Polymerization Properties of n-Butyl Cyanoacrylate Mixed with Ethiodized Oil in the Lymphatic System: In Vivo Investigation in a Rabbit Model.

PURPOSE: To evaluate the polymerization properties of a mixture of n-butyl cyanoacrylate (nBCA) and ethiodized oil in the lymphatic system using an animal model. MATERIALS AND METHODS: Nineteen male Japanese White rabbits underwent 28 lymphatic embolization procedures under fluoroscopic guidance using manually injected mixtures of nBCA and ethiodized oil at ratios of 1:2 (nBCA density of 33%), 1:4 (20%), 1:6 (14%), and 1:8 (11%) via the popliteal lymph node. The time required for polymerization and the distance traveled by the mixture were evaluated and compared among the groups using the Kruskal-Wallis test. Histopathologic intergroup comparisons and time-course changes were also evaluated using embolized lymph nodes. RESULTS: Among 23 successful procedures, the mean polymerization times were 14 ± 3, 88 ± 93, 331 ± 292, and 932 seconds ± 540 and the mean distances traveled were 13 ± 10, 31 ± 44, 85 ± 89, and 108 mm ± 35 in the 33% (n = 5), 20% (n = 6), 14% (n = 6), and 11% (n = 6) groups, respectively. The 11% group demonstrated a significantly longer polymerization time than the 33%, 20%, and 14% groups and distance traveled than the 33% group. Pathologically, the embolized lymph nodes showed inflammatory changes and massive necrosis regardless of the nBCA density. CONCLUSIONS: Polymerization times and distances traveled were increased when nBCA was diluted with increasing quantitites of ethiodized oil in this rabbit model of lymphatic embolization. These relationships should be considered when dilution is prescribed for clinical use.

Tuning the lipophilic nature of pyclen-based 90Y3+ radiopharmaceuticals for ß-radiotherapy.

Pyclen-dipicolinate chelates proved to be very efficient chelators for the radiolabeling with ß--emitters such as 90Y. In this study, a pyclen-dipicolinate ligand functionalized with additional C12 alkyl chains was synthesized. The radiolabeling with 90Y proved that the addition of saturated carbon chains does not affect the efficiency of the radiolabeling, whereas a notable increase in lipophilicity of the resulting 90Y radiocomplex was observed. As a result, the compound could be extracted in Lipiodol® and encapsulated in biodegrable pegylated poly(malic acid) nanoparticles demonstrating the potential of lipophilic pyclen-dipicolinate derivatives as platforms for the design of radiopharmaceuticals for the treatment of liver or brain cancers by internal radiotherapy.

Empirical 188Re-HDD/lipiodol intra-arterial therapy based on tumor volume, in patients with solitary inoperable hepatocellular carcinoma.

