Polyglycidol, Its Derivatives, and Polyglycidol-Containing Copolymers—Synthesis and Medical Applications

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). There areare several several routes routes for thefor synthesisthe synthesis of glycidol of glycidol (see Scheme (see 3)[Scheme12–21 ].3) Industrial [12–21]. productionIndustrial productionof glycidol isof basedglycidol on is the based epoxidation on the epoxidation of allyl alcohol of allyl with alcohol hydrogen with peroxide hydrogen or peroxide on the conversion or on the conversionof glycerol intoof glycerol glycerol into monochlorohydrin glycerol monochlorohy and itsdrin subsequent and its subsequent conversion conversion into glycidol into under glycidol the underaction ofthe a strongaction base of (e.g.,a strong KOH) base [12,13 (e.g.,]. However, KOH) these[12,13]. processes However, are not these environmentally processes are friendly, not environmentallyproducing significant friendly, amounts producing of harmful significant waste am andounts causing of harmful corrosion waste ofand equipment. causing corrosion Recently, of equipment.some researchers Recently, concentrated some researchers their attention concentrated on the their much attention moreconvenient on the much approach more convenient based on decarboxylation of glycerol carbonate. Using tetraethylammonium amino acid ionic liquids (TAAILs) as catalysts allows us to carry out this synthesis in one pot [17,18,20,21]. Polymers 2016, 8, 227 3 of 24

Polymers 2016, 8, 227 3 of 24 PolymersapproachPolymers2016 2016, 8based,, 2278, 227 on decarboxylation of glycerol carbonate. Using tetraethylammonium amino 3acid of3 24 of 25 ionicPolymers liquids 2016, 8 ,(TAAILs) 227 as catalysts allows us to carry out this synthesis in one pot [17,18,20,21]. 3 of 24 approach based on decarboxylation of glycerol carbonate. Using tetraethylammonium amino acid ionic liquids (TAAILs) as catalysts allows us to carry out this synthesis in one pot [17,18,20,21]. approachionic liquids based (TAAILs) on decarboxylation as catalysts allows of glycerol us to carry carbonate. out this Using synthesis tetraethylammonium in one pot [17,18,20,21]. amino acid ionic liquids (TAAILs) as catalysts allows us to carry out this synthesis in one pot [17,18,20,21].

SchemeScheme 2. 2.Structure Structure ofof glycidol and 1-ethoxyethylglycidyl 1-ethoxyethylglycidyl ether. ether. Scheme 2. Structure of glycidol and 1-ethoxyethylglycidyl ether. Scheme 2. Structure of glycidol and 1-ethoxyethylglycidyl ether.

Scheme 3. Synthetic routes to glycidol. Scheme 3. Synthetic routes to glycidol. The glycidol molecule containsSchemeScheme a chiral 3. 3.Synthetic Synthetic carbon routesatom into glycidol.the glycidol. ring. Since for some applications the enantiomerically pure polyglycidolScheme (or polyglycidol 3. Synthetic routes enriched to glycidol. in polymeric units of one enantiomer) The glycidol molecule contains a chiral carbon atom in the ring. Since for some applications the mightThe be glycidolneeded, moleculesome researchers contains investigated a chiral carbon the atom stereocontrolled in the ring. Sincesynthesis for some of glycidol. applications Already the enantiomericallyThe glycidol molecule pure polyglycidol contains a(or chiral polyglycidol carbon atom enriched in the in ring.polymeric Since units for some of one applications enantiomer) the inenantiomerically 1991,The R. glycidol M. Hanson puremolecule polyglycidolpublished contains an (ora extensivechiral polyglycidol carbon review atom enriched on in this the in subjectring. polymeric Since [12]. for unitsThe some reviewedof oneapplications enantiomer) methods the enantiomericallymight be needed, pure some polyglycidol researchers (or investigated polyglycidol the enrichedstereocontrolled in polymeric synthesis units of glycidol. of one enantiomer) Already includedenantiomericallymight be synthesisneeded, pure some of the polyglycidol researchers optically active (orinvestigated polyglycidol monomers the enrichedstereocontrolledfrom the inoptically polymeric synthesis active units substrates of of glycidol. one enantiomer) (e.g., Already from mightin 1991, be needed, R. M. Hanson some researchers published investigatedan extensive thereview stereocontrolled on this subject synthesis [12]. The of reviewed glycidol. methods Already in Dmightin-mannitol 1991, be R. needed, orM. LHanson-serine), some publishedresearcherssyntheses byan investigated asymmetricextensive re th viewepoxidation,e stereocontrolled on this enzymaticsubject synthesis [12]. transformation The of reviewed glycidol. of methodsAlready achiral 1991,included R. M. Hansonsynthesis published of the optically an extensive active reviewmonomers on this from subject the optically [12]. The active reviewed substrates methods (e.g., included from substrates,inincluded 1991, R. synthesis andM. Hansonchiral of resolution.the published optically The an active latterextensive monomers is especially review from oninteresting thisthe opticallysubject because [12]. active itThe could substrates reviewed be based (e.g., methods on from the synthesisD of the opticallyL active monomers from the optically active substrates (e.g., from D-mannitol D-mannitol or L-serine), syntheses by asymmetric epoxidation, enzymatic transformation of achiral alreadyincluded synthesized synthesis of glycidol the optically with blockedactive monomers –CH2OH groups.from the Using optically the properlyactive substrates chosen lipase(e.g., from and or substrates,L-serine), synthesesand chiral byresolution. asymmetric The latter epoxidation, is especially enzymatic interesting transformation because it could of achiral be based substrates, on the hydrolysisDsubstrates,-mannitol andconditionsor L -serine),chiral resolution.allowed syntheses synthesis The by latterasymmetric of is glycidespecially epoxidation,ol with interesting nearly enzymatic because100% enantiomerictransformation it could be basedpurity of achiral on (see the andalready chiral synthesized resolution. glycidol The latter with is especiallyblocked –CH interesting2OH groups. because Using itthe could properly be based chosen on lipase the already and Schemesubstrates,already 4)synthesized [22]. and chiral glycidol resolution. with The blocked latter is–CH especially2OH groups. interesting Using because the properly it could chosen be based lipase on andthe hydrolysis conditions allowed synthesis of glycidol with nearly 100% enantiomeric purity (see synthesizedalreadyhydrolysis synthesized glycidol conditions with glycidol allowed blocked with synthesis –CH blocked2OH of groups.–CH glycid2OHol Using groups. with the nearly Using properly 100%the properly chosen enantiomeric lipase chosen and puritylipase hydrolysis and(see Scheme 4) [22]. conditionshydrolysisScheme 4) allowed [22].conditions synthesis allowed of glycidol synthesis with of nearlyglycidol 100% with enantiomeric nearly 100% purity enantiomeric (see Scheme purity4)[ (see22]. Scheme 4) [22].

