pH-Responsive Micelle Sequestrant Polymers Inhibit Fat Absorption

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 <i>in vitro</i>. <i>In vivo</i> 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

Nonabsorbable Iron Binding Polymers Prevent Dietary Iron Absorption for the Treatment of Iron Overload

Chronic iron overload is a serious condition that develops as a consequence of long-term accumulation of iron, eventually overwhelming iron storage systems and causing oxidative stress and subsequent organ damage. Current pharmaceuticals used to treat iron overload typically suffer from toxicities leading to relatively high rates of adverse events. To address this need, we designed a new class of nonabsorbable iron binding polymers (IBPs) that bind and sequester iron within the gastrointestinal (GI) tract. IBPs were synthesized by cross-linking polyallylamine containing various amounts of conjugated 2,3-dihydroxybenzoic acid (DHBA). In vitro studies indicated that IBPs possessed high affinity, substantial binding capacity, and excellent selectivity toward iron. Moreover, in vivo studies demonstrated that IBPs showed no signs of side effects in mice and increased fecal iron excretion when compared to a similar dose of cross-linked polyallylamine. IBPs are a novel, nonabsorbed oral therapeutic agent that may ultimately prevent iron absorption as a safe alternative to iron chelation therapies for patients with hemochromatosis or other iron overload diseases

Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co-delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis

Many current therapies for autoimmune diseases such as multiple sclerosis (MS) result in global immunosuppression, rendering insufficient efficacy with increased risk of adverse side effects. Multivalent soluble antigen arrays, nanomaterials presenting both autoantigen and secondary inhibitory signals on a flexible polymer backbone, are hypothesized to shift the immune response toward selective autoantigenic tolerance to repress autoimmune disease. Two-signal co-delivery of both autoantigen and secondary signal were deemed necessary for therapeutic efficacy against experimental autoimmune encephalomyelitis, a murine model of MS. Dynamic light scattering and in silico molecular dynamics simulations complemented these studies to illuminate the role of two-signal co-delivery in determining therapeutic potential. Physicochemical characteristics such as particle size and molecular affinity for intermolecular interactions and chain entanglement likely facilitated cotransport of two signals to produce efficacy. These findings elucidate potential mechanisms whereby soluble antigen arrays enact their therapeutic effect and help to guide the development of future multivalent antigen-specific immunotherapies