Intranasal Delivery and Transfection of mRNA Therapeutics in the Brain Using Cationic Liposomes.

Nucleic acid-based therapeutics, including the use of messenger RNA (mRNA) as a drug molecule, has tremendous potential in the treatment of chronic diseases, such as age-related neurodegenerative diseases. In this study, we have developed a cationic liposomal formulation of mRNA and evaluated the potential of intranasal delivery to the brain in murine model. Preliminary in vitro studies in J774A.1 murine macrophages showed GFP expression up to 24 h and stably expressed GFP protein in the cytosol. Upon intranasal administration of GFP-mRNA/cationic liposomes (3 mg/kg dose) in mice, there was significantly higher GFP-mRNA expression in the brain post 24 h as compared to either naked mRNA or the vehicle-treated group. Luciferase mRNA encapsulated in cationic liposomes was used for quantification of mRNA expression distribution in the brain. The results showed increased luciferase activity in the whole brain in a dose-dependent manner. Specifically, the luciferase-mRNA/cationic liposome group (3 mg/kg dose) showed significantly higher luciferase activity in the cortex, striatum, and midbrain regions as compared with the control groups, with minimal systemic exposure. Overall, the results of this study demonstrate the feasibility of brain-specific, nonviral mRNA delivery for the treatment of various neurological disorders.

Site-specific intestinal DMT1 silencing to mitigate iron absorption using pH-sensitive multi-compartmental nanoparticulate oral delivery system.

Iron is a nutrient metal, but excess iron promotes tissue damage. Since iron chelation therapies exhibit multiple off-target toxicities, there is a substantial demand for more specific approaches to decrease iron burden in iron overload. While the divalent metal transporter 1 (DMT1) plays a well-established role in the absorption of dietary iron, up-regulation of intestinal DMT1 is associated with iron overload in both humans and rodents. Hence, we developed a novel pH-sensitive multi-compartmental particulate (MCP) oral delivery system that encapsulates DMT1 siRNA and validated its efficacy in mice. Using the gelatin NPs coated with Eudragit® L100-55, we demonstrated that DMT1 siRNA-loaded MCPs down-regulated DMT1 mRNA levels in the duodenum, which was consistent with decreased intestinal absorption of orally-administered 59Fe. Together, the Eudragit® L100-55-based oral siRNA delivery system could provide an effective strategy to specifically down-regulate duodenal DMT1 and mitigate iron absorption.

Injectable Thermosensitive Hydrogels for a Sustained Release of Iron Nanochelators.

Deferoxamine (DFO) is an FDA-approved iron-chelating agent which shows good therapeutic efficacy, however, its short blood half-life presents challenges such as the need for repeated injections or continuous infusions. Considering the lifelong need of chelating agents for iron overload patients, a sustained-release formulation that can reduce the number of chelator administrations is essential. Here, injectable hydrogel formulations prepared by integrating crosslinked hyaluronic acid into Pluronic F127 for an extended release of DFO nanochelators are reported. The subcutaneously injected hydrogel shows a thermosensitive sol-gel transition at physiological body temperature and provides a prolonged release of renal clearable nanochelators over 2 weeks, resulting in a half-life 47-fold longer than that of the nanochelator alone. In addition, no chronic toxicity of the nanochelator-loaded hydrogel is confirmed by biochemical and histological analyses. This injectable hydrogel formulation with DFO nanochelators has the potential to be a promising formulation for the treatment of iron overload disorders.

[Clinical outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C].

BACKGROUND/AIMS: The purpose of this study is to elucidate the efficacy and safety of combined peginterferon and ribavirin therapy in Korean patients with chronic HCV infection. METHODS: We retrospectively analyzed the clinical records of 84 patients. Thirty five patients with genotype 1 HCV infection were treated with peginterferon alpha-2a 180 microg/week and ribavirin 1,000-1,200 mg/day for 48 weeks, and 49 patients with genotype non-1 were treated with peginterferon alpha-2a 180 microg/week and ribavirin 800 mg/day for 24 weeks. RESULTS: An early virologic response was seen in 87.0% of patients with genotype 1 HCV. An end of treatment response (ETR) was seen in 82.6% and 97.6% of patients with genotype 1 and genotype non-1, respectively. An overall sustained virologic response (SVR) was seen in 53 patients (82.8%) of the 64 patients: in 16 (69.6%) of 23 patients with genotype 1 and in 37 (90.2%) of 41 patients with genotype non-1. An end of treatment biochemical response was seen in 58 patients (90.6%) [genotype 1, 20 patients (87.0%); genotype non-1, 38 patients (92.7%)], and a sustained biochemical response was achieved in 49 patients (76.6%) [genotype 1, 14 patients (60.9%); genotype non-1, 35 patients (85.4%)]. Independent factors affecting an SVR were HCV genotype and the baseline HCV RNA level. CONCLUSIONS: This study shows that a combination therapy of peginterferon and ribavirin is highly effective for chronic HCV infection, producing a high SVR and ETR.

Lymph Node Dissection Using Bipolar Vessel-Sealing Device During Reduced Port Laparoscopic Distal Gastrectomy for Gastric Cancer: Result of a Pilot Study from a Single Institute.

INTRODUCTION: The electrothermal bipolar vessel-sealing device (BVSD) is known to supply a strong vessel-sealing power. However, only few studies have reported lymph node dissection (LND) using only BVSD during laparoscopic surgery for gastric cancer. The purpose of this study was to investigate the feasibility of LND using BVSD during reduced port laparoscopic distal gastrectomy for gastric cancer. METHODS: From May 2015, patients in whom three- or single-port laparoscopic distal gastrectomy had been engaged for gastric cancer were enrolled in this study. We performed D1+ or D2 LND using only LigaSure™ Maryland (Medtronics, Minneapolis, MN), a recently developed BVSD. Clinical outcomes of these patients were investigated. RESULTS: From May 2015 to November 2016, 20 patients were enrolled in this study. The mean operation time was 262.6 ± 36.6 (200-340) minutes. The mean time for LND was 124.7 ± 19.2 (93-171) minutes. Only one patient had a morbidity of Clavien-Dindo grade more than II. No mortality was observed in all patients. The mean number of retrieved lymph nodes was 46.8 ± 22.8 (15-105). CONCLUSIONS: LND using the Maryland jaw type BVSD was feasible during reduced port (single- or three-port) laparoscopic distal gastrectomy for gastric cancer. Objectively evaluating the potential advantages of BVSD in reduced port laparoscopic surgery is necessary.