Molecularly Imprinted Bile Acid Sequestrants: Synthesis and Biological Studies
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Molecularly Imprinted Bile Acid Sequestrants: Synthesis and Biological Studies
Chad C. Huval, Xi Chen, S. Randall Holmes-Farley, W. Harry Mandeville, Steven C. Polomoscanik, Robert J. Sacchiero, and Pradeep K. Dhal* Genzyme Corporation, Drug Discovery and Development, 153 Second Avenue, Waltham, MA 02451, U.S.A. ABSTRACT
Novel bile acid sequestrants based on a polyammonium backbone were synthesized using molecular imprinting technique. These imprinted polymer networks were prepared by crosslinking different polymeric amines with crosslinking agents in the presence of sodium cholate as the template. The template molecules were completely removed from the polymer matrices by repeated washings. The bile acid sequestration properties of these polymeric resins were evaluated under both in vitro and in vivo conditions. Adsorption isotherms performed in physiologically relevant media revealed that molecular imprinting led to improvement in bile acid sequestration with about a twofold increase in the Ka (association constant). More importantly, hamsters fed with imprinted polymers in their diet excreted more bile acids than the non-imprinted control polymer. These results suggest that molecular imprinting may be potentially an interesting approach to prepare novel polymer therapeutics.
INTRODUCTION Increased plasma total cholesterol and low-density lipoprotein cholesterol (LDLc) are established risk factors for antherosclerosis, the underlying cause of coronary heart disease and most strokes [1]. Therefore, reduction of elevated LDLc is one of the most common therapeutic treatments for this disease [2]. Bile acids are formed in the liver as a result of cholesterol metabolism. These steroid derived amphiphilic molecules have detergent-like properties and serve an important role in food digestion. Therefore, removal of bile acids from the GI tract is a novel approach to prevent atherosclerosis [3]. Bile acid sequestrants (BAS) are cationically charged polymeric gels that bind anionic bile acids in the GI tract. The mode of action of these polymeric sorbents involves sequestration and removal of bile acid from the digestive tract leading to a net decrease in serum cholesterol. In fact, use of BAS is an established approach for treating elevated cholesterol levels in the plasma. Being non-absorbed, these polymeric drugs do not exhibit the systemic side effects that are associated with the systemic cholesterol lowering drugs such as statins [4]. The effectiveness of a cationic polymer to be a potent bile acid sequestrant depends upon its high binding capacity and strong binding strength towards bile acids in the competing desorbing forces of the GI tract. Thus, a potent bile acid sequestrant needs to exhibit slow off-rates of bound bile acids from the polymer resin to effectively overcome the active transport of bile acids from the lumen through the ileum wall. Over the past few years, rational design of polymer structures that incorporate
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a variety of functional properties has led to the discovery of a numb
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