer.

Cervical cancer is one of the most common and serious tumors in women. Finding new biomarkers and therapeutic targets plays an important role in the diagnosis, prognosis, and treatment of cervical cancer. Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a purine ligand cation channel, activated by adenosine triphosphate (ATP). Studies have shown that P2X7R plays an important role in a variety of diseases and cancers. More and more studies have shown that P2X7R is also closely related to cervical cancer; therefore, the role of P2X7R in the development of cervical cancer deserves further discussion. The expression level of P2X7R in uterine epithelial cancer tissues was lower than that of the corresponding normal tissues. P2X7R plays an important role in the apoptotic process of cervical cancer through various mechanisms of action, and both antagonists and agonists of P2X7R can inhibit the proliferation of cervical cancer cells, while P2X7R is involved in the antitumor effect of Atr-I on cervical cancer cells. This review evaluates the current role of P2X7R in cervical cancer in order to develop more specific therapies for cervical cancer. In conclusion, P2X7R may become a biomarker for cervical cancer screening, and even a new target for clinical treatment of cervical cancer.

Progress in the relationship between P2X7R and colorectal cancer.

Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a nonselective cation channel of the purinergic receptor family. P2X7R is activated by adenosine triphosphate (ATP) and plays a significant role in inflammatory and autoimmune diseases by triggering cellular signal transduction. More importantly, P2X7R is abnormally expressed in many tumor cells and is involved in the progression of various tumor cells. Studies have shown that the irregular expression of P2X7R in colorectal cancer (CRC) can not only indirectly affect the occurrence and development of CRC by promoting inflammatory bowel disease but also directly affect the proliferation and metastasis of CRC cells. P2X7R plays a bidirectional role in cancer induction and inhibition by mediating complex signaling pathways in CRC, and its expression level is closely related to the overall survival of CRC patients. Therefore, P2X7R may be a biomarker and potential therapeutic target for the development and prognosis of CRC. In this paper, we review the research progress on P2X7R in CRC.

Research progress on the P2X7 receptor in liver injury and hepatocellular carcinoma.

Purinergic ligand-gated ion channel 7 receptor (P2X7 receptor) is an adenosine triphosphate (ATP)-gated ion channel that is widely distributed on the surfaces of immune cells and tissues such as those in the liver, kidney, lung, intestine, and nervous system. Hepatocellular carcinoma (HCC) is one of the most common malignancies with increasing incidence and mortality. Although many treatments for liver cancer have been studied, the prognosis for liver cancer is still very poor. Therefore, new liver cancer treatments are urgently needed. P2X7 receptor activation can secrete proinflammatory factors through the P2X7 receptor-NLRP3 signaling pathway, thereby affecting the progression of liver injury. The P2X7 receptor may be a target for growth inhibition of HCC cells and may affect the invasion and migration of HCC cells through the PI3K/AKT and AMPK signaling pathways. In recent years, P2X7 receptor antagonists or inhibitors have attracted widespread attention as therapeutic targets for hepatocellular carcinoma and liver injury. Therefore, this review covers the basic concepts of the P2X7 receptor and role of the P2X7 receptor in liver cancer and liver injury, providing new potential therapeutic targets for hepatocellular carcinoma and liver injury.

In vitro characterization of immune modulating drug-eluting immunobeads towards transarterial embolization in cancer.

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.

Characterization of Lactate Metabolism Score in Breast and Thyroid Cancers to Assist Immunotherapy via Large-Scale Transcriptomic Data Analysis.

Breast cancer (BC) and thyroid cancer (TC) have the highest rate of incidence, especially in women. Previous studies have revealed that lactate provides energetic and anabolic support to cancer cells, thus serving as an important oncometabolite with both extracellular and intracellular signaling functions. However, the correlation of lactate metabolism scores with thyroid and breast cancer immune characteristics remains to be systematically analyzed. To investigate the role of lactate at the transcriptome level and its correlation with the clinical outcome of BC and TC, transcriptome data of 1,217 patients with breast cancer (BC) and 568 patients with thyroid cancer (TC) were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets with their corresponding clinical and somatic mutation data. The lactate metabolism score was calculated based on a single-sample gene set enrichment analysis (ssGSEA). The results showed that lactate metabolism-related genes and lactate metabolism scores was significantly associated with the survival of patients with BRCA and THCA. Notably, the lactate metabolism scores were strongly correlated with human leukocyte antigen (HLA) expression, tumor-infiltrating lymphocyte (TIL) infiltration, and interferon (IFN) response in BC and TC. Furthermore, the lactate metabolism score was an independent prognostic factor and could serve as a reliable predictor of overall survival, clinical characteristics, and immune cell infiltration, with the potential to be applied in immunotherapy or precise chemotherapy of BC and TC.