OBJECTIVE: This study aimed to assess the potential benefits and tolerability of an empirical dose of approximately 0.8-1.2 mCi (29.6-44.4 MBq) of Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol (Re-HDD/lipiodol) per milliliter of tumor volume, administered after super-selection of the tumor feeding branches of hepatic artery for treatment of inoperable hepatocellular carcinoma (HCC). METHODS: Patients with advanced HCC or classified as inoperable, with no demonstrated extrahepatic disease and no significant comorbidities were eligible. The patients selected for this study had a single tumoral lesion, measuring less than 150 cc. The range of total activity administered was between 30 and 100 mCi (1.2-3.7) GBq Re-HDD/lipiodol, administered in the super selected branches of the hepatic artery supplying the tumor in 42 Patients. Whole-body scintigraphies and single-photon emission computed tomography-computed tomography (SPECT-CT) of the liver including tumor were performed at four-time points after injection. Absorbed doses to the various organs were calculated according to the Medical Internal Radiation Dose formalism. Blood and urine samples were collected at multiple time points until 72 h after injection. Hematological, hepatic and pulmonary toxicity was assessed until 12 weeks after administration using the Common Toxicity Criteria for Adverse Events (version 3.0) scale. Responses were evaluated on contrast enhanced computed tomography (CECT) and by alfa-fetoprotein (AFP) level monitoring. RESULTS: About 40.6 ± 4.8% of the injected activity was excreted in the urine by 72 h after injection. The mean absorbed dose to the liver, lungs, stomach, kidney and intestine was 14.4 ± 1.8, 4.8 ± 0.6, 5.5 ± 1.1, 5.1 ± 0.7, and 6.5 ± 1.0 Gy (mean ± SD), respectively. Up to 6 days after administration, 26 of 44 patients had adverse events consisting of aggravations of preexisting laboratory changes (24 patients), fatigue (5 patients), vomiting (6 patients), fever (2 patients), right hypochondrial pain (8 patients), and pain at site of femoral catheter insertion (8 patients). Toxicity assessment at weeks 6 and 12 revealed two cases of mild worsening of liver function tests and no lung or hematological toxicity noted. Two patients were lost to follow-up after the 6-week visit. The response was assessed on CECT in all the remaining patients and the classification of results was more standardized when using European Association for the Study of the Liver (EASL) criteria rather than response evaluation criteria in solid tumors (RECIST) criteria. According to EASL criteria, 8 patients had a partial response, 28 patients had a complete response, 4 patients had progressive disease and 4 patients with stable disease were reported. Thirty-six patients had a baseline elevated AFP and on follow-up at 6 weeks, 6 of these patients showed stable AFP, progression in 4 patients and 26 showed a reduction. CONCLUSION: After the administration of 1.2-3.7 GBq Re-HDD/lipiodol based on empirical activity calculation of 0.8-1.2 mCi/mL of tumor volume, more than half of the patients in the present study had an objective response on imaging and biochemically. No significant adverse side effects were noted and most of the laboratory markers as well as symptoms returned to normal after 48-72 h post-administration. Selective administration of the radiopharmaceutical into the tumor feeding arteries gives a good anti-tumoral effect with minimal side effects and damage to surrounding normal liver tissue.

Glue Embolization of Lymphopseudoaneurysm for Chylous Ascites after Retroperitoneal Surgery.

OBJECTIVE: To assess the safety and efficacy of lymphopseudoaneurysm (LPA) glue (n-butyl cyanoacrylate [NBCA]) embolization in the management of chylous ascites after retroperitoneal surgery. MATERIALS AND METHODS: A retrospective analysis from January 2014 to October 2018 was performed in six patients (4 females and 2 males; mean age, 45.3 ± 14.2 years; range, 26-61 years) who underwent LPA embolization for chylous ascites developing after retroperitoneal surgery involving the perirenal space (four donor nephrectomies, one partial nephrectomy, and one retroperitoneal lymphadenectomy). After placing a percutaneous drainage catheter into the LPA or adjacent lymphocele, embolization was performed by filling the LPA itself with a mixture of glue and Lipiodol (Guerbet). RESULTS: Daily drainage from percutaneously placed drains exceeded 300 mL/day despite medical and surgical treatment (volume: mean, 1173 ± 1098 mL; range, 305-2800 mL). Intranodal lymphangiography was performed in four of the six patients and revealed leakage in 2 patients. Percutaneous embolization of the LPA was successful in all patients using an NBCA and Lipiodol mixture in a ratio of 1:1-1:2 (volume: mean, 4.3 ± 1.1 mL; range, 3-6 mL). Chylous ascites was resolved and the drainage catheter was removed in all patients within 4 days after the procedure (mean, 2.0 ± 1.8 days; range, 0-4 days). No procedure-related complications or recurrence of chylous ascites occurred during a mean follow-up period of 37.3 months (range, 21.1-48.4 months). CONCLUSION: Glue embolization of LPA has the potential to be a feasible and effective treatment method for the management of chylous ascites after retroperitoneal surgery.

Chemical stability of oil-infused polyethylene.

