title: pH-Responsive Micelle Sequestrant Polymers Inhibit Fat Absorption.
abstract: Current antiobesity therapeutics are associated with side effects and/or poor long-term patient compliance, necessitating development of more efficacious and safer alternatives. Herein, we designed and engineered a new class of orally acting pharmaceutical agents, or micelle sequestrant polymers (MSPs), that could respond to the pH change in the gastrointestinal (GI) tract and potentially sequester lipid micelles; inhibiting lipid absorption through a pH-triggered flocculation process. These MSPs, derived from poly(2-(diisopropylamino)ethyl methacrylate) and poly(2-(dibutylamino)ethyl methacrylate), were soluble in acidic media, but they transitioned to become insoluble around pH 7.2 and 6.1, respectively. MSPs showed substantial bile acid and triglyceride sequestration capacity with fast pH response tested in vitro. In vivo study showed that orally dosed MSPs significantly enhanced fecal elimination of triglycerides and bile acids. Several MSPs increased fecal elimination of triglycerides by 9-10 times compared with that of the control. In contrast, fecal concentration of bile acids, but not triglycerides, was increased by cholestyramine or Welchol. Importantly, fecal elimination of bile acids and triglycerides was unaltered by addition of control dietary fibers. MSPs may serve as a novel approach to weight loss that inhibits excess caloric intake by preventing absorption of excess dietary triglycerides.
authors.affiliation: †Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Qian
authors.affiliation: †Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.affiliation: †Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, United States.|‡Department of Chemical and Petroleum Engineering, The University of Kansas, Lawrence, Kansas 66045, United States.
authors.forename: Cory
authors.initials: C
authors.lastname: Berkland
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism; D004043:Dietary Fiber / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008823:Micelles; D011108:Polymers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D014280:Triglycerides / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D004043:Dietary Fiber; D008055:Lipids; D008823:Micelles; D011108:Polymers; D011109:Polymethacrylic Acids; D014280:Triglycerides; C511861:poly(2-(diisopropylamino)ethyl methacrylate)