Scheme 4. Synthetic pathway to enentiomerically pure glycidol. Scheme 4. Synthetic pathway to enentiomerically pure glycidol. Synthesis of linearScheme poly 4.glycidolSynthetic requires pathway a monomer to enentiomerically with blocked pure –CH glycidol.2OH groups. Otherwise, the unblocked groupsScheme participate 4. Synthetic in chain pathway transfer, to enenti whichomerically leads pure to glycidol.the branching. Fitton et al. Synthesis of linear polyglycidol requires a monomer with blocked –CH2OH groups. Otherwise, describedSynthesis synthesis of linear of glycidol polyglycidol in which requires the hydrox a monomeryls were with blocked blocked with –CH 1-ethoxyethyl2OH groups. groups Otherwise, [23]. theSynthesis unblocked of lineargroups polyglycidol participate requiresin chain atransfer, monomer which with leads blocked to the –CH branching.OH groups. Fitton Otherwise, et al. Thethe blockedunblockedSynthesis monomer of groups linear waspolyparticipate synthesizedglycidol in requires chain in a simple atransfer, monomer re actionwhich with of leadsblocked glycidol to –CH thewith 2branching.OH2 vinyl groups. ethyl Fitton Otherwise,ether. et The al. thedescribed unblocked synthesis groups of participate glycidol in in which chain the transfer, hydrox whichyls were leads blocked to the with branching. 1-ethoxyethyl Fitton et groups al. described [23]. processthedescribed unblocked was synthesis catalyzed groups of withglycidol participate p-toluenesulfonic in which in chain the hydrox acidtransfer, (seeyls Schemewerewhich blocked leads5). withto the 1-ethoxyethyl branching. Fittongroups et [23]. al. The blocked monomer was synthesized in a simple reaction of glycidol with vinyl ethyl ether. The synthesisdescribedThe blocked of glycidolsynthesis monomer in of which glycidol was thesynthesized in hydroxyls which thein were ahydrox simple blockedyls re wereaction with blocked of 1-ethoxyethyl glycidol with with 1-ethoxyethyl groups vinyl ethyl [23 ].groups ether. The blocked [23]. The process was catalyzed with p-toluenesulfonic acid (see Scheme 5). monomerTheprocess blocked was catalyzedmonomer synthesized withwas in psynthesized-toluenesulfonic a simple reaction in a simple acid of (see glycidol re actionScheme with of 5). glycidol vinyl ethylwith ether.vinyl ethyl The processether. The was catalyzedprocess withwas catalyzedp-toluenesulfonic with p-toluenesulfonic acid (see Scheme acid5 (see). Scheme 5).

Scheme 5. Synthetic route to 1-ethoxyethylglycidyl ether.

Scheme 5. Synthetic route to 1-ethoxyethylglycidyl ether. Scheme 5. Synthetic route to 1-ethoxyethylglycidyl ether. Scheme 5. Synthetic route to 1-ethoxyethylglycidyl ether.

Polymers 2016, 8, 227 4 of 25 Polymers 2016, 8, 227 4 of 24 Polymers 2016, 8, 227 4 of 24 2.2. Synthesis of Linear Polyglycidol 2.2. Synthesis of Linear Polyglycidol In 1994 N. Spassky and co-workers provided the first reliable data on the synthesis of linear In 1994 N. Spassky and co-workers provided the first first reliable data on the synthesis of linear polyglicidol with molar masses up to 30,000 [24]. The polymer was obtained by anionic polyglicidol withwith molar molar masses masses up to up 30,000 to [30,00024]. The [24]. polymer The waspolymer obtained was by anionicobtained polymerization by anionic polymerization of 1-ethoxyethylglycidyl ether (blocked glycidol) initiated with cesium hydroxide ofpolymerization 1-ethoxyethylglycidyl of 1-ethoxyethylglycidyl ether (blocked glycidol) ether (blocked initiated glycidol) with cesium initiated hydroxide with andcesium by deblockinghydroxide and by deblocking removing protecting groups at acidic conditions. removingand by deblocking protecting removing groups at protecti acidicng conditions. groups at acidic conditions. Mono- and difunctional potassium alkoxides and sec-BuLi/phosphazene base were used later Mono- andand difunctionaldifunctional potassiumpotassium alkoxides alkoxides and and sec-BuLi/phosphazene sec-BuLi/phosphazene base base were were used used later later as as initiators [25–30]. However, detailed studies of the anionic polymerization of initiatorsas initiators [25– 30].[25–30]. However, However, detailed studiesdetailed of thestudies anionic polymerizationof the anionic of 1-ethoxyethylglycidylpolymerization of 1-ethoxyethylglycidyl ether revealed that in these processes propagation is accompanied by chain ether1-ethoxyethylglycidyl revealed that in theseether processesrevealed that propagation in these isprocesses accompanied propagation by chain is transfer,accompanied which by leads chain to transfer, which leads to polymers with decreased molar masses (see Scheme 6 [28]). polymerstransfer, which with decreasedleads to polymers molar masses with decreased (see Scheme molar6[28 ]).masses (see Scheme 6 [28]).