ATP-gated P2X7 receptor as a potential target for prostate cancer.

Prostate cancer is the most common malignancy of the male genitourinary system and is one of the leading causes of male cancer death. The P2X7 receptor is an important member of purine receptor family. It is a gated ion channel with adenosine triphosphate (ATP) as the ligand, which exists in a variety of immune tissues and cells and can be involved in tumorigenesis and tumor progression. Studies have shown that the P2X7 receptor is abnormally expressed in prostate cancer, and is related to the level of prostate-specific antigen, P2X7 receptor may be an early biomarker of prostate cancer. The P2X7 receptor is essential in the occurrence and development of prostate cancer. The P2X7 receptor mainly affects the invasion and metastasis of prostate cancer cells through epithelial mesenchymal transition/invasion-related genes and the PI3K/AKT and ERK1/2 signaling pathways. The P2X7 receptor could be a promising therapeutic target for prostate cancer.

In situ evaluation of spatiotemporal distribution of doxorubicin from Drug-eluting Beads in a tissue mimicking phantom.

Understanding the intra-tumoral distribution of chemotherapeutic drugs is extremely important in predicting therapeutic outcome. Tissue mimicking gel phantoms are useful for studying drug distribution in vitro but quantifying distribution is laborious due to the need to section phantoms over the relevant time course and individually quantify drug elution. In this study we compare a bespoke version of the traditional phantom sectioning approach, with a novel confocal microscopy technique that enables dynamic in situ measurements of drug concentration. Release of doxorubicin from Drug-eluting Embolization Beads (DEBs) was measured in phantoms composed of alginate and agarose over comparable time intervals. Drug release from several different types of bead were measured. The non-radiopaque DC Bead™ generated a higher concentration at the boundary between the beads and the phantom and larger drug penetration distance within the release period, compared with the radiopaque DC Bead LUMI™. This is likely due to the difference of compositional and structural characteristics of the hydrogel beads interacting differently with the loaded drug. Comparison of in vitro results against historical in vivo data show good agreement in terms of drug penetration, when confounding factors such as geometry, elimination and bead chemistry were accounted for. Hence these methods have demonstrated potential for both bead and gel phantom validation, and provide opportunities for optimisation of bead design and embolization protocols through in vitro-in vivo comparison.

Safety and Tolerability of Topotecan-Eluting Radiopaque Microspheres for Hepatic Chemoembolization in a Rabbit Preclinical Model.

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.

Music Performance Anxiety: Can Expressive Writing Intervention Help?

Performance is an essential part of music education; however, many music professionals and students suffer from music performance anxiety (MPA). The purpose of this study was to investigate whether a 10-min expressive writing intervention (EWI) can effectively reduce performance anxiety and improve overall performance outcomes in college-level piano students. Two groups of music students (16 piano major students and 19 group/secondary piano students) participated in the study. Piano major students performed a solo work from memory, while group/secondary piano students took a sight-reading exam of an eight-measure piano musical selection. All students performed twice, at baseline and post-EWI, with 2 or 3 days between performances. During the EWI phase, students were randomly divided into two groups: an expressive writing group and a control group. Students in the expressive writing group wrote down feelings and thoughts about their upcoming performances, while students in the control group wrote about a topic unrelated to performing. Each student's pulse was recorded immediately before performing, and each performance was videotaped. Three independent judges evaluated the recordings using a modified version of the Observational Scale for Piano Practicing (OSPP) by Gruson (1988). The results revealed that, by simply writing out their thoughts and feelings right before performing, students who had high MPA improved their performance quality significantly and reduced their MPA significantly. Our findings suggest that EWI may be a viable tool to alleviate music performance anxiety.

Handling and performance characteristics of a new small caliber radiopaque embolic microsphere.

