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While polymeric nano-formulations for RNAi therapeutics hold great promise for molecularly-targeted, personalized medicine, they possess significant systemic delivery challenges including rapid clearance from circulation and the potential for carrier-associated toxicity due to cationic polymer or lipid components. Herein, we evaluated the in vivo pharmacokinetic and safety impact of often-overlooked formulation parameters, including the ratio of carrier polymer to cargo siRNA and hydrophobic siRNA modification in combination with hydrophobic polymer components (dual hydrophobization). For these studies, we used nano-polyplexes (NPs) with well-shielded, zwitterionic coronas, resulting in various NP formulations of equivalent hydrodynamic size and neutral surface charge regardless of charge ratio. Doubling nano-polyplex charge ratio from 10 to 20 increased circulation half-life five-fold and pharmacokinetic area under the curve four-fold, but was also associated with increased liver enzymes, a marker of hepatic damage. Dual hydrophobization achieved by formulating NPs with palmitic acid-modified siRNA (siPA-NPs) both reduced the amount of carrier polymer required to achieve optimal pharmacokinetic profiles and abrogated liver toxicities. We also show that optimized zwitterionic siPA-NPs are well-tolerated upon long-term, repeated administration in mice and exhibit greater than two-fold increased uptake in orthotopic MDA-MB-231 xenografts compared to commercial transfection reagent, in vivo-jetPEI. These data suggest that charge ratio optimization has important in vivo implications and that dual hydrophobization strategies can be used to maximize both NP circulation time and safety.
Copyright © 2018 Elsevier Ltd. All rights reserved.
OBJECTIVES - This study sought to assess long-term left atrial appendage (LAA) closure efficacy of the Atriclip applied via totally thoracoscopic (TT) approach with computed tomographic angiography.
BACKGROUND - LAA closure is associated with a low risk for atrial fibrillation-related embolic stroke. The Atriclip exclusion device allows epicardial LAA closure, avoiding the need for post-operative oral anticoagulation. Previous data with Atriclip during open chest procedures show a high efficacy rate of closure >95%.
METHODS - Three-dimensional volumetric 2-phase computed tomographic angiography ≥90 days post-implantation was independently assessed by chest radiology for complete LAA closure on all consented subjects identified retrospectively as having had a TT-placed Atriclip at Vanderbilt University Medical Center from June 13, 2011, to October 6, 2015.
RESULTS - Complete LAA closure (defined by complete exclusion of the LAA with no exposed trabeculations, and clip within 1 cm from the left circumflex artery) was found in 61 of 65 subjects (93.9%). Four cases had incomplete closure (6.2%). Two clips were placed too distally, leaving a large stump with exposed trabeculae. Two clips failed to address a secondary LAA lobe. No major complications were associated with TT placement of the Atriclip. Follow-up over 183 patient-years revealed 1 stroke in a patient with complete LAA closure and no thrombus (hypertensive cerebrovascular accident).
CONCLUSIONS - Angiographic LAA closure efficacy with a TT-placed Atriclip is high (93.9%). The clinical significance of a remnant stump is unknown. Confirmation of complete LAA occlusion should be made before cessation of systemic anticoagulation.
Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PURPOSE - Amplitudes of electroretinograms (ERG) are enhanced during acute, moderate elevation of intraocular pressure (IOP) in rats anaesthetised with isoflurane. As anaesthetics alone are known to affect ERG amplitudes, the present study compares the effects of inhalant isoflurane and injected ketamine:xylazine on the scotopic threshold response (STR) in rats with moderate IOP elevation.
METHODS - Isoflurane-anaesthetised (n = 9) and ketamine:xylazine-anaesthetised (n = 6) rats underwent acute unilateral IOP elevation using a vascular loop anterior to the equator of the right eye. STRs to a luminance series (subthreshold to -3.04 log scotopic cd s/m) were recorded from each eye of Sprague-Dawley rats before, during, and after IOP elevation.