Scheme 6. Propagation and cain transfer in the anionic polymerization of 1-ethoxyethylglycidyl Scheme 6. Propagation and cain transfer in the anionic polymerization of 1-ethoxyethylglycidyl Schemeether. 6. Propagation and cain transfer in the anionic polymerization of 1-ethoxyethylglycidyl ether. ether. Polymers with with higher higher molar molar masses masses (up (up to to85,000 85,000 for forpoly(1-ethoxyethylglycidyl poly(1-ethoxyethylglycidyl ether) ether) and Polymers with higher molar masses (up to 85,000 for poly(1-ethoxyethylglycidyl ether) and and53,000 53,000 for forpoly( poly(tert-butyltert-butyl glycidyl glycidyl ether)) ether)) were were obtained obtained by by monomer-activated monomer-activated anionicanionic 53,000 for poly(tert-butyl glycidyl ether)) were obtained by monomer-activated anionic polymerization initiatedinitiated with with tetraoctylammonium tetraoctylammonium bromide bromide or tetrabutylammonium or tetrabutylammonium azide initiators azide polymerization initiated with tetraoctylammonium bromide or tetrabutylammonium azide andinitiators a triisobutylaluminum and a triisobutylaluminum catalyst [29 ,31catalyst]. Deblocking [29,31]. of Deblocking hydroxyl groups of hydroxyl in the abovementioned groups in the initiators and a triisobutylaluminum catalyst [29,31]. Deblocking of hydroxyl groups in the polymersabovementioned gave polyglycidol polymers gave samples polyglycidol with M nsamples= 74,000 with and M 30,200,n = 74,000 respectively. and 30,200, The respectively. mechanism The of abovementioned polymers gave polyglycidol samples with Mn = 74,000 and 30,200, respectively. The initiationmechanism and of propagationinitiation and for propagation the polymerization for the po oflymerization 1-ethoxyethylglycidyl of 1-ethoxyethylglycidyl ether in a process ether with in a mechanism of initiation and propagation for the polymerization of 1-ethoxyethylglycidyl ether in a tetrabutylammoniumprocess with tetrabutylammonium azide initiator andazide triisobutylaluminum initiator and triisobutylaluminum catalyst (monomer catalyst activator) (monomer is shown process with tetrabutylammonium azide initiator and triisobutylaluminum catalyst (monomer inactivator) Scheme is7. shown in Scheme 7. activator) is shown in Scheme 7.

Scheme 7. Polymerization of 1-ethoxyethylglycidyl ether with tetrabutylammonium azide initiator Scheme 7.7. Polymerization of 1-ethoxyethylglycidyl1-ethoxyethylglycidyl etherether with tetrabutylammoniumtetrabutylammonium azide initiator and triisobutylaluminum catalyst (monomer activator). and triisobutylaluminum catalystcatalyst (monomer activator).

