polymers Review Polyglycidol, Its Derivatives, and Polyglycidol-Containing Copolymers—Synthesis and Medical Applications Mateusz Gosecki, Mariusz Gadzinowski, Monika Gosecka, Teresa Basinska and Stanislaw Slomkowski * Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland; [email protected] (M.Gosecki); [email protected] (M.Ga.); [email protected] (M.Gosecka); [email protected] (T.B.) * Correspondence: [email protected]; Tel.: +48-42-680-3253 Academic Editor: Jianxun Ding Received: 9 May 2016; Accepted: 31 May 2016; Published: 9 June 2016 Abstract: Polyglycidol (or polyglycerol) is a biocompatible polymer with a main chain structure similar to that of poly(ethylene oxide) but with a –CH2OH reactive side group in every structural unit. The hydroxyl groups in polyglycidol not only increase the hydrophilicity of this polymer but also allow for its modification, leading to polymers with carboxyl, amine, and vinyl groups, as well as to polymers with bonded aliphatic chains, sugar moieties, and covalently immobilized bioactive compounds in particular proteins. The paper describes the current state of knowledge on the synthesis of polyglycidols with various topology (linear, branched, and star-like) and with various molar masses. We provide information on polyglycidol-rich surfaces with protein-repelling properties. We also describe methods for the synthesis of polyglycidol-containing copolymers and the preparation of nano- and microparticles that could be derived from these copolymers. The paper summarizes recent advances in the application of polyglycidol and polyglycidol-containing polymers as drug carriers, reagents for diagnostic systems, and elements of biosensors. Keywords: polyglycidol; linear; branched; copolymer; nanoparticles; microparticles; carriers of bioactive compounds 1. Introduction Generally, polymers should be chemically stable to ensure the maintenance of their properties during storage, processing into products, and usage. Typical examples are polyethylene, polypropylene, and several other vinyl polymers. However, for many applications polymers with special properties resulting from the presence in their chains of properly selected reactive groups are needed, such as groups with hydroxyl, carboxyl, aldehyde, and amine functions. Linear poly(ethylene oxide), one polymer that has found many applications in medicine in spite of some pros and contras, is sufficiently stable, hydrophilic, and biocompatible; when attached to surfaces it makes them protein repellent, and provides “stealth” properties to the poly(ethylene oxide)-modified nanoparticles [1–6]. However, the chains of linear poly(ethylene oxide) cannot have more than two reactive end-groups, whereas, in many instances, polymers with similar properties, but bearing multiple functional groups, are needed. Such multifunctional polymers are suitable for covalent immobilization of various drugs, receptor-targeting moieties, fluorescent labels, and many other uses. The closest multifunctional analogue of poly(ethylene oxide) is polyglycidol (see Scheme1). The number of hydroxyl –CH2OH groups in the polyglycidol chain is equal to its degree of polymerization. Thus, polymers with high molar masses provide many options for immobilization and labeling. Polymers 2016, 8, 227; doi:10.3390/polym8060227 www.mdpi.com/journal/polymers Polymers 2016, 8, 227 2 of 24 polymerization.Polymers 2016, 8, 227 Thus, polymers with high molar masses provide many options for immobilization2 of 25 and labeling. Scheme 1. Poly(ethylenePoly(ethylene oxide) and polygl polyglycidolycidol constitutional units. Poly(ethylene oxide) and polyglycidol are used in medicine as protecting and stabilizing Poly(ethylene oxide) and polyglycidol are used in medicine as protecting and stabilizing agents. agents. Direct intravenous or oral administration of many bioactive drug components, particularly Direct intravenous or oral administration of many bioactive drug components, particularly nucleic nucleic acids and almost all kinds of proteins, is ineffective. Various hydrolases and components of acids and almost all kinds of proteins, is ineffective. Various hydrolases and components of molecular molecular and cellular immune system induce degradation and elimination of these species from the and cellular immune system induce degradation and elimination of these species from the blood. blood. Digestion accompanies oral administration of unprotected nucleic acids and proteins. Digestion accompanies oral administration of unprotected nucleic acids and proteins. Moreover, even Moreover, even if some large fragments of partially degraded proteins or nucleic acids administered if some large fragments of partially degraded proteins or nucleic acids administered