Oxime Functionalization Strategy for Iodinated Poly(epsilon-caprolactone) X-ray Opaque Materials Samantha E. Nicolau, 1 Lundy L. Davis, 1 Caroline C. Duncan, 1 Timothy R. Olsen, 2 Frank Alexis, 2,3 Daniel C. Whitehead, 4 Brooke A. Van Horn 1 1 Department of Chemistry and Biochemistry, College of Charleston, 66 George St., Charleston, South Carolina 29424 2 Department of Bioengineering, Clemson University, 203 Rhodes Research Center Annex, Clemson, South Carolina 29634 3 Institute of Biological Interfaces of Engineering, Department of Bioengineering, Clemson University, Clemson, South Carolina 29634-0905 4 Department of Chemistry, Clemson University, 467 Hunter Laboratories, Clemson, South Carolina 29634 Correspondence to: B. A. Van Horn (E - mail: vanhornba@cofc.edu) Received 16 March 2015; accepted 13 May 2015; published online 16 June 2015 DOI: 10.1002/pola.27706 ABSTRACT: Since two of the most common technologies for imaging the human body are X-ray radiography and computed tomography (CT), researchers are focused on developing bio- degradable and biocompatible polymeric molecules as an alternative to the traditional small molecule contrast agents. This report highlights the synthesis of novel biodegradable iodinated poly(e-caprolactone) copolymers by oxime “Click” ligation reactions. A series of ketone-bearing materials are built by tin (II)-mediated ring-opening polymerization followed by a postpolymerization deprotection step. The intended X-ray opacity is imparted through acid-catalyzed oxime postpolyme- rization modification of the resultant polymers with an iodin- ated hydroxylamine. All small molecules and polymeric materials are characterized using proton nuclear magnetic res- onance (NMR) for purity, functional group stoichiometry, and number-averaged molecular weight calculations. Additionally, the polymers are evaluated with gel permeation chromatogra- phy (GPC) to determine polymer sample polydispersity and general molecular weight distribution shapes and by differen- tial scanning calorimetry (DSC) and thermogravimetric analysis (TGA) for thermal properties. V C 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2421–2430 KEYWORDS: biodegradable; iodine; oxime; polyesters; X-ray INTRODUCTION Biomedical imaging technologies can be used for both diagnostic and therapeutic purposes, thus making imaging science a critical part of the success of a patient treatment plan in the applied clinical setting. The technologies that find broad use are generally either non- or minimally invasive, 1–19 and among those, X-ray and com- puted tomography (CT) imaging are the most common and broadly available. Many of the currently utilized X-ray and CT imaging agents are injectable small molecules with cova- lently bound iodine that allow for high X-ray attenuation but only when the contrast molecule is in locally high concentra- tion. Nonetheless, these small molecules suffer from non- specific and not easily defined residence in the blood pool and tissues, and experience rapid clearance from circulation. Also, they often have to be administered in high doses to produce significant imaging capability. Our research aims to overcome these limitations by covalently bonding iodine- bearing species onto copolymers through postpolymerization reactions as a new design for biodegradable X-ray contrast materials, whether for circulation in the body or in implant- able devices. There are many parallel strategies being undertaken to address the challenge of preparing well-defined X-ray opaque materials that have controllable and/or predictable biodistri- bution. Some current investigations include the “packaging” of the contrast agent as separate small molecules within sta- bilized organic structures including conventional liposomes, micelles, and emulsions. 20–25 Unfortunately, these methods of imparting contrast to the material can still suffer from the "leakage" of the contrast agent from the material over time. Other strategies have focused on the covalent attachment of iodine or iodine-containing molecules to the polymer chains, particles, or matrix. 26–32 Various polymeric structures and architectures such as dendrimers, linear, block, graft, and hyperbranched polymers are also being investigated. These materials can differ in the placement of the radiolabels, with some having the contrast within main chain/backbone of the polymer, 33–37 at the chain end, 38 or as a side group on the Additional Supporting Information may be found in the online version of this article. V C 2015 Wiley Periodicals, Inc. WWW.MATERIALSVIEWS.COM JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2015, 53, 2421–2430 2421 JOURNAL OF POLYMER SCIENCE WWW.POLYMERCHEMISTRY.ORG ARTICLE