Ultra-high molecular weight polyethylene (UHMWPE) can be made radiopaque for medical imaging applications through the diffusion of an iodised oil-based contrast agent (Lipiodol Ultra Fluid). A similar process is used for Vitamin E incorporated polyethylene which provides antioxidant properties. This study aimed to investigate the critical long-term properties of oil-infused medical polyethylene after 4 weeks of accelerated thermal ageing. Samples treated with an oil (Vitamin E or Lipiodol) had a higher oxidation stability than currently used medical grade polyethylene, indicated by a smaller increase in oxidation index after ageing (Vitamin E + 36%, Lipiodol +40%, Untreated +136%, Thermally treated +164%). The tensile properties of oil treated polyethylene after ageing were significantly higher than the Untreated and Thermally treated controls (p<0.05) indicating less mechanical degradation. There was also no alteration in the percentage crystallinity of oil treated samples after ageing, though the radiopacity of the Lipiodol treated samples reduced by 54% after ageing. The leaching of oil with time was also investigated; the leaching of Lipiodol and Vitamin E followed the same trend and reached a steady state by two weeks. Overall, it can be concluded that the diffusion of an oil-based fluid into polyethylene not only increases the oxidative and chemical stability of polyethylene but also adds additional functionality (e.g. radiopacity) providing a more suitable material for long-term medical applications.

Pickering emulsions with ethiodized oil and nanoparticles for slow release of intratumoral anti-CTLA4 immune checkpoint antibodies.

BACKGROUND: Intratumorous immunotherapy for cancer is currently thriving. The aim of such local strategy is to improve the therapeutic index of these treatments, for higher on-target/on-tumor activity and less on-target/off-tumor adverse events. Strategies allowing for slow release of anti-CTLA4 in the tumor microenvironment could improve their clinical efficacy.The purpose of the study was to develop a radiopaque delivery platform to improve the targeting and exposure of intratumorous anti-CTLA4 antibodies for cancer immunotherapy. METHODS: Pickering emulsions of anti-CTLA4 antibodies were formulated with radiopaque ethiodized oil and poly-lactic-co-glycolic acid (PLGA) nanoparticles. We characterized the microscopic aspect and stability of such emulsions using Turbiscan. We monitored the release of anti-CTLA4 over time from these emulsions and evaluated their structure using mass spectrometry. We then tested the functionality of the released antibodies by preforming ex vivo competitive binding assays. Finally, we assessed the in vivo efficacy of intratumorous anti-CTLA4 Pickering emulsions. RESULTS: Pickering emulsions of ethiodized oil and PLGA nanoparticles (PEEPs) resulted in a radiopaque water-in-oil emulsion with average internal phase droplet size of 42±5 µm at day 7. Confocal microscopy showed that anti-CTLA4 antibodies were effectively encapsulated by ethiodized oil with PLGA nanoparticles located at the interface between the aqueous and the oily phase. Turbiscan analysis showed that emulsions were stable with continuous and progressive release of anti-CTLA4 antibodies reaching 70% at 3 weeks. Structural and functional analysis of the released antibodies did not show significant differences with native anti-CTLA4 antibodies. Finally, intratumorous anti-CTLA4 PEEPs were able to eradicate tumors and cure mice in a syngeneic immunocompetent preclinical tumor model. CONCLUSION: Pickering emulsions of ethiodized oil and PLGA is an innovative radiopaque delivery platform that does not alter the functionality of anti-CTLA4 immune checkpoint antibodies. Beyond local anti-CTLA4 applications, these emulsions might be used with other therapeutic molecules for optimal intratumorous or intra-arterial delivery of novel cancer immunotherapies.

Characterisation of the physical, chemical and mechanical properties of a radiopaque polyethylene.

Ultra-high molecular weight polyethylene has a low X-ray attenuation, hence, the performance of the polyethylene implants used for joint replacements cannot be directly investigated using X-ray-based imaging techniques. In this study, the X-ray attenuation of polyethylene was increased by diffusing an FDA-approved oil-based contrast agent (Lipiodol ultra fluid) into the surface of the samples, and the suitability of this novel radiopaque ultra-high molecular weight polyethylene for clinical applications was examined. Different levels of radiopacity were created by controlling the diffusion parameters, and the level of radiopacity was quantified from computed tomography scans and reported in Hounsfield units. The physical, chemical and tensile properties of the radiopaque ultra-high molecular weight polyethylene were examined and compared to untreated and thermally treated controls. The results of this study confirmed that for the samples treated at 115°C or less the diffusion of the contrast agent did not significantly alter the crystallinity (p = 0.7) or melting point (p = 0.4) of the polyethylene. Concomitantly, the tensile properties were not significantly different from the control samples (p > 0.05 for all properties). In conclusion, the radiopaque ultra-high molecular weight polyethylene treated for less than 18 h at a temperature of 115°C or below is a promising candidate for joint replacement applications as it can be identified in a standard X-ray while retaining the tensile properties of clinically used radiolucent ultra-high molecular weight polyethylene.

