Magnetically Assisted Drug Delivery of Topical Eye Drops Maintains Retinal Function In Vivo in Mice.

Barded-Biedl syndrome (BBS) is a rare genetic disorder with an unmet medical need for retinal degeneration. Small-molecule drugs were previously identified to slow down the apoptosis of photoreceptors in BBS mouse models. Clinical translation was not practical due to the necessity of repetitive invasive intravitreal injections for pediatric populations. Non-invasive methods of retinal drug targeting are a prerequisite for acceptable adaptation to the targeted pediatric patient population. Here, we present the development and functional testing of a non-invasive, topical, magnetically assisted delivery system, harnessing the ability of magnetic nanoparticles (MNPs) to cargo two drugs (guanabenz and valproic acid) with anti-unfolded protein response (UPR) properties towards the retina. Using magnetic resonance imaging (MRI), we showed the MNPs' presence in the retina of Bbs wild-type mice, and their photoreceptor localization was validated using transmission electron microscopy (TEM). Subsequent electroretinogram recordings (ERGs) demonstrated that we achieved beneficial biological effects with the magnetically assisted treatment translating the maintained light detection in Bbs-/- mice (KO). To our knowledge, this is the first demonstration of efficient magnetic drug targeting in the photoreceptors in vivo after topical administration. This non-invasive, needle-free technology expands the application of SMDs for the treatment of a vast spectrum of retinal degenerations and other ocular diseases.

Percutaneous ablation for locally advanced hepatocellular carcinoma with tumor portal invasion.

INTRODUCTION: We aim to assess the outcomes of percutaneous ablation of locally advanced HCC in a tertiary center, which is usually not indicated. We compared to sorafenib or trans-arterial radioembolization (TARE). METHODS: We included 272 patients with HCC and tumor portal invasion treated by percutaneous ablation (n = 44) assessed retrospectively from one center compared to a control group from the SARAH trial including patients treated with sorafenib (n = 123) or TARE (n = 105). A propensity-score matching was performed in a subgroup of patients with similar baselines characteristics. RESULTS: 84% of patients treated by ablation were male with a unique nodule (median size 50 mm) in 72.7% of the case. Complete tumor ablation was achieved in 75% of the patients with 20% Dindo-Clavien III-V adverse events including 6.8% of 90-days mortality. Sum of tumor size ≥70 mm was associated with incomplete ablation (p = 0.0239) and a higher risk of death (p = 0.0375). Patients in control group had a higher tumor burden, and more Vp3/4 compared to ablation group. Median overall survival was similar in the ablation and in the control group (16.4 and 14.0 months respectively, p = 0.48). The median progression-free survival was 6.6 months in ablation group compared to 4.2 months in the control group (p = 0.12). CONCLUSION: Percutaneous ablation for locally advanced HCC was feasible and associated with similar long-term outcomes to sorafenib or TARE.

Combination of Model for End-Stage Liver Disease and Lactate Predicts Death in Patients Treated With Salvage Transjugular Intrahepatic Portosystemic Shunt for Refractory Variceal Bleeding.

BACKGROUND AND AIMS: Data about the prognosis of salvage transjugular intrahepatic portosystemic shunt (TIPS) using covered stents for refractory variceal bleeding caused by portal hypertension are scarce. We aimed to assess survival and to identify predictors of mortality in these patients. APPROACH AND RESULTS: One hundred sixty-four patients with cirrhosis from five centers treated with salvage TIPS between 2007 and 2017 were retrospectively divided into a derivation cohort (83 patients) and a validation cohort (81 patients). Comparisons were performed using the Mann-Whitney and Fischer's exact test. Six-week overall survival (OS) was correlated with variables on the day of the TIPS using Kaplan-Meier curves with log-rank test and univariate/multivariate analyses using the Cox model. Eighty-three patients were included in the derivation cohort (male, 78%; age, 55 years, alcohol-associated cirrhosis, 88%; Model for End-Stage Liver Disease [MELD], 19 [15-27]; arterial lactate, 3.7 mmol/L [2.0-8.3]). Six-week OS rate was 58%. At multivariate analysis, the MELD score (OR, 1.064; 95% CI, 1.005-1.126; P = 0.028) and arterial lactate (OR, 1.063; 95% CI, 1.013-1.114; P = 0.032) were associated with 6-week OS. Six-week OS rates were 100% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 5% in patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. The 81 patients of the validation cohort had similar MELD and arterial lactate level but lower creatinine level (94 vs 106 µmol/L, P = 0.008); 6-week OS was 67%. Six-week OS rates were 86% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 10% for patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. In the overall cohort, rebleeding rate was 15.8% at 6 weeks, and the acute-on-chronic liver failure grade (OR, 1.699; 95% CI, 1.056-1.663; P = 0.040) was independently associated with rebleeding. CONCLUSIONS: After salvage TIPS, 6-week mortality remains high and can be predicted by MELD score and lactate. Survival rate at 6 weeks was >85% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15, while mortality was >90% for lactate ≥12 mmol/L and/or MELD score ≥ 30.

Acute pericarditis: A rare complication of gastric variceal obturation with cyanoacrylate glue.

Endoscopic obturation by cyanoacrylate glue is currently the treatment of reference of gastric varices bleeding in patients with portal hypertension with a good efficacy for bleeding control and secondary prophylaxis. However, several adverse events related to this treatment have been described including immediate rebleeding and glue embolism. Here we present a case of gastric variceal obturation by cyanoacrylate inducing an acute pericarditis due to glue embolism in mediastinal, pericardial and phrenic veins that was managed conservatively. We also discussed pathophysiological explanations and surveillance modality.

TIPS for management of portal-hypertension-related complications in patients with cirrhosis.

