European Polymer Journal 142 (2021) 110151 Available online 19 November 2020 0014-3057/© 2020 Published by Elsevier Ltd. Phosphorus-containing star-shaped polymer conjugates for biomedical applications Zornica Todorova a , Oyundari Tumurbaatar a , Jordana Todorova b , Iva Ugrinova b , Neli Koseva a, * a Institute of Polymers, Bulgarian Academy of Sciences, Akad. G. Bonchev Str, Bl. 103A, Sofa 1113, Bulgaria b Institute of Molecular Biology “Acad. Roumen Tsanev”, Bulgarian Academy of Sciences, Akad. G. Bonchev Str, Bl. 21, Sofa 1113, Bulgaria A R T I C L E INFO Keywords: Polyphosphoramidate Star-shaped glycopolymer AZT conjugate Staudinger reaction Cytotoxicity ABSTRACT A novel phosphorus-containing biocompatible and biodegradable star-shaped polymer was designed as a pre- cursor polymer for obtaining sugar or drug conjugates. The star polymer bearing three arms was synthesized applying the “coupling on” approach. Linear oligo(oxyethylene H-phosphonate) with a terminal hydroxyl group was prepared and used as functional arms able to react with tris(2,3-epoxypropyl) isocyanurate as core in the presence of boron trifuoride etherate as catalyst. The H-phosphonate moieties in the arm chains were trans- formed into trimethylsilyl phosphite groups and further via Staudinger reaction they were converted into phosphoramidates bearing specifc residues. When the Staudinger reaction was carried out with a glucose- containing azide, i.e. 2-p-azidobenzamide-2-deoxy-1,3,4,6-tetra-O-trimethylsilyl-alpha-D-glucopyranose, the product was a star-shaped glycopolymer. The conjugation of AZT yielded a star-shaped polymer-drug conjugate. Multinuclear NMR spectroscopy was applied as a powerful tool for determination of the conversion and structure of the reaction products. Analytical ultracentrifugation, dynamic and electrophoretic light scattering techniques were used for characterization of the star polymers and conjugates, as well as in binding studies with Conca- navalin A. Drug release measurements and cytotoxicity tests were also performed. The obtained results evidenced feasible synthetic procedures for preparation of biocompatible phosphorus containing star-shaped glycopolymer and drug conjugate. 1. Introduction Glycans play an important role in the biological functions and pro- cesses that occur in living organisms. They are a source of energy for cells, a key element in cell recognition and growth regulation, modu- lation of enzymatic activity, etc. In recent years, many research efforts have been focused on the design of synthetic polymers called glyco- polymers, which can mimic the structure and function of glycans. Gly- copolymers with various composition and architecture, such as linear, grafted, highly branched (dendrimers) or star-shaped macromolecules have been prepared [1] and studied in multivalent binding with lectins, as carriers of bioactive substances, etc. [2,3]. The occurrence of branching in macromolecules induces signifcant variations in their properties and functionality. Like dendrimers, the branched polymers have a large number of functional groups and their macromolecular structure imparts them specifc physical and chemical properties, lower intrinsic viscosity and lower glass transition temperature than their linear equivalents, and signifcantly improved solubility due to the low degree of crystallinity and crosslinking [4,5]. Star-shaped polymers are the simplest type of branched polymers that consist of several (at least three) linear chains linked to a common center. In general, there are three basic methods for obtaining star- shaped polymers: “arm-frst”, “core-frst” and “coupling on” (a method with bifunctional linear molecules/arms). [6] Star-shaped glycopolymers have been synthesized using the “core- frst” method, i.e. synthesis of multifunctional initiators and subsequent polymerizations [7] as well as via the “arm-frst” approach - advance- ment of “arms” with subsequent binding reaction with carbohydrates. [8] Procedures combining different polymerization and coupling tech- niques for the synthesis of star-shaped glycopolymers have been devel- oped. Qiu et al. obtained star-shaped polypeptides/block glycosylamides consisting of poly (benzyl L-glutamate) and poly(D- gluconamidoethyl methacrylate) via a combination of ring-opening polymerisation and ATRP [9]. Chen et al. have reported the * Corresponding author. E-mail address: koseva@polymer.bas.bg (N. Koseva). Contents lists available at ScienceDirect European Polymer Journal journal homepage: www.elsevier.com/locate/europolj https://doi.org/10.1016/j.eurpolymj.2020.110151 Received 11 September 2020; Received in revised form 1 November 2020; Accepted 9 November 2020