Polymers 2016, 8, 227 5 of 25 Polymers 2016, 8, 227 5 of 24 Polymers 2016, 8, 227 5 of 24 PolymersActivationActivation 2016, 8, 227 of of the the monomer monomer molecule molecule with with Al( iAl(-Bu)i-Bu)3 leads3 leads toformation to formation of a of partial a partial positive positive5 chargeof 24 atcharge the endocyclicActivation at the endocyclic –CHof the2– monomer group,–CH2– group, which molecule which facilitates with facilitates Al( thei-Bu) nucleophilic the3 leadsnucleophilic to attackformation attack during ofduring a thepartial the initiation initiation positive and propagationandcharge propagationActivation at the steps. endocyclic of steps. the monomer –CH2– group, molecule which with facilitates Al(i-Bu) the3 leads nucleophilic to formation attack ofduring a partial the initiationpositive chargeandPolymerization propagationPolymerization at the endocyclic steps. of of 1-ethoxyethylglycidyl 1-ethoxyethylglycidyl –CH2– group, which facilitatesether and and the deblocking deblocking nucleophilic of of –OH attack –OH groups groupsduring is the isnot not initiation the the only only pathwayandpathway propagationPolymerization to to creating creating steps. linearof linear 1-ethoxyethylglycidyl polyglycidol. polyglycidol. Other ether monomers, and deblocking like like trimethylsilylglycidyl trimethylsilylglycidylof –OH groups is not ether the ether onlyand and t-butylglycidyltpathway-butylglycidylPolymerization to creating ether, ether, couldof couldlinear 1-ethoxyethylglycidyl also alsopolyglycidol. be be used used forfor Other thisthis ether purposepurpose monomers, and deblocking [32]. [32]. Itlike It is is worthtrimethylsilylglycidyl worth of –OH noting noting groups that that ist-butylglycidyl tnot-butylglycidyl ether the onlyand pathwayethert-butylglycidyl is commerciallyto creating ether, linearcould available. alsopolyglycidol. be However,used for Other this the purpose monomers,advantage [32]. likeItof is synthesis worthtrimethylsilylglycidyl noting via thatpolymerization t-butylglycidyl ether and of ether is commercially available. However, the advantage of synthesis via polymerization of t1-ethoxyethylglycidylether-butylglycidyl is commercially ether, could ether available. also consists be usedHowever, is thefor thiseasy the purpose deblockingadvantage [32]. ofItof is–OH synthesisworth groups noting via by that polymerizationremoval t-butylglycidyl of acetal of 1-ethoxyethylglycidyl ether consists is the easy deblocking of –OH groups by removal of acetal ethermoieties1-ethoxyethylglycidyl is incommercially mildly acidic etheravailable. conditions. consists However, is the easy the deblockingadvantage ofof –OHsynthesis groups via by polymerization removal of acetal of moieties in mildly acidic conditions. 1-ethoxyethylglycidylmoietiesIn some in mildly instances acidic ether the conditions. differenceconsists is in the deprotection easy deblocking rates forof acetal–OH groupsand t-butyl by removal groups ofcould acetal be In some instances the difference in deprotection rates for acetal and t-butyl groups could be beneficial. moietiesbeneficial.In some in Formildly instances example, acidic the inconditions. Sectiondifference 2.7 in(on deprotection functionalized rates polyglycidol for acetal andand tpolyglycidol-containing-butyl groups could be Forcopolymers)beneficial. example,In some For in weinstances Section example, discuss 2.7 the thein(on Sectiondifference synthesis functionalized 2.7 of in(on polyglycidoldeprotection functi polyglycidolonalized derivativesrates and polyglycidol for polyglycidol-containing acetal with and differentand tpolyglycidol-containing-butyl labels, groups copolymers) based could on thebe we discussbeneficial.selectivecopolymers) the synthesis Forremoval we example, discuss of polyglycidol of inthe Section synthesisacetal 2.7 derivatives of(onand polyglycidol functi t-butyl withonalized different derivativesgroups polyglycidol labels, within based differentandpoly(1-ethoxyethylglycidyl onpolyglycidol-containing the labels, selective based removal on the of acetalcopolymers)ether)-selective andb-poly(t -butyl removalwet-butylglycidyl groups discuss in ofthe poly(1-ethoxyethylglycidyl synthesis ether).acetal ofand polyglycidol t-butyl ether)-derivativesgroupsb-poly( withtin-butylglycidyl differentpoly(1-ethoxyethylglycidyl labels, ether). based on the selectiveether)-b-poly( removalt-butylglycidyl of ether).acetal and t-butyl groups in poly(1-ethoxyethylglycidyl 2.3. Synthesis of Star-Like Polyglycidol ether)-2.3. Synthesisb-poly( oft-butylglycidyl Star-Like Polyglycidol ether). 2.3. Synthesis of Star-Like Polyglycidol PolymerizationPolymerization of of blocked blocked glycidolglycidol withwith multifunctional initiators initiators leads leads to to star-like star-like polymers, polymers, 2.3. Synthesis of Star-Like Polyglycidol whichwhich afterPolymerization after deblocking deblocking of yield yieldblocked star-like star-like glycidol polyglycidols polyglycidols with multifunctional [[26,33].26,33]. initiators leads to star-like polymers, whichExamplesPolymerizationExamples after deblocking of of multifunctional multifunctional of blockedyield star-like glycidol initiators initiators polyglycidols with areare multifunctional shownshown [26,33]. in Scheme initiators 88.. leads to star-like polymers, whichExamples after deblocking of multifunctional yield star-like initiators polyglycidols are shown [26,33]. in Scheme 8. Examples of multifunctional initiators are shown in Scheme 8.

Scheme 8. Multifunctional initiators used for polymerization of blocked glycidol. Scheme 8. Multifunctional initiators used for polymerization of blocked glycidol. Scheme 8. Multifunctional initiators used for polymerization of blocked glycidol. The numberScheme of arms 8. Multifunctional in the star-like initiators polyglycidol used for polymerizationis equal to the of number blocked of glycidol. hydroxyl groups in theThe alcoholThe number number used of for of arms synthesisarms in in the the of star-like star-likethe initiator. polyglycidol polyglycidol is is equal equal to to the the number number of of hydroxyl hydroxyl groups groups in in the alcoholthe alcoholThe used number forused synthesis forof armssynthesis ofin thethe of initiator. star-likethe initiator. polyglycidol is equal to the number of hydroxyl groups in the2.4. alcoholSynthesis used of Branched for synthesis Polyglycidol of the initiator. 2.4.2.4. Synthesis Synthesis of of Branched Branched Polyglycidol Polyglycidol In anionic polymerization of glycidol, the propagation step consists of the nucleophilic attack of 2.4. Synthesis of Branched Polyglycidol theIn alkoxideIn anionic anionic active polymerization polymerization center on ofthe of glycidol, glycidol,endocyclic thethe CH propagationpropagation2 group and step step the consists consists scission of ofof the thethe nucleophilic nucleophilicCH2–O bond. attack attack As ofa of theresult,the alkoxide alkoxideIn theanionic newly active active polymerization added center center unit on on thecontains the of endocyclic glycidol,endocyclic the primary the CHCH propagation22 hydroxylgroup and step side the the consists group scission scission (see of ofthe ofScheme the thenucleophilic CH CH 9).2–O2 –O bond. bond.attack As of As a a result,theresult, alkoxide the the newly newly active added added center unit unit on contains contains the endocyclic the the primary primary CH2 hydroxylgrouphydroxyl and side the group groupscission (see (see of Scheme Schemethe CH 9).29–O). bond. As a result, the newly added unit contains the primary hydroxyl side group (see Scheme 9).