RESULTS - Positive STR (pSTR) amplitudes for all conditions were significantly smaller (p = 0.0001) for isoflurane- than for ketamine:xylazine-anaesthetised rats. In addition, ketamine:xylazine was associated with a progressive increase in pSTR amplitudes over time (p = 0.0028). IOP elevation was associated with an increase in pSTR amplitude (both anaesthetics p < 0.0001). The absolute interocular differences in IOP-associated enhancement of pSTR amplitudes for ketamine:xylazine and isoflurane were similar (66.3 ± 35.5 vs. 54.2 ± 24.1 µV, respectively). However, the fold increase in amplitude during IOP elevation was significantly higher in the isoflurane- than in the ketamine:xylazine-anaesthetised rats (16.8 ± 29.7x vs. 2.1 ± 2.7x, respectively, p = 0.0004).
CONCLUSIONS - The anaesthetics differentially affect the STRs in the rat model with markedly reduced amplitudes with isoflurane compared to ketamine:xylazine. However, the IOP-associated enhancement is of similar absolute magnitude for the two anaesthetics, suggesting that IOP stress and anaesthetic effects operate on separate retinal mechanisms.
Although siRNA-based nanomedicines hold promise for cancer treatment, conventional siRNA-polymer complex (polyplex) nanocarrier systems have poor pharmacokinetics following intravenous delivery, hindering tumor accumulation. Here, we determined the impact of surface chemistry on the in vivo pharmacokinetics and tumor delivery of siRNA polyplexes. A library of diblock polymers was synthesized, all containing the same pH-responsive, endosomolytic polyplex core-forming block but different corona blocks: 5 kDa (benchmark) and 20 kDa linear polyethylene glycol (PEG), 10 kDa and 20 kDa brush-like poly(oligo ethylene glycol), and 10 kDa and 20 kDa zwitterionic phosphorylcholine-based polymers (PMPC). In vitro, it was found that 20 kDa PEG and 20 kDa PMPC had the highest stability in the presence of salt or heparin and were the most effective at blocking protein adsorption. Following intravenous delivery, 20 kDa PEG and PMPC coronas both extended circulation half-lives 5-fold compared to 5 kDa PEG. However, in mouse orthotopic xenograft tumors, zwitterionic PMPC-based polyplexes showed highest in vivo luciferase silencing (>75% knockdown for 10 days with single IV 1 mg/kg dose) and 3-fold higher average tumor cell uptake than 5 kDa PEG polyplexes (20 kDa PEG polyplexes were only 2-fold higher than 5 kDa PEG). These results show that high molecular weight zwitterionic polyplex coronas significantly enhance siRNA polyplex pharmacokinetics without sacrificing polyplex uptake and bioactivity within tumors when compared to traditional PEG architectures.
The present study investigated the immunoenhancing property of our newly designed nanovaccine, that is, its ability to induce antigen-specific immunity. This study also evaluated the synergistic effect of a novel compound PBS-44, an α-galactosylceramide analog, in boosting the immune response induced by our nanovaccine. The nanovaccine was prepared by encapsulating ovalbumin (ova) and an adjuvant within the poly(lactic-co-glycolic acid) nanoparticles. Quantitative analysis of our study data showed that the encapsulated vaccine was physically and biologically stable; the core content of our nanovaccine was found to be released steadily and slowly, and nearly 90% of the core content was slowly released over the course of 25 days. The in vivo immunization studies exhibited that the nanovaccine induced stronger and longer immune responses compared to its soluble counterpart. Similarly, intranasal inhalation of the nanovaccine induced more robust antigen-specific CD8 T cell response than intraperitoneal injection of nanovaccine.
The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine (1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), (2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and (3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats. Oprm1 mRNA and protein expression were greater in the NAc of HVR rats, and application of the Oprm1 agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to dissociated NAc neurons produced greater depolarizing responses in neurons from HVR versus LVR rats. Naltrexone injection dose-dependently decreased wheel running and food intake in HVR, but not LVR, rats. Naltrexone (20mg/kg) decreased tyrosine hydroxylase mRNA in the ventral tegmental area and Fos and Drd5 mRNA in NAc shell of HVR, but not LVR, rats. Additionally, lesion of dopaminergic neurons in the NAc with 6-hydroxydopamine (6-OHDA) ablated the decrease in running, but not food intake, in HVR rats following i.p. naltrexone administration. Collectively, these data suggest the higher levels of running observed in HVR rats, compared to LVR rats, are mediated, in part, by increased mesolimbic opioidergic signaling that requires downstream dopaminergic activity to influence voluntary running, but not food intake.
Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Background - Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) study.
Methods - The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor.
Results - In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%–10.9%] vs 45.6% [28.9%–72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit.
Conclusions - Bicarbonate markedly enhances the anticancer activity of TACE.
Funding - Funded by National Natural Science Foundation of China.
Clinical trial number - ChiCTR-IOR-14005319.
Self-assembled polymer/porous silicon nanocomposites overcome intracellular and systemic barriers for in vivo application of peptide nucleic acid (PNA) anti-microRNA therapeutics. Porous silicon (PSi) is leveraged as a biodegradable scaffold with high drug-cargo-loading capacity. Functionalization with a diblock polymer improves PSi nanoparticle colloidal stability, in vivo pharmacokinetics, and intracellular bioavailability through endosomal escape, enabling PNA to inhibit miR-122 in vivo.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PURPOSE - Erythropoietin (EPO) is a promising neuroprotective agent and is currently in Phase III clinical trials for the treatment of traumatic brain injury. The goal of this study was to determine if EPO is also protective in traumatic eye injury.
METHODS - The left eyes of anesthetized DBA/2J or Balb/c mice were exposed to a single 26 psi overpressure air-wave while the rest of the body was shielded. DBA/2J mice were given intraperitoneal injections of EPO or buffer and analyses were performed at 3 or 7 days post-blast. Balb/c mice were given intramuscular injections of rAAV.EpoR76E or rAAV.eGFP either pre- or post-blast and analyses were performed at 1 month post-blast.
RESULTS - EPO had a bimodal effect on cell death, glial reactivity, and oxidative stress. All measures were increased at 3 days post-blast and decreased at 7-days post-blast. Increased retinal ferritin and NADPH oxygenases were detected in retinas from EPO-treated mice. The gene therapy approach protected against axon degeneration, cell death, and oxidative stress when given after blast, but not before.
CONCLUSIONS - Systemic, exogenous EPO and EPO-R76E protects the retina after trauma even when initiation of treatment is delayed by up to 3 weeks. Systemic treatment with EPO or EPO-R76E beginning before or soon after trauma may exacerbate protective effects of EPO within the retina as a result of increased iron levels from erythropoiesis and, thus, increased oxidative stress within the retina. This is likely overcome with time as a result of an increase in levels of antioxidant enzymes. Either intraocular delivery of EPO or treatment with non-erythropoietic forms of EPO may be more efficacious.
OBJECTIVE - Ultrasound-guided intravenous catheter (USGIV) insertion is increasingly being used for administration of intravenous (IV) contrast for computed tomography (CT) scans. The goal of this investigation was to evaluate the risk of contrast extravasation among patients receiving contrast through USGIV catheters.
METHODS - A retrospective observational study of adult patients who underwent a contrast-enhanced CT scan at a tertiary care emergency department during a recent 64-month period was conducted. The unadjusted prevalence of contrast extravasation was compared between patients with an USGIV and those with a standard peripheral IV inserted without ultrasound. Then, a two-stage sampling design was used to select a subset of the population for a multivariable logistic regression model evaluating USGIVs as a risk factor for extravasation while adjusting for potential confounders.
RESULTS - In total, 40,143 patients underwent a contrasted CT scan, including 364 (0.9%) who had contrast administered through an USGIV. Unadjusted prevalence of extravasation was 3.6% for contrast administration through USGIVs and 0.3% for standard IVs (relative risk = 13.9, 95% confidence interval [CI] = 7.9 to 24.6). After potential confounders were adjusted for, CT contrast administered through USGIVs was associated with extravasation (adjusted odds ratio = 8.6, 95% CI = 4.6 to 16.2). No patients required surgical management for contrast extravasation; one patient in the standard IV group was admitted for observation due to extravasation.
CONCLUSIONS - Patients who received contrast for a CT scan through an USGIV had a higher risk of extravasation than those who received contrast through a standard peripheral IV. Clinicians should consider this extravasation risk when weighing the risks and benefits of a contrast-enhanced CT scan in a patient with USGIV vascular access.
© 2016 by the Society for Academic Emergency Medicine.