Cyclodextrin polymer improves atherosclerosis therapy and reduces ototoxicity

Abstract

Recently, cyclodextrin (CD) has shown the potential for effective treatment of atherosclerotic plaques in mice by solubilizing plaque cholesterol. While promising as a new therapy for atherosclerosis, poor pharmacokinetics and ototoxicity of CD pose a therapeutic challenge. Thus far, however, there has been no attempts to overcome such limitations. Here, we showed that cyclodextrin polymer (CDP) with a diameter of similar to 10 nm exhibits outstanding pharmacokinetics and plaque targeting efficacy compared to a monomeric CD. Furthermore, we found out that CDP does not induce plasma membrane disruption as opposed to CD, which eliminated cytotoxicity and hemolytic activity of CD. In a mouse model of atherosclerosis, subcutaneous injections of beta-cyclodextrin polymer (beta CDP) significantly inhibited plaque growth compared to monomeric hydroxypropyl-beta-cyclodextrin (HP beta CD) at the same dose (1 g/kg). More importantly, beta CDP did not induce significant ototoxicity at a high-dose (8 g/kg) where HP beta CD reduced the outer hair cell content by 36%. These findings suggest that the polymerization of CD can overcome major limitations of CD therapy for treatment of atherosclerosis.