A Canine Model for Lymphangiography and Thoracic Duct Access.

OBJECTIVE: To evaluate the technical feasibility of intranodal lymphangiography and thoracic duct (TD) access in a canine model. MATERIALS AND METHODS: Five male mongrel dogs were studied. The dog was placed in the supine position, and the most prominent lymph node in the groin was accessed using a 26-gauge spinal needle under ultrasonography (US) guidance. If the cisterna chyli (CC) was not opacified by bilateral lymphangiography, the medial iliac lymph nodes were directly punctured and Lipiodol was injected. After opacification, the CC was directly punctured with a 22-gauge needle. A 0.018-in microguidewire was advanced through the CC and TD. A 4-Fr introducer and dilator were then advanced over the wire. The microguidewire was changed to a 0.035-in guidewire, and this was advanced into the left subclavian vein through the terminal valve of the TD. Retrograde TD access was performed using a snare kit. RESULTS: US-guided lymphangiography (including intranodal injection of Lipiodol [Guerbet]) was successful in all five dogs. However, in three of the five dogs (60%), the medial iliac lymph nodes were not fully opacified due to overt Lipiodol extravasation at the initial injection site. In these dogs, contralateral superficial inguinal intranodal injection was performed. However, two of these three dogs subsequently underwent direct medial iliac lymph node puncture under fluoroscopy guidance to deliver additional Lipiodol into the lymphatic system. Transabdominal CC puncture and cannulation with a 4-Fr introducer was successful in all five dogs. Transvenous retrograde catheterization of the TD (performed using a snare kit) was also successful in all five dogs. CONCLUSION: A canine model may be appropriate for intranodal lymphangiography and TD access. Most lymphatic intervention techniques can be performed in a canine using the same instruments that are employed in a clinical setting.

Sustained release of arsenic trioxide benefits interventional therapy on rabbit VX2 liver tumor.

The benefit of chemotherapy as a constituent of transcatheter arterial chemoembolization (TACE) is still in debate. Recently we have developed arsenic trioxide nanoparticle prodrug (ATONP) as a new anticancer drug, but its systemic toxicity is a big issue. In this preclinical TACE study, ATONP emulsified in lipiodol behaved as drug-eluting bead manner. Sustained release of arsenic from ATONP within occluded tumor caused very low arsenic level in plasma, avoiding the "rushing out" effect as ATO did. Correspondingly, intratumoral arsenic accumulation and inorganic phosphate deprivation were simultaneously observed, and arsenic concentration was much higher as ATONP was transarterially administered than ATO, or intravenously injected. Tumor necrosis and apoptosis were remarkably more severe in ATONP group than ATO, but no significant hepatic and renal toxicity was perceived. In brief, ATONP alleviated arsenic toxicity and boosted the therapeutic effect of TACE via Pi-activated drug sustainable release.

Is the Cessation of Blood Flow Faster than the Polymerization of an n-Butyl Cyanoacrylate-Lipiodol Mixture? An In Vitro Phantom Study.

PURPOSE: To compare the polymerization time of n-butyl cyanoacrylate (NBCA) and lipiodol mixture in a static model and a pulsating flow model simulating embolization procedure of small caliber arteries. MATERIALS AND METHODS: The polymerization time of NBCA-lipiodol mixture was measured by the morphological changes of a glue droplet in a petri dish. For the flow model, we used a 2-mm-inner-diameter polyvinyl alcohol tube connected to a pulsation pump. Bovine serum was supplied from the pump and circulated into the system at 30 ml/min and 60 bpm. A 0.64-mm-inner-diameter silicon microcatheter was inserted into this system, and then, 0.5 ml of glue was injected into the tube. The flow cessation time was defined as the time it took to stop the serum draining from the end of the tube. Six samples of 100, 66, 50, 40, 33, and 20 vol% NBCA were assessed. RESULTS: The median polymerization times for each concentration were 0.12, 3.72, 12.30, 27.41, 57.68, and 63.67 s, respectively. The median flow cessation times were 0.28, 0.78, 1.43, 3.75, 4.50, and 9.29 s, respectively. The flow cessation time was significantly shorter than the polymerization time for all samples except for 100 vol% cyanoacrylate (p < 0.05). CONCLUSION: The flow cessation time of cyanoacrylate glue was significantly shorter than the polymerization time in an in vitro experiment. The injected glue possibly stops the blood flow before the completion of polymerization in the vascular system.

