pharmaceutics; oral delivery; polymersomes; hyperammonemia
Schmidt Aaron C., Hebels Erik R., Weitzel Charlotte, Kletzmayr Anna, Bao Yinyin, Steuer Christian, Leroux Jean‐Christophe (2020), Engineered Polymersomes for the Treatment of Fish Odor Syndrome: A First Randomized Double Blind Olfactory Study, in Advanced Science
Schmidt Aaron C., Hebels Erik R., Weitzel Charlotte, Stoessel Barbara, Bao Yinyin, Altmann Karl-Heinz, Leroux Jean-Christophe (2020), Ammonia uptake by transmembrane pH gradient poly(isoprene)- block -poly(ethylene glycol) polymersomes, in Soft Matter
Matoori Simon, Bao Yinyin, Schmidt Aaron, Fischer Eric J., Ochoa‐Sanchez Rafael, Tremblay Mélanie, Oliveira Mariana M., Rose Christopher F., Leroux Jean‐Christophe (2019), An Investigation of PS‐ b ‐PEO Polymersomes for the Oral Treatment and Diagnosis of Hyperammonemia, in Small
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.