Scheme 9. Monomer addition in the anionic polymerization of glycidol. Scheme 9. Monomer addition in the anionic polymerization of glycidol. Scheme 9. Monomer addition in the anionic polymerization of glycidol. However, theScheme intramolecular 9. Monomer additionchain transfer in the anionic leads polymerization to formation of ofglycidol. the primary alkoxide propagatingHowever, species the (seeintramolecular Scheme 10) chain[34]. transfer leads to formation of the primary alkoxide propagatingHowever,However, thespecies the intramolecular intramolecular(see Scheme chain 10) chain[34]. transfer transfer leads leads to formation to formation of the primary of the alkoxideprimary propagatingalkoxide speciespropagating (see Scheme species 10 (see)[34 Scheme]. 10) [34].

Scheme 10. Intramolecular chain transfer in the anionic polymerization of glycidol. Scheme 10. Intramolecular chain transfer in the anionic polymerization of glycidol. Because in polymer chains the primary and secondary hydroxyl side groups can be converted SchemeScheme 10. 10.Intramolecular Intramolecular chainchain transfer in in the the anionic anionic polymerization polymerization of of glycidol. glycidol. into propagatingBecause in polymer alkoxide chains species, the branchingprimary and is insecondaryevitable (see hydroxyl Scheme side 11) groups [34]. It can is worthbe converted noting into Becausepropagating in polymer alkoxide chains species, the branchingprimary and is insecondaryevitable (seehydroxyl Scheme side 11) groups [34]. Itcan is beworth converted noting into Because propagating in polymer alkoxide chains species, the primarybranching and is in secondaryevitable (see hydroxyl Scheme side 11) groups[34]. It is can worth be converted noting into propagating alkoxide species, branching is inevitable (see Scheme 11)[34]. It is worth noting that Polymers 2016, 8, 227 6 of 25

Polymers 2016, 8, 227 6 of 24 not all hydroxyl groups participate in the chain transfer leading to branching. Thus, after completion that not all hydroxyl groups participate in the chain transfer leading to branching. Thus, after of thecompletion polymerization of the process polymerization and the killingprocess of and the the active killing species, of the the active branched species, macromolecules the branched may Polymers 2016, 8, 227 6 of 24 containmacromolecules primary and may secondary contain hydroxylprimary and groups secondary not onlyhydroxyl at the groups chain not ends only but at the also chain along ends the but chains, insidealsothat the alongnot branches. all the hydroxyl chains, inside groups the participate branches. in the chain transfer leading to branching. Thus, after completion of the polymerization process and the killing of the active species, the branched macromolecules may contain primary and secondary hydroxyl groups not only at the chain ends but also along the chains, inside the branches.

Scheme 11. Hyperbranched polymer formed in the anionic polymerization of glycidol. Scheme 11. Hyperbranched polymer formed in the anionic polymerization of glycidol. It has been established that the slow addition of glycidol allows for obtaining branched polymers with a narrow molar mass distribution [35–37]. The following considerations explain these It has beenScheme established 11. Hyperbranched that the polymer slow formed addition in th ofe anionic glycidol polymerization allows for of glycidol. obtaining branched polymersobservations. with a narrow molar mass distribution [35–37]. The following considerations explain these observations.ItAlkoxides has been of establishedprimary and that secondary the slow alcohols addition diff ofer glycidolwith respect allows to fortheir obtaining reactivity. branched Thus, a narrow molar mass distribution is possible only when at any time in each growing macromolecule Alkoxidespolymers with of primary a narrow and molar secondary mass distribution alcohols differ[35–37]. with The respectfollowing to considerations their reactivity. explain Thus, these a narrow the primary and secondary propagating species are present with the same probability, i.e., when for molarobservations. mass distribution is possible only when at any time in each growing macromolecule the primary each Alkoxidesgrowing chain of primary the apparent and secondary rate of propag alcoholsation diff iser thewith same. respect Every to theiraddition reactivity. of a monomer Thus, a and secondary propagating species are present with the same probability, i.e., when for each growing narrowmolecule molar leads mass to formation distribution of the is possiblepropagating only speciewhen containingat any time an in alkoxideeach growing of secondary macromolecule alcohol chain the apparent rate of propagation is the same. Every addition of a monomer− molecule− leads theand primary a primary and hydroxyl secondary side propagating group. Thus, species to maintain are present the same with probability the same probability,of –CH2O and i.e., =CHOwhen for in to formationeveryeach growing macromolecule, of the chain propagating the the apparent average specie rate time containing of betweenpropagation anthe alkoxide additionis the same. of secondarymonomer Every addition molecules alcohol of a and shouldmonomer a primary be ´ ´ hydroxyllongermolecule side than leads group. the to time formation Thus, needed to of for maintain the establishing propagating the sameeq specieuilibrium probability containing between ofan the –CHalkoxide abov2Oementioned ofand secondary =CHO alkoxides. alcoholin every Such conditions could be assured by slow monomer additions, maintaining low monomer macromolecule,and a primary the hydroxyl average side time group. between Thus, the to maintain addition the of same monomer probability molecules of –CH should2O− and be =CHO longer− in than the timeconcentrationevery needed macromolecule, for during establishing the the whole average equilibrium polymerization time between between process. the the addition abovementioned of monomer alkoxides. molecules Such should conditions be couldlonger be assuredGlycidol than the byalso time slow polymerizes needed monomer for by establishing additions, cationic means. eq maintaininguilibrium Cationic between low polymerization monomer the abovementioned concentration of oxiranes alkoxides. proceeds during the according to the active chain-end (ACE) and/or activated monomer (AM) mechanisms [38]. In wholeSuch polymerization conditions could process. be assured by slow monomer additions, maintaining low monomer polymerization proceeding by ACE mechanism, the active species are tertiary oxonium ions located Glycidolconcentration also during polymerizes the whole by polymerization cationic means. process. Cationic polymerization of oxiranes proceeds at theGlycidol ends of growingalso polymerizes chains. For by glycidol, cationic themeans. propagation Cationic by polymerization the ACE mechanism, of oxiranes independently proceeds according to the active chain-end (ACE) and/or activated monomer (AM) mechanisms [38]. ofaccording the ring-opening to the active mode chain-end during propagation,(ACE) and/or le adsactivated exclusively monomer to polymers (AM) mechanisms with primary [38]. side In In polymerization proceeding by ACE mechanism, the active species are tertiary oxonium ions located hydroxylpolymerization groups proceeding (see Scheme by 12). ACE mechanism, the active species are tertiary oxonium ions located at theat ends the ends of growing of growing chains. chains. For For glycidol, glycidol, the the propagation propagation byby thethe ACEACE me mechanism,chanism, independently independently of the ring-openingof the ring-opening mode during mode during propagation, propagation, leads exclusivelyleads exclusively to polymers to polymers with primarywith primary side hydroxylside groupshydroxyl (see Scheme groups 12 (see). Scheme 12).