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.

Evaluation of novel formulations for transarterial chemoembolization: combining elements of Lipiodol emulsions with Drug-eluting Beads.

There are currently two methods widely used in clinical practice to perform transarterial chemoembolization (TACE). One is based on mixing an aqueous drug with an iodized oil (Lipiodol) and creating an emulsion that is delivered intraarterially, followed by embolization with a particulate agent. The other is based on a one-step TACE using Drug-eluting Beads (DEBs) loaded with drug. It is not recommended to mix Lipiodol with DEBs due to incompatibility. For the first time, novel DEB: Lipiodol: doxorubicin (Dox) emulsions are identified using lyophilized polyvinyl alcohol (PVA) hydrogels (non-iodinated or iodinated) DEBs. METHODS: 15 DEB emulsions (50mg Dox) were assessed for stability and deliverability in vitro and in vivo in a swine model. Dox release from selected formulations was measured in vitro using a vascular flow model and in vivo in a VX2 rabbit tumor model. RESULTS: Both DEB formats were shown to be able to form emulsions, however only Iodinated DEBs consistently met defined handling criteria. Those based on the non-iodinated DEB achieved >99%+ Dox loading in <5 minutes but were generally less stable. Those prepared using iodinated DEBs, which are more hydrophobic, were able to form stable Pickering-like emulsions (separation time ≥ 20 minutes) and demonstrated handling, administration and imaging observations more akin to Lipiodol™ TACE emulsions in both embolization models. Controlled Dox release and hence beneficial in vivo pharmacokinetics associated with DEB-TACE were maintained. CONCLUSIONS: This study demonstrates that it is possible to formulate novel DEB emulsions suitable for TACE that combine positive elements of both Lipiodol™ based and DEB-TACE procedures.

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.

Characterizing Drug-Polymer Bead Interactions Using Isothermal Titration Calorimetry.

Isothermal titration calorimetry was used to investigate thermodynamic and kinetic binding interactions between 4 clinically relevant drugs: doxorubicin (Dox), irinotecan (Iri), mitoxantrone (Mitox), and topotecan (Topo) and a range of commercially available embolization microspheres. Five drug-eluting beads were chosen to consider the effect of bead size (ranging from 70-150 µm to 500-700 µm) and bead type (sulfonate-modified polyvinylalcohol hydrogel, known commercially as DC BeadM1™, and a sulfonate-modified polyethylene glycol hydrogel bead, known commercially as LifePearl™). The molar ratio of drug to SO3- was found to be 0.9:1, 0.8:1, 0.4:1, and 0.9:1 for Dox, Iri, Mitox, and Topo, respectively. These findings indicate the steric effects of drug shape, charge, and size on binding ability. Four distinct bead sizes all produced drug:bead binding ratios of >0.9:1 doxorubicin:SO3-, thus indicating that bead size does not affect binding stoichiometry. Interestingly, bead size did affect the rate of binding as bead size was found to be indirectly proportional to binding rate. Finally, it was found for the sulfonate-modified polyethylene glycol hydrogel beads that doxorubicin binding was faster (at certain ratios of drug to bead) than that for the sulfonate-modified polyvinylalcohol hydrogel yet was maximal at a drug to bead ratio of only 0.7:1.

Bench-to-clinic development of imageable drug-eluting embolization beads: finding the balance.

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.

Characterization of a novel intrinsically radiopaque Drug-eluting Bead for image-guided therapy: DC Bead LUMI™.

We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~150mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™). Despite the chemical modification increasing the density of the beads to ~1.3g/cm3 and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.

Evaluation of ion exchange processes in drug-eluting embolization beads by use of an improved flow-through elution method.

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.

DC BeadM1™: towards an optimal transcatheter hepatic tumour therapy.

Clinical use of DC Bead™ loaded with doxorubicin (DEBDOX™) or irinotecan (DEBIRI™), 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 BeadM1 (TM), 70-150 µm) 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 µm 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 µm compared to 100-300 µm beads. Radiopaque versions of 70-150 and 100-300 µm beads were prepared in order to evaluate distribution ex vivo using µ-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 µm) beads should permit an increased dose of drug to be administered to both hypervascular and hypovascular tumours as compared to 100-300 µm beads.