Conventional versus drug-eluting beads chemoembolization for infiltrative hepatocellular carcinoma: a comparison of efficacy and safety.

BACKGROUND: To compare the efficacy and safety between conventional transarterial chemoembolization (cTACE) and drug-eluting beads TACE (DEB-TACE) in patients with infiltrative hepatocellular carcinoma (iHCC). METHODS: A total of 89 iHCC patients who were treated with either cTACE (n = 33) or DEB-TACE (n = 56) between April 2013 and September 2017 were included in this retrospective study. Patients with the situations that might have a poor outcome were defined as advanced disease including Child-Pugh class B, bilobar lesions, tumor size greater than 10 cm, ECOG 1-2, tumor burden of 50-70%, and the presence of ascites, arterioportal shunt (APS), and portal venous tumor thrombus (PVTT). The tumor response was measured 1-month and 3-month after the procedure. Progression-free survival (PFS) was calculated. Toxicity was graded by Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). The differences in tumor response, PFS, and toxicity were compared between the DEB-TACE group and cTACE group. RESULTS: At 1-month and 3-month after the procedure, the objective response rate (ORR) in the overall study population was similar in DEB-TACE group and cTACE group. The disease control rate (DCR), at 1-month after the procedure, was significantly higher in the patients treated with DEB-TACE relative to those treated with cTACE (P = 0.034), while after 3 months, the difference did not differ between two groups. DEB-TACE showed a higher DCR than cTACE in patients with tumor size greater than 10 cm (P = 0.036) or associated with APS (P = 0.030) at 1-month after the procedure, while after 3 months, the difference was only noted in patients with APS (P = 0.036). The median PFS in DEB-TACE group was 96 days, while in cTACE group was 94 days, and there was no difference in PFS between two groups (P = 0.831). In the side effect analysis, abdominal pain (P = 0.034) and fever (P = 0.009) were more frequently present in the cTACE group than DEB-TACE group, but there was no difference in high grade liver toxicity between the two groups. CONCLUSIONS: Compared to cTACE, DEB-TACE offers slightly better DCR and tolerability for iHCC patients, particularly in patients associated with APS and large tumor size. However, DEB-TACE does not provide higher PFS than cTACE.

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.

A Nanoemulsion with A Porphyrin Shell for Cancer Theranostics.

A nanoemulsion with a porphyrin shell (NewPS) was created by the self-assembly of porphyrin salt around an oil core. The NewPS system has excellent colloidal stability, is amenable to different porphyrin salts and oils, and is capable of co-loading with chemotherapeutics. The porphyrin salt shell enables porphyrin-dependent optical tunability. The NewPS consisting of pyropheophorbide a mono-salt has a porphyrin shell of ordered J-aggregates, which produced a narrow, red-shifted Q-band with increased absorbance. Upon nanostructure dissociation, the fluorescence and photodynamic reactivity of the porphyrin monomers are restored. The spectrally distinct photoacoustic imaging (at 715 nm by intact NewPS) and fluorescence increase (at 671 nm by disrupted NewPS) allow the monitoring of NewPS accumulation and disruption in mice bearing KB tumors to guide effective photodynamic therapy. Substituting the oil core with Lipiodol affords additional CT contrast, whereas loading paclitaxel into NewPS facilitates drug delivery.

Photon and electron backscatter dose and energy spectrum analysis around Lipiodol using flattened and unflattened beams.