Scheme 12. Monomer addition routes in the cationic polymerization of glycidol.

Propagation according to the AM mechanism consists of a reaction of protonated monomer molecules with the hydroxyl end-groups of the growing chains. Depending on the mode of ring Scheme 12. Monomer addition routes in the cationic polymerization of glycidol. Scheme 12. Monomer addition routes in the cationic polymerization of glycidol.

Propagation according to the AM mechanism consists of a reaction of protonated monomer Propagationmolecules with according the hydroxyl to the end-groups AM mechanism of the growing consists chains. of a Depending reaction of on protonated the mode of monomer ring molecules with the hydroxyl end-groups of the growing chains. Depending on the mode of ring scission in the activated monomer molecule, the primary and secondary hydroxyl groups are formed. Polymers 2016, 8, 227 7 of 24 Polymers 2016, 8, 227 7 of 24 Polymers 2016, 8, 227 7 of 25 scissionscission inin thethe activatedactivated monomermonomer molecule,molecule, thethe primaryprimary andand secondarysecondary hydroxylhydroxyl groupsgroups areare formed.formed. A studystudy byby S. S. Penczek Penczeket etet al. al.al.revealed revealedrevealed that thatthat in theinin thethe cationic cationiccationic polymerization polymerizationpolymerization of glycidol ofof glycidolglycidol initiated initiatedinitiated with withBrønsted Brønsted acids acids the AM the mechanism AM mechanism plays plays an important an important role [38 role]. Because [38]. Because activated activated glycidol glycidol also reacts also withreactsreacts hydroxyl withwith hydroxylhydroxyl groups groupsgroups along the alongalong polyglycidol thethe polpolyglycidol chains, chains, branching branching is inevitable. is inevitable. The polymerpolymer formed formed after after the completethe complete monomer monomer conversion conversion contains contains the primary the andprimary secondary and secondaryhydroxylsecondary groups. hydroxylhydroxyl The groups.groups. primary TheThe hydroxyl primaryprimary groups hydroxylhydroxyl are the groupsgroups exocyclic areare thethe groups exocyclicexocyclic remaining groupsgroups from remainingremaining the monomer. fromfrom Thethethe monomer. secondarymonomer. hydroxylTheThe secondarysecondary groups hydroxylhydroxyl are formed groupsgroups as a result areare formed offormed propagation asas aa resultresult along ofof the propagationpropagation pathway, as alongalong shown thethe in pathway,Scheme 13 as. shown in Scheme 13.

Scheme 13. Cationic polymerization of glycidol by the activated monomer mechanism. Scheme 13. Cationic polymerization of glycidol by the activated monomer mechanism.

