title: In vitro experiments showing enhanced release of doxorubicin from Doxil® in the presence of ammonia may explain drug release at tumor site.
abstract: The anticancer nanodrug Doxil®, a pegylated liposomal doxorubicin (PLD), accumulates at the tumor site due to the enhanced permeability and retention effect. However, the mechanism of doxorubicin release from the liposome within the tumor is unknown. We propose that ammonia produced at the tumor site by glutaminolysis enhances release. Using tumor cells in culture, we show that PLD, when ammonia is present, kills tumor cells with an efficacy similar to that of free doxorubicin, while PLD without ammonia and ammonia without PLD have very poor cytotoxicity. We confirm in tumor mouse models that ammonium/ammonia levels measured at the tumors are in the millimolar range, much higher than in the plasma of these mice. This is a new concept of stimulus-response, therapeutically efficacious drug release in tumors, with ammonia derived from tumor cell glutaminolysis acting as the stimulus. There may also be additional microenvironment-related variables that influence therapeutic efficacy.
  
  
  BACKGROUND
  The use of liposomal platform as a drug carrier has brought success to Doxil. Nonetheless, the underlying mechanism of drug release at tumor site and subsequent tumor killing was largely unknown. In this article, the authors demonstrated in their experiments that higher ammonia level in the tumor environment was the main mechanism for drug release.
authors.affiliation: Lab of Membrane and Liposome Research, Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Electronic address: silverman.liza@gmail.com.
authors.forename: Lisa
authors.initials: L
authors.lastname: Silverman
authors.affiliation: Lab of Membrane and Liposome Research, Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Electronic address: chezyb@ekmd.huji.ac.il.
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
mesh_terms: D000641:Ammonia / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D020285:Cryoelectron Microscopy; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000641:Ammonia; D004317:Doxorubicin
keywords: Ammonia; Doxorubicin; Drug delivery; Glutaminolysis; Liposomal drug release; Liposomes