Project

pharmaceutics; oral delivery; polymersomes; hyperammonemia

Lead
Die hepatische Enzephalopathie ist eine schwere Komplikation in Patienten mit eingeschränkter Leberfunktion. In diesem Projekt wird eine perorale Formulierung zur Behandlung dieser Krankheit entwickelt.
Lay summary
Inhalt und Ziele des Forschungsprojekts Die hepatische Enzephalopathie, eine weit verbreitete Komplikation in Patienten mit akutem Leberversagen und Zirrhose, ist eng verbunden mit einer eingeschränkten Fähigkeit der Leber, den neurotoxischen Metaboliten Ammoniak zu entgiften und erhöhte Blutammoniakspiegel (Hyperammonämie) zu vermeiden. Die Erkrankung präsentiert sich mit neuropsychiatrischen Symptomen und kann letal verlaufen. Zurzeit gültige Behandlungsleitlinien empfehlen prioritär Medikamente, welche die Ammoniakproduktion im Colon, der Hauptquelle systemischen Ammoniaks, vermindern, jedoch bei vielen Patienten nur beschränkt wirksam und verträglich sind. Dieses Projekt zielt darauf ab, eine perorale Formulierung zu finden, die Ammoniak im Dickdarm gezielt sequestriert und den Blutammoniakspiegel senkt. Verschiedene Formulierungen werden in magendarmtraktsimulierenden Flüssigkeiten auf ihre Fähigkeit zur Ammoniakbindung getestet und anschliessend in vivo evaluiert. Am Ende des Projekts wird die Erkenntnis stehen, ob die beste Formulierung Potenzial für eine ausführlichere präklinische und klinische Untersuchung hat. Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts In diesem angewandten Forschungsprojekt werden Erkenntnisse der Pathophysiologie der hepatischen Enzephalopathie genutzt, um gezielt ein möglichst effektives, sicheres und simples Therapeutikum zu entwickeln.

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Last update: 02.04.2016

Active participation

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While intoxication with exogenous substances can severely tamper with the homeostasis of the human body, the latter itself can also be an unexpected reservoir of “poisons”. Organ failure, as well as inborn or acquired metabolic diseases, can undermine the body’s natural eliminating mechanisms, resulting in the accumulation of potentially toxic endogenous metabolites associated with serious morbidities. The blood level of ammonia, an important player in protein metabolism, is tightly controlled by metabolic detoxification processes in the liver. In patients with impaired liver function (e.g., liver cirrhosis), blood ammonia levels can be greatly increased (hyperammonemia), leading to neurotoxicity concomitant with serious and in certain cases fatal neuropsychiatric complications known as hepatic encephalopathy. Currently, the recommended first- and second-line treatments for hepatic encephalopathy are the non-absorbable disaccharide lactulose and the antibiotic rifaximin, respectively. These therapies address the bacterial production and intestinal absorption of ammonia in the colon, the main site of ammonia generation. Unfortunately, both therapies fail to control the symptoms and progression of hepatic encephalopathy in a considerable fraction of patients. Recently, we established the proof-of-concept of ammonia capture via liposome-supported peritoneal dialysis in vivo, where we demonstrated the capacity of transmembrane pH-gradient liposomes to sequester high amounts of systemic ammonia in a relatively selective fashion following intraperitoneal administration. The mechanism of action of pH-gradient vesicles is based on the diffusion of ammonia across the hydrophobic membrane and its subsequent protonation in the acidic core, where the positively charged ammonium remains trapped. However, this peritoneal dialysis approach may only be applied in acute life-threatening cases of hepatic encephalopathy (e.g., acute liver failure).In order to develop a maintenance treatment for cirrhotic patients with chronically elevated blood ammonia levels, the established strategy of ammonia sequestration by pH-gradient vesicles needs to be transposed to the gastrointestinal tract. Therefore, the main objective of this grant application is to develop vesicles to be administered via the oral route in order to trap ammonia in the colon, thereby reducing its intestinal absorption and ultimately lowering its concentration in the blood. In view of the harsh conditions found in the gastrointestinal tract (low pH, digestive enzymes), non-biodegradable polymersomes will be used instead of liposomes.As laid out in this proposal, we will first synthesize polymers reported to form non-biodegradable polymersomes and subsequently generate vesicles of different sizes using various methods. After a thorough investigation of the morphological properties and stability of the polymersomes in simulated gastrointestinal fluids, their capacity to capture and retain ammonia will be determined in vitro. Finally, the therapeutic potential of the best polymersome formulations will be investigated in vivo in bile duct-ligated rats, an established animal model of hepatic encephalopathy. The goal of this research is to develop an oral vesicle formulation with the capacity to capture ammonia in the gastrointestinal tract. We believe that this approach has great potential to become a first-line treatment for chronic and episodic hyperammonemia, and promises to alleviate the disease burden in patients suffering from hepatic encephalopathy.