PURPOSE: The aim of the current study was to evaluate the backscatter dose and energy spectrum from the Lipiodol with flattening filter (FF) and flattening filter-free (FFF) beams. Moreover, the backscatter range, that was defined as the backscatter distance (BD) are revealed. METHODS: 6 MVX FF and FFF beams were delivered by TrueBeam. Two dose calculation methods with Monte Carlo calculation were used with a virtual phantom in which the Lipiodol (3 × 3 × 3 cm3 ) was located at a depth of 5.0 cm in a water-equivalent phantom (20 × 20 × 20 cm3 ). The first dose calculation was an analysis of the dose and energy spectrum with the complete scattering of photons and electrons, and the other was a specified dose analysis only with scattering from a specified region. The specified dose analysis was divided into a scattering of primary photons and a scattering of electrons. RESULTS: The lower-energy photons contributed to the backscatter, while the high-energy photons contributed the difference of the backscatter dose between the FF and FFF beams. Although the difference in the dose from the scattered electrons between the FF and FFF beams was within 1%, the difference of the dose from the scattered photons between the FF and FFF beams was 5.4% at a depth of 4.98 cm. CONCLUSIONS: The backscatter range from the Lipiodol was within 3 mm and depended on the Compton scatter from the primary photons. The backscatter dose from the Lipiodol can be useful in clinical applications in cases where the backscatter region is located within a tumor.

Biodegradable Pickering emulsions of Lipiodol for liver trans-arterial chemo-embolization.

Water-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 µm at 25 mg/mL to 69 µm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2. STATEMENT OF SIGNIFICANCE: We present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants. These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations.

Angio-Computed Tomograph-Guided Immediate Lipiodol Computed Tomograph for Diagnosis of Small Hepatocellular Carcinoma Lesions during Transarterial Chemoembolization.

BACKGROUND: The diagnosis and treatment of small hepatocellular carcinoma (HCC) play a vital role in the prognosis of patients with HCC. The purpose of our study was to evaluate angio-computed tomography (angio-CT)-guided immediate lipiodol CT (a CT scan performed immediately after transarterial chemoembolization [TACE]) in the diagnosis of potential HCCs ≤1 cm in diameter. METHODS: This study retrospectively analyzed 31 patients diagnosed with HCCs after routine imaging (contrast-enhanced CT or magnetic resonance imaging) or pathologic examinations with undefined or undetermined tumor lesions (diameter ≤1 cm) from February 2016 to September 2016. After TACE guided by digital subtraction angiography of the angio-CT system, potential HCC lesions with a diameter ≤1 cm were diagnosed by immediate lipiodol CT. The number of well-demarcated lesions was recorded to calculate the true positive rate. The correlation between the number of small HCCs detected by immediate lipiodol CT and the size of HCC lesions (diameter >1 cm) diagnosed preoperatively was analyzed 1 month after TACE. A paired t-test was used to analyze differences in liver function. Pearson analysis was used to analyze correlation. Chi-square test was used to compare the rates. RESULTS: Fifty-eight lesions were detected on preoperative routine imaging examinations in 31 patients including 15 lesions with a diameter ≤1 cm. Ninety-one lesions were detected on immediate lipiodol CT, of which 48 had a diameter ≤1 cm. After 1 month, CT showed that 45 lesions had lipiodol deposition and three lesions had lipiodol clearance. Correlation analysis showed that the number of small HCCs detected by lipiodol CT was positively correlated with the size of HCC lesions diagnosed by conventional imaging examination (R2 = 0.54, P < 0.05). CONCLUSION: Immediate lipiodol CT may be a useful tool in the diagnosis of potential HCC lesions with a diameter of ≤1 cm.

Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment.

It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.

The ten commandments of chemoembolization: expert discussion and report from Mediterranean Interventional Oncology (MIOLive) congress 2017.

Transarterial therapies in the setting of primary and secondary liver malignancies are becoming an essential part of the oncology landscape. The mechanism of action of c-TACE is the induction of tumor necrosis due to the high concentration of the chemotherapeutic that is delivered only locally and to the embolic effect that causes ischemia and increased dwell time of the chemotherapeutic in the tumor. Recently, DEB-TACE has emerged as a variation of c-TACE with the potential for the selective delivery of large amounts of drugs to the tumor for a prolonged period, thereby decreasing plasma levels of the chemotherapeutic agent and related systemic effects. There is an increasing consensus that compared with conventional lipiodol-based regimen, DEB-TACE offers standardized methodology, is more reproducible and is associated with improved response and significantly better safety profile. Using an easy to access point by point format, this manuscript summarizes the expert discussion from the Mediterranean Interventional Oncology Live Congress (MIOLive 2017) about the role of TACE in the treatment of liver tumors.

A systematic characterization of the factors influencing polymerization and dynamic behavior of n-butyl cyanoacrylate.

INTRODUCTION: Brain arteriovenous malformations are abnormal connections between arteries and veins without an intervening capillary bed. Endovascular glue embolization with N-butyl cyanoacrylate (NBCA) is an accepted form of treatment. The reported complication rates vary widely from 2% to 15%, and timing of polymerization appears to play a major role. Additionally, the interaction between NBCA and vessel surface as well as the presence of biological catalysts are poorly understood. METHODS: Polymerization time was measured for mixtures of Lipiodol/NBCA of 50/50, 70/30, and 60/40. The influence of pH, temperature, and the presence of biological catalysts on polymerization time was investigated. Contact angles were measured on polyvinyl alcohol cryogel (PVA-C), silicone, and endothelial surfaces in a submerged aqueous environment to assess physical surface interactions. High speed video analysis of glue injection through a microcatheter was performed to characterize simulated coaxial flow. RESULTS: NBCA polymerization rate increased with pH and temperature. A hydrophilic surface such as PVA-C was better than silicone at mimicking the physical properties of endothelium. Live endothelium provided a catalytic surface that at least doubled the rate of polymerization. Blood products further increased the polymerization rate in the following order (slowest to fastest): plasma, platelets, red blood cells (RBCs), and lysed RBCs. These factors could explain the discrepancy between in vitro and in vivo results reported in the current literature. High speed video analysis of NBCA injection showed dripping to jetting transition with significant wall effect which deviated from previous ideal assumptions. CONCLUSIONS: The determinants of NBCA polymerization rate are multifactorial and dependent mainly on the presence of biological catalysts coupled with flow related wall interaction.

Studies of KP46 and KP1019 and the Hydrolysis Product of KP1019 in Lipiodol Emulsions: Preparation and Initial Characterizations as Potential Theragnostic Agents.

BACKGROUND: Lipiodol (iodized poppy seed oil) accumulates predominately in the tumor rather than in the liver tissue [1, 2]. Therefore, mixing anticancer drugs with Lipiodol may enhance the antitumor effect by increasing the local drug concentration. OBJECTIVE: In this pilot study, we made use of Lipiodol as a potential carrier of three promising antitumor metal complexes (tris(8-quinolato)gallium(III) (KP46), tetrachlorobis(indazole)ruthenate(III) (KP1019) and the hydrolysis product of KP1019, mer,trans-[RuCl3(H2O)(Hind)2]. METHODS: The stability of the drugs in Lipiodol and the release profile into the aqueous phase were examined independently by three different analytical techniques (high pressure liquid chromatography, HPLC; atom absorption spectroscopy, AAS; and electron spray ionization mass spectrometry, ESI-MS). RESULTS: The complexes were stable and remained in the Lipiodol emulsion over 3 days. In contrast to KP1019 and KP46, evaluation of Lipiodol emulsions of mer,trans-[RuCl3 (H2O) (Hind) 2] was not possible due to the insolubility of the compound in Lipiodol. KP1019 released rapidly into the aqueous phase in the first week and after 1 month it was not possible to detect the complex in the emulsion. KP46 showed a gradual release with the time resulting in the release of about 6.4 % of KP46 into the aqueous phase after 1 month of incubation. CONCLUSION: The initial results show that Lipiodol can be successfully employed as a carrier of anticancer Ru- or Ga-complexes. Furthermore, advantages can overcome the poor water solubility of the metal complexes, opening new perspectives for the use of Lipiodol emulsions in molecular imaging and cancer therapy as theragnostic agents.