Prostate artery chemoembolization in prostate cancer: A proof of concept study in spontaneous prostate cancer in a canine model.

PURPOSE: The purpose of this study was to assess the feasibility and efficacy of docetaxel-loaded bead chemoembolization in spontaneous prostate cancer in a canine model. MATERIALS AND METHODS: Five pet dogs with histopathologically proven prostate cancer were referred for prostate artery chemoembolization (PACE). After PACE, all animals were followed, including pharmacokinetic study and clinical and biological evolution, until death. Pelvic contrast-enhanced computed tomography examination was performed at one and two months. Animals were subjected to pathological examination after death. RESULTS: Both prostate arteries were successfully chemoembolized in all dogs. A median dose of 18 mg (Q1, Q3; 11.8, 20 mg) docetaxel loaded in 3 mL of 50-100 µm super absorbent polymer beads was injected into each dog. At one month, four of the five dogs were still alive and the median prostate volume was 51% lower (prePACE median prostate volume, 18.4 mL [Q1, Q3; 12, 32.1 mL] vs. postPACE median prostate volume, 6.2 mL [Q1, Q3; 6.2, 11 mL]). At two months, three dogs died because of disease progression. The two remaining dogs showed a 70% median decrease in prostate volume. Prostate pathological examination showed 73% of necrosis. No worsening of urinary symptoms was observed. Pharmacokinetic analysis showed limited systemic passage of docetaxel. All dogs died of metastatic spread at nine months. CONCLUSION: This study suggests that PACE is feasible and safe for the treatment of spontaneous prostate cancer in a canine model and may provide a new approach to treat selected patients with prostate cancer.

Safety and efficacy compared between irinotecan-loaded microspheres HepaSphere and DC bead in a model of VX2 liver metastases in the rabbit.

PURPOSE: To compare irinotecan-eluting HepaSphere (BioSphere Medical, Roissy-en-France, France) and DC Bead (Biocompatibles UK Ltd, London, United Kingdom) embolization microspheres for distribution in tumors, release properties, tolerance, and antitumor effects in a model of liver metastases in the rabbit. MATERIALS AND METHODS: Multiple liver tumors were created by injection of a VX2 cell suspension in the portal vein of rabbits. After 2 weeks, embolization of the proper hepatic artery was performed with a fixed volume of bland HepaSphere (n = 5), irinotecan-loaded HepaSphere (n = 6), or irinotecan-loaded DC Bead (n = 5) microspheres. Untreated animals injected with VX2 cells served as control animals (n = 5). Plasma pharmacokinetics of irinotecan and its metabolite SN38 were assessed. Histopathology and gene expression analysis were performed 3 days after treatment. RESULTS: Among all treated groups, there was no significant difference in liver enzymes or liver damage on histology. Irinotecan-loaded HepaSphere microspheres showed a faster release of drug than DC Bead microspheres leading to a twofold higher concentration of drug in plasma for HepaSphere microspheres. HepaSphere microspheres were less frequently found inside tumor nodules on histology than DC Bead microspheres (11% vs 48%, P < .001) because of their larger size. Tumor necrosis was significantly greater for rabbits given irinotecan-loaded HepaSphere microspheres (69% of total tumor surface) and rabbits given DC Bead microspheres (50% of total tumor surface) compared with control animals (24% of total tumor surface, P = .006 and P = .047). CONCLUSIONS: HepaSphere and DC Bead microspheres loaded with irinotecan caused significant necrosis of tumor nodules in a model of VX2 liver metastases. This outcome was mostly due to irinotecan delivery rather than vascular occlusion by the microspheres and was greater for HepaSphere microspheres compared with DC Bead microspheres.

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Acoustic characterization of a new trisacryl contrast agent. Part I: In vitro study.

The objective of the study was to acoustically characterize trisacryl polymeric microparticles (TMP), which are derived from biocompatible embolic agents. With significant acoustic properties, these polymeric particles could be potentially used as targeted ultrasound contrast agents, directed towards a specific site, with ligands conjugation on the polymeric network surface. In the in vitro study, a pulser/receiver (PRF of 1 kHz), associated to different transducers (5, 10 and 15 MHz), was used to measure the acoustic properties of the TMP inserted in a Couette flow device. Acoustic characterization according to TMP concentration (0.12-15.63 mg/ml), frequency (4.5-17 MHz, defined by each transducer bandwidth), ultrasound pressure (137-378 kPa) and exposure time (0-30 min) was conducted. Particle attenuation was also evaluated according to TMP concentration and emission frequency. Backscattering increased non linearly with concentration and maximum enhancement was of 16.4 dB+/-0.89 dB above 7.8 mg/ml. This parameter was found non-linear with increasing applied pressure and no harmonic oscillation could be noticed. Attenuation reached approximately 1.4 dB/cm at 15 MHz and for the 15.6 mg/ml suspension. The TMP have revealed in vitro ultrasound properties comparable to those observed with known contrast agents, studied in similar in vitro systems. However, such set-ups combined with a rather aqueous suspending medium, have some limitations and further investigations need now to be conducted to approach in vivo conditions in terms of flow and blood environment.

In vitro study of the compatibility of tris-acryl gelatin microspheres with various chemotherapeutic agents.

PURPOSE: To evaluate the in-vitro effects of chemotherapeutic agents on the physical structure of tris-acryl gelatin microspheres. MATERIALS AND METHODS: Microspheres (Embospheres) were mixed in vitro with carboplatin, mitomycin C, 5-fluorouracil, or pirarubicin as experimental samples and with distilled water as control samples and kept for 24 hours at 37 degrees C. The microspheres used measured 100-300 micro m and 700-900 micro m in diameter. Microsphere morphology, including appearance, overall shape, smoothness of surface, and thickness of gelatin coating, was examined with use of a microscope equipped with a cold light. Microsphere dimensions including larger diameter, smaller diameter, and surface area were measured by granulometry. Microsphere geometry was evaluated by calculating a sphericity index and surface regularity index. Qualitative and quantitative variables, respectively, were analyzed with the two-sided Fisher exact test and Wilcoxon signed-rank test for paired values, with a significance level of 0.05. RESULTS: No broken microspheres or microscopic degradations in the appearance, overall shape, smoothness of surface, or thickness of gelatin coating of any microspheres were observed. The respective distributions of large and small diameters, surface area, sphericity index, or surface regularity index of the microspheres were not significantly different between the experimental samples containing carboplatin, mitomycin C, 5-fluorouracil, or pirarubicin and the control sample of microspheres with similar diameters. CONCLUSION: Embosphere microspheres can be mixed with carboplatin, mitomycin C, 5-fluorouracil, or pirarubicin for chemoembolization therapy without any risk of damaging their morphology, dimensions, or geometric characteristics.