orally succeed in orally succeed in crossing the endothelium barrier of the intestine and reaching the blood stream, the crossing the endothelium barrier of the intestine and reaching the blood stream, the immune system immune system would degrade them further and eliminate from the organism. Covalent binding of would degrade them further and eliminate from the organism. Covalent binding of poly(ethylene poly(ethylene oxide) to proteins and nucleic acids hinders their degradation by protecting them oxide) to proteins and nucleic acids hinders their degradation by protecting them from enzymes, from enzymes, antibodies, and macrophages. Thus, modification of proteins, nucleic acids, and their antibodies, and macrophages. Thus, modification of proteins, nucleic acids, and their carriers by carriers by immobilization of poly(ethylene oxide) significantly increases the circulation of these immobilization of poly(ethylene oxide) significantly increases the circulation of these species in the species in the blood [1,3,4,6–9]. This process is usually called pegylation (the term is derived from blood [1,3,4,6–9]. This process is usually called pegylation (the term is derived from poly(ethylene poly(ethylene glycol), denoting poly(ethylene oxide) with low molar mass). glycol), denoting poly(ethylene oxide) with low molar mass). In many instances, the protection of bioactive compounds by pegylation is insufficient. In some In many instances, the protection of bioactive compounds by pegylation is insufficient. In some cases good results were obtained by using liposome or nanoparticle carriers with a protecting externalcases good layer results rich werein poly(ethylene obtained by oxide). using liposome or nanoparticle carriers with a protecting external layerDense rich in grafting poly(ethylene of poly(ethylene oxide). oxide) strongly increases the hydrophilicity of surfaces, making themDense resistant grafting to protein of poly(ethylene adsorption and oxide) more strongly biocompatible increases [2,10]. the hydrophilicity In the case of ofdiagnostic surfaces, devices, making thethem tailored resistant modification to protein adsorption of surfaces and morewith biocompatible poly(ethylene [2 ,10oxide)]. In thereduces case of diagnosticthe uncontrolled, devices, adventitiousthe tailored modification adsorption of of proteins, surfaces withwhich poly(ethylene is important oxide)for the reduces specificity the of uncontrolled, diagnostic tests adventitious [5,11]. adsorptionPoly(ethylene of proteins, oxide) which is used is important for many for medical the specificity applications. of diagnostic However, tests polyglycidol [5,11]. equipped with Poly(ethylenehydroxyl groups oxide) in each is used polymeric for many unit medical opens a applications. way for many However, others. polyglycidol equipped withThere hydroxyl are groupsthousands in each of polymericoriginal and unit review opens papers a way for devoted many others.to the medical applications of poly(ethyleneThere are oxide). thousands On the of originalcontrary, and the reviewknowledge papers on devotedmedical toapplications the medical of applicationspolyglycidol ofis significantlypoly(ethylene more oxide). limited. On the The contrary, aim of the this knowledge paper is onto medicalgive an applicationsoverview of ofthe polyglycidol synthesis of is polyglycidolsignificantly moreand polyglycidol-containing limited. The aim of this papercopolymers is to give with an varied overview microstructure of the synthesis and of topology polyglycidol and someand polyglycidol-containing of their medical applications. copolymers with varied microstructure and topology and some of their medical applications. 2. Synthesis of Polyglycidol- and Oilyglycidol-Containing Copolymers 2. Synthesis of Polyglycidol- and Oilyglycidol-Containing Copolymers 2.1. Monomers Monomers Glycidol containscontains twotwo reactive reactive groups groups in ain molecule, a molecule, epoxide epoxide and hydroxyland hydroxyl (Scheme (Scheme2). In anionic 2). In anionicpolymerization polymerization the epoxide the groupepoxide is involvedgroup is ininvolved propagation, in propagation, whereas the whereas hydroxyl the one hydroxyl is responsible one is responsiblefor chain transfer for chain reactions. transfer Therefore,reactions. Therefore, the polymerization the polymerization of glycidol of always glycidol leads always to branched leads to branchedpolymers. polymers. Linear polyglycidol Linear polyglycidol could be synthesized could be onlysynthesized by polymerization only by polymerization of the monomer of withthe monomer with blocked –CH2OH groups (e.g., with 1-ethoxyethyl or trityl moieties). blocked –CH2OH groups (e.g., with 1-ethoxyethyl or trityl moieties).