2.5. Synthesis of Polyglycidol with Varied TopologyTopology byby GraftingGrafting fromfrom thethe LinearLinear PolyglycidolPolyglycidol Linear polyglycidolpolyglycidol containing containing hydroxyls hydroxyls not not only on aslyly theasas thethe end endend groups groupsgroups but also butbut alongalsoalso alongalong the chain thethe couldchainchain couldbecould functionalized bebe functionalizedfunctionalized and modified andand modifimodifi in variouseded inin variousvarious ways. Recently ways.ways. RecentlyRecently Frey discussed FreyFrey discusseddiscussed this subject thisthis in subjectsubject a detailed inin aa detailedmanner [manner32]. Equilibration [32]. Equilibration of low molarof low massmolar metal mass alkoxidesmetal alkoxides with polyglycidol with polyglycidol converts converts some somehydroxylsome hydroxylhydroxyl groups groupsgroups along the alongalong polymer thethe chainpolymerpolymer into chainchain alkoxides, intointo whichalkoxides,alkoxides, are able whichwhich to initiate areare ableable the polymerizationtoto initiateinitiate thethe polymerizationof oxiranes and cyclicof oxiranes esters and (see cyclic Scheme esters 14). (see Alkoxide Scheme anions 14). Alkoxide along the anions polyglycidol along the chain polyglycidol could also chainbechain formed couldcould by alsoalso contact bebe formedformed of the polyglycidol byby contactcontact solutionofof thethe popo withlyglycidollyglycidol sodium solutionsolution or a potassium withwith sodiumsodium mirror. oror Since aa potassiumpotassium reactions mirror.of alkoxide Since and reactions hydroxyl of alkoxide groups are and reversible, hydroxyl agroups new chain are reversible, may be grown a new from chain practically may be grown every fromhydroxylfrom practicallypractically group. everyevery hydroxylhydroxyl group.group.

Scheme 14. Macroinitiators on the basis of linear polyglycidol. Scheme 14. Macroinitiators on the ba basissis of linear polyglycidol.

The structure of the obtained polymer depends on the monomer used for the synthesis of the The structure of the obtained polymer depends on the monomer used for the synthesis of the grafts. grafts. For example, formation of grafts from linear polyglycidol carried out by polymerization of For example, formation of grafts from linear polyglycidol carried out by polymerization of blocked

Polymers 2016, 8, 227 8 of 25 Polymers 2016, 8, 227 8 of 24 blockedglycidol glycidol (e.g., 1-ethoxyethylglycidyl (e.g., 1-ethoxyethylglycidyl or tert-butylglycidyl or tert-butylglycidyl ether) yields ether) polymers yields polymers with a comb-like with a comb-likestructure,Polymers whereasstructure, 2016, 8, 227 grafting whereas of glycidolgrafting would of glycid resultol inwould hyperbranched result in grafts.hyperbranched The abovementioned grafts.8 of 24 The processesabovementioned are shown processes in Schemes are shown 15 and in 16Schemes, illustrating 15 and syntheses 16, illustrating of polyglycidol syntheses withof polyglycidol linear and withhyperbranched linearblocked and glycidol grafts,hyperbranched (e.g., respectively. 1-ethoxyethylglycidyl grafts, respectively. or tert -butylglycidyl ether) yields polymers with a comb-like structure, whereas grafting of glycidol would result in hyperbranched grafts. The abovementioned processes are shown in Schemes 15 and 16, illustrating syntheses of polyglycidol with linear and hyperbranched grafts, respectively.

Scheme 15. Synthesis of comb-like polyglycidol. SchemeScheme 15. 15.Synthesis Synthesis ofof comb-like polyglycidol. polyglycidol.

Scheme 16. Linear polyglycidol with hyperbranched grafts. Scheme 16. Linear polyglycidol with hyperbranched grafts. 2.6. Synthesis of Polyglycidol-Containing Copolymers 2.6. Synthesis of Polyglycidol-Containing Copolymers The presence of hydroxyl groups (which may be protected or not) in glycidol and Theglycidol-related presencepresence of of hydroxylmonomers hydroxyl groups opensgroups (which possibilities(which may be ma protected fory bethe protected or not)synthesis in glycidolor ofnot) anda invariety glycidol-relatedglycidol of and glycidol-relatedmonomerspolyglycidol-containing opens possibilitiesmonomers copolymers. foropens the synthesisGenerally,possibilities ofthe a possible variety for routes ofthe polyglycidol-containing include:synthesis of a copolymers.variety of polyglycidol-containingGenerally,a. synthesis the possible of the routes copolymers. linear include: di-block Generally, copolymers the possibleby polymerization routes include: of glycidol with blocked hydroxyl groups in the process initiated with macroinitiator, i.e., with other polymers a. synthesis of the linear di-block copolymers by polymerization of glycidol with blocked a synthesiscontaining of the active linear centers di-block at the copolymers ends of their by chains; polymerization of glycidol with blocked hydroxyl hydroxylb.groups synthesis in groups the of process the inlinear the initiated di-block process with copolymers initiated macroinitiator, usinwithg polyglycidol macroinitiator,i.e., with otherwith blocked polymersi.e., with hydroxyl containingother groups polymers active containingcentersalong at theactive endschain centers ofand their atactive chains;the endsend ofgroups, their chains;as an initiator for the polymerization of other b.b synthesissynthesiscomonomers; of of the the linear linear di-block di-block copolymers copolymers usin usingg polyglycidol with blocked hydroxyl groups alongc.along synthesis thethe chainchain of andthe and linear active active tri-block end groups,end copolymers groups, as an initiator usingas an di-block initiator for the copolymers polymerization for the withpolymerization active of other end comonomers; groups of other (obtained by routes a or b) as macroinitiatiors for the polymerization leading to addition of the c comonomers;synthesis of the linear tri-block copolymers using di-block copolymers with active end groups third block; c. synthesis(obtained of by the routes linear a ortri-block b) as macroinitiatiors copolymers using for thedi-block polymerization copolymers leading with active to addition end groups of the (obtained third block; by routes a or b) as macroinitiatiors for the polymerization leading to addition of the third block;

Polymers 2016, 8, 227 9 of 25 Polymers 2016, 8, 227 9 of 24

d. synthesis of the linear tri-block copolymer by polymerization of glycidol with a blocked d synthesis of the linear tri-block copolymer by polymerization of glycidol with a blocked hydroxyl hydroxyl group, initiated by a di-functional initiator and using the synthesized di-block group, initiated by a di-functional initiator and using the synthesized di-block macroinitiator for macroinitiator for the polymerization of other monomers, resulting in the addition of new the polymerization of other monomers, resulting in the addition of new blocks at both ends; blocks at both ends; e synthesis of the linear tri-block copolymer in a way similar to route d but by using glycidol with e. synthesis of the linear tri-block copolymer in a way similar to route d but by using glycidol with blocked hydroxyl groups as a second comonomer; blocked hydroxyl groups as a second comonomer; f synthesis of a comb-like copolymer by using polyglycidol (with unprotected hydroxyl groups) f. synthesis of a comb-like copolymer by using polyglycidol (with unprotected hydroxyl groups) as a macroinitiator and catalyst (e.g., Sn(Oct)2) for polymerization of other comonomers; as a macroinitiator and catalyst (e.g., Sn(Oct)2) for polymerization of other comonomers; g.g synthesis of the branched copolymer in aa wayway similarsimilar toto routeroute ff butbut usingusing hyperbranchedhyperbranched polyglycidol as a macroinitiator; hh. synthesis of the linear-hyperbranched copolymercopolymer inin aa wayway similarsimilar toto routeroute aa butbut usingusing glycidolglycidol (i.e., a monomer withwith unblockedunblocked hydroxylhydroxyl groups)groups) asas aa secondsecond monomer;monomer; i.i synthesis ofof thethe hyperbranchedhyperbranched copolymer copolymer by by polymerization polymerization of of glycidol glycidol from from reactive reactive groups groups in inthe the corona corona of anotherof another hyperbranched hyperbranched copolymer. copolymer.

SchemesSchemes 17 17 and and 18 18 illustrate illustrate somesome of of the the abovementioned abovementioned routes. routes.

Scheme 17. Selected routes leading to copolymers with blocked polyglycidol blocks. Scheme 17. Selected routes leading to copolymers with blocked polyglycidol blocks.

Polymers 2016, 8, 227 10 of 25 Polymers 2016, 8, 227 10 of 24

Polymers 2016, 8, 227 10 of 24

Scheme 18. Selected routes leading to copolymers with blocked polyglycidol blocks. Scheme 18. Selected routes leading to copolymers with blocked polyglycidol blocks. Not all Schemeroutes 18.shown Selected in Schemesroutes leading 17 and to copolyme 18 werers verified with blocked experimentally. polyglycidol blocks. However, taking into accountNot all routesour present shown knowledge, in Schemes they 17 andall should 18 were allow verified for synthesis experimentally. of the desired However, products. taking Below into Not all routes shown in Schemes 17 and 18 were verified experimentally. However, taking into accountare ourlisted present some examples knowledge, of copolymer they all should synthesis. allow for synthesis of the desired products. Below are account our present knowledge, they all should allow for synthesis of the desired products. Below listed someMöller examples et al. synthesized of copolymer polystyrene- synthesis.b-polyglycidol in a sequential polymerization of styrene are listed some examples of copolymer synthesis. andMöller 1-ethoxyethylglycidylet al. synthesized polystyrene- ether (blockedb-polyglycidol glycidol) inwith a sequential subsequent polymerization deprotection of of styrene hydroxyl and Möller et al. synthesized polystyrene-b-polyglycidol in a sequential polymerization of styrene 1-ethoxyethylglycidylgroups,and 1-ethoxyethylglycidyl using concentrated ether (blocked ether HCl glycidol)(blockedor acidic glycidol withion-exchange subsequent) with resinssubsequent deprotection [39,40]. deprotection It ofshould hydroxyl be of mentioned groups,hydroxyl using that concentratedpolystyrenegroups, using HCl and orconcentrated acidicpolydiene ion-exchange HCl blocks or acidic are resins usually ion-exchange [39 obtained,40]. Itresins should using [39,40]. belithium mentioned It should initiators. be that mentioned This polystyrene is especially that and polydieneimportantpolystyrene blocks in and arethe polydiene usuallycase of obtaineddienes blocks like are using butadieneusually lithium obtained an initiators.d isoprene, using Thislithium when is especially initiators. a high content importantThis is ofespecially 1–4 in theunits case is of dienesrequired.important like butadienePolystyrene–Liin the case andof dienes isoprene,and polydiene–Li like butadiene when a highactive and contentisoprene, speciesof arewhen 1–4 sufficiently unitsa high is content required. reactive of 1–4 Polystyrene–Lito addunits epoxide is and polydiene–Limolecules.required. Polystyrene–Li However, active species lithium and arepolydiene–Li alkoxides sufficiently formed active reactive speciesas a to result addare sufficiently epoxideof the abovementioned molecules. reactive to However, add additions epoxide lithium are alkoxidesmuchmolecules. formed less reactiveHowever, as a result and lithium are of theunable alkoxides abovementioned to add formed subsequent as additions a result monomer of are the much abovementionedmolecules less reactive [41,42]. additions and As are a result, unable are the to add subsequentone-potmuch less chain reactive monomer extension and moleculesare of unable polyvinyl [41to ,add42 ].block subsequent As a with result, poly(1-ethoxyethylglycidyl monomer the one-pot molecules chain extension [41,42]. ether)As of a polyvinyl result, is ineffective. the block + + + withThus,one-pot poly(1-ethoxyethylglycidyl before