Portal hypertension is primarily due to liver cirrhosis, and is responsible for complications that include variceal bleeding, ascites and hepatorenal syndrome. The transjugular intrahepatic portosystemic shunt (TIPS) is a low-resistance channel between the portal vein and the hepatic vein, created by interventional radiology, that aims to reduce portal pressure. TIPS is a potential treatment for severe portal-hypertension-related complications, including esophageal and gastric variceal bleeding. TIPS is currently indicated as salvage therapy in this setting when patients fail to respond to standard endoscopic and medical treatment. More recently, early TIPS has been shown to be effective in decreasing risk of rebleeding after variceal hemorrhage and mortality in Child-Pugh B patients with active hemorrhage at endoscopy, and in Child-Pugh C patients. TIPS is also an efficient treatment for refractory ascites and hepatic hydrothorax. In contrast, the role of TIPS in the hepatorenal syndrome has not been precisely defined. The aim of this review was to specifically describe the current role of TIPS in management of portal hypertension in patients with cirrhosis.

Interference of engineered nanomaterials in flow cytometry: A case study.

Nanotechnology is regarded as the enabling technology of the 21st century. However, only a relatively small number of nano-enabled medical and healthcare products finally made their way to the market. There are several reasons why such innovative approaches fail in translation, with one key factor being the uncertainty surrounding their safety assessment. Although well described, interference reactions of engineered nanomaterials (ENM) with classical cytotoxicity assays remain a major source of uncertainty. Flow cytometry is a powerful, widely used, in vitro technique. Its readout is based on the detection of refracted laser light and fluorescence signals. It is therefore susceptible to ENM interference. Here we investigated possible interferences of ENM in the Annexin V/propidium iodide (PI) assay, which quantifies apoptotic and necrotic cell populations by flow cytometry. Two case studies were conducted using either silica or gold nanoparticles differing in size, specific surface area and surface chemistry. Both ENM types were found to cause distinct interference reactions at realistic concentrations. Silica particles induced false-positive signals; however only in the absence of a protein corona and in conjunction with a particular fluorophore combination (FITC/PI). In contrast, gold particles led to complex quenching effects which were only marginally influenced by the presence of proteins and occurred for both fluorophore combinations analyzed. We present a versatile spike-in approach which is applicable to all ENM and cell types. It further allows for the identification of a broad range of different interference phenomena, thereby increasing the reliability and quality of flow cytometry and ENM hazard assessment.

Effect of the Functionalization Process on the Colloidal, Magnetic Resonance Imaging, and Bioelimination Properties of Mono- or Bisphosphonate-Anchored Dendronized Iron Oxide Nanoparticles.

The functionalization process of iron oxide nanoparticles (NPs) is a major step and has to ensure a small particle size distribution (below 100 nm) and to preserve good magnetic properties suitable for in vivo applications. Two functionalization processes are here compared to coat iron oxide NPs, synthesized by thermal decomposition, with dendron molecules bearing either a mono- or a bisphosphonate anchoring group. The two processes are direct ligand exchange and the simultaneous ligand exchange and phase transfer process. The latter process led to a larger size distribution than the former. The phosphonate group is confirmed to be a strong anchoring agent from X-ray photoelectron spectroscopy (XPS) and IR characterizations whatever the grafting process and the number of phosphonate groups, it also confirms the preservation of the NPs' magnetic properties. All dendronized NPs display good in vitro MRI properties and those obtained by direct exchange showed no cell internalization, an efficient in vivo MRI contrast enhancement, and elimination by both urinary and hepato-biliary ways.

Design of iron oxide-based nanoparticles for MRI and magnetic hyperthermia.

Iron oxide nanoparticles are widely used for biological applications thanks to their outstanding balance between magnetic properties, surface-to-volume ratio suitable for efficient functionalization and proven biocompatibility. Their development for MRI or magnetic particle hyperthermia concentrates much of the attention as these nanomaterials are already used within the health system as contrast agents and heating mediators. As such, the constant improvement and development for better and more reliable materials is of key importance. On this basis, this review aims to cover the rational design of iron oxide nanoparticles to be used as MRI contrast agents or heating mediators in magnetic hyperthermia, and reviews the state of the art of their use as nanomedicine tools.

Preparation of core/shell NaYF4:Yb,Tm@dendrons nanoparticles with enhanced upconversion luminescence for in vivo imaging.

Upconverting nanoparticles (UCNPs) were successfully dendronized for fluorescence medical imaging applications. The structural and morphological characterizations of resulting core/shell NaYF4:Yb,Tm@dendrons nanoparticles were performed by means of X-ray diffraction, infrared spectroscopy and transmission electron microscopy. In vitro cytotoxicity assays have evidenced their low toxicity. In vivo fluorescence imaging study was performed in mice upon IR excitation, showing promising imaging capacities at low concentrations (0.5mg/mL) and low power (50mW/cm2).

Dendrimer-nanoparticle conjugates in nanomedicine.

Nanomedicine can take advantage of the recent developments in nanobiotechnology research areas for the creation of platforms with superior drug carrier capabilities, selective responsiveness to the environment, unique contrast enhancement profiles and improved accumulation at the disease site. Colloidal inorganic nanoparticles (NPs) have been attracting considerable interest in biomedicine, from drug and gene delivery to imaging, sensing and diagnostics. It is essential to modify the NPs surface to have enhanced biocompatibility and reach multifunctional systems for the in vitro and in vivo applications, especially in delivering drugs locally and recognizing overexpressed biomolecules. This paper describes the rational design for dendrimer-nanoparticle conjugates elaboration and reviews their state-of-the-art uses as efficient nanomedicine tools.