an-orthotopic-bladder-tumor-model-evaluation-intravesical-sarna

An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment

We present a novel method for treating bladder cancer with intravesically delivered small activating RNA (saRNA) in an orthotopic xenograft mouse bladder ...

Injectable local anesthetics that would last for many days could have a marked impact on periprocedural care and pain management. Formulations have often been limited in duration of action, or by systemic toxicity, local tissue toxicity from local anesthetics, and inflammation. To address those issues, we developed liposomal formulations of saxitoxin (STX), a compound with ultrapotent local anesthetic properties but little or no cytotoxicity. In vitro, the release of bupivacaine and STX from liposomes depended on the lipid composition and on whether dexamethasone was incorporated. In cell culture, bupivacaine, but not STX, was myotoxic (to C2C12 cells) and neurotoxic (to PC12 cells) in a concentration- and time-dependent manner. Liposomal formulations containing combinations of the above compounds produced sciatic nerve blockade lasting up to 7.5 days (with STX + dexamethasone liposomes) in male Sprague-Dawley rats. Systemic toxicity only occurred where high loadings of dexamethasone increased the release of liposomal STX. Mild myotoxicity was only seen in formulations containing bupivacaine. There was no nerve injury on Epon-embedded sections, and these liposomes did not up-regulate the expression of 4 genes associated with nerve injury in the dorsal root ganglia. These results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.

Prolonged duration local anesthesia with minimal toxicity.

Injizierbaren Lokalan&auml;sthetika, die f&uuml;r viele Tage dauern w&uuml;rde, k&ouml;nnte deutliche Auswirkungen auf Periprocedural-Pflege und Schmerz-Management haben. Formulierungen waren oft die Dauer der Aktion oder durch systemische Toxizit&auml;t, lokale Gewebe-Toxizit&auml;t von Lokalan&auml;sthetika und Entz&uuml;ndung begrenzt. Um diese Probleme anzugehen, haben wir liposomale Formulierungen von Saxitoxin (STX), eine Verbindung mit der ultrapotent Lokalan&auml;sthetikum Eigenschaften aber wenig oder gar keine Zytotoxizit&auml;t entwickelt. In-vitro, hing die Freisetzung von Bupivacain und STX aus Liposomen auf die Lipid-Zusammensetzung und ob Dexamethason eingegliedert wurde. Zellkultur, Bupivacain, aber nicht STX, war Myotoxic (auf C2C12 Zellen) und neurotoxische (an PC12-Zellen) in einer Konzentration und zeitabh&auml;ngigen Weise. Liposomale Formulierungen mit Kombinationen der oben genannten Verbindungen produziert ischiadicus-Blockade bis zu 7,5 Tage dauert (mit STX + Dexamethason Liposomen) bei m&auml;nnlichen Sprague-Dawley Ratten. Systemische Toxizit&auml;t ist nur aufgetreten, wo hohe Belastungen von Dexamethason erh&ouml;ht die Freisetzung von liposomalen STX. Milde Myotoxicity wurde nur in Formulierungen mit Bupivacain gesehen. Gab es keine Nervenverletzung auf Epon eingebettete Abschnitte und diese Liposomen nicht bis-Regeln des Ausdrucks 4 Gene, die Sch&auml;digung der Nerven in den Spinalganglien zugeordnet. Diese Ergebnisse legen nahe, dass kontrollierte Freisetzung von STX und &auml;hnliche Verbindungen sehr verl&auml;ngerte Nerv Bl&ouml;cke mit minimaler systemischer und lokaler Toxizit&auml;t bieten kann.

Verl&auml;ngerte Dauer Lokalan&auml;sthesie mit minimaler Toxizit&auml;t.

Here we develop an injectable composite system based for repeated ultrasound-triggered on-demand drug delivery. An in situ-cross-linking hydrogel maintains model drug (dye)-containing liposomes in close proximity to gas-filled microbubbles that serve to enhance release events induced by ultrasound application. Dye release is tunable by varying the proportions of the liposomal and microbubble components, as well as the duration and intensity of the ultrasound pulses in vitro. Dye is minimal at baseline. The composite shows minimal cytotoxicity in vitro, and benign tissue reaction after subcutaneous injection in rats. Ultrasound application also triggers drug release for two weeks after injection in vivo.

A microcomposite hydrogel for repeated on-demand ultrasound-triggered drug delivery.

Hier entwickeln wir ein injizierbares zusammengesetzte System f&uuml;r wiederholte Ultraschall-ausgel&ouml;sten Anforderungs-Drug-Delivery. Ein in Situ-Kreuz-Verkn&uuml;pfung Hydrogel unterh&auml;lt Modell Droge (Farbstoff)-mit Liposomen in unmittelbarer N&auml;he zum gasgef&uuml;llte Mikrobl&auml;schen, die dienen Freigabe Veranstaltungen induziert durch Ultraschall-Anwendung. Farbstoff-Release ist tunable durch Variation der Proportionen der liposomalen und Microbubble-Komponenten, sowie die Dauer und Intensit&auml;t der in-vitro-Ultraschall-Impulse. Farbstoff ist minimal bei Studienbeginn. Der Verbund zeigt minimal in-vitro-Zytotoxizit&auml;t und gutartige Gewebe Reaktion nach subkutaner Injektion bei Ratten. Ultraschall-Anwendung l&ouml;st auch ARZNEIMITTELFREISETZUNG f&uuml;r zwei Wochen nach der Injektion in-vivo.

Ein Microcomposite-Hydrogel f&uuml;r wiederholte Anforderungs-Ultraschall-ausgel&ouml;sten Drug-Delivery.

Excessive and prolonged activity of inflammatory monocytes is a hallmark of many diseases with an inflammatory component. In such conditions, precise targeting of these cells could be therapeutically beneficial while sparing many essential functions of the innate immune system, thus limiting unwanted effects. Inflammatory monocytes-but not the noninflammatory subset-depend on the chemokine receptor CCR2 for localization to injured tissue. Here we present an optimized lipid nanoparticle and a CCR2-silencing short interfering RNA that, when administered systemically in mice, show rapid blood clearance, accumulate in spleen and bone marrow, and localize to monocytes. Efficient degradation of CCR2 mRNA in monocytes prevents their accumulation in sites of inflammation. Specifically, the treatment attenuates their number in atherosclerotic plaques, reduces infarct size after coronary artery occlusion, prolongs normoglycemia in diabetic mice after pancreatic islet transplantation, and results in reduced tumor volumes and lower numbers of tumor-associated macrophages.

Therapeutic siRNA silencing in inflammatory monocytes in mice.

There is a clear need for methods to provide a safe controlled release of therapeutic proteins, either to achieve and maintain high local protein concentrations, or for sustained systemic delivery. We have developed a protein delivery system that combines in situ cross-linkable polysaccharide hydrogels with gelatin. This formulation is injectable, easy to apply, and obviates the need for organic solvents or potentially toxic cross-linking agents in the formulation process. The cross-linked polysaccharides themselves (comprising hyaluronic acid, dextran and/or carboxymethylcellulose) provided prolonged release of fluorescently labeled albumin (FITC-albumin). The duration of release was markedly extended by the incorporation of gelatin into the formulation: FITC-albumin and interleukin-2 (IL-2) were released over the course of more than 3 weeks. The IL-2 maintained >70% activity throughout that time. Gelatin also accelerated the gelation time of the hydrogels, and reduced their swelling in phosphate-buffered saline. The composite hydrogel (dextran-carboxymethylcellulose-gelatin) showed minimal cytotoxicity in vitro, and benign tissue reaction after subcutaneous injection in rats.

Article	Year
Prolonged duration local anesthesia with minimal toxicity. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 19365067	2009
A microcomposite hydrogel for repeated on-demand ultrasound-triggered drug delivery. Biomaterials\| PubMed ID: 20347484	2010
Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 20359513	2010
Therapeutic siRNA silencing in inflammatory monocytes in mice. Nature biotechnology\| PubMed ID: 21983520	2011
Advances in experimental medicine and biology\| PubMed ID: 22101722	2012
An in situ cross-linking hybrid hydrogel for controlled release of proteins. Acta biomaterialia\| PubMed ID: 22342597	2012
Nature\| PubMed ID: 22622570	2012

Hila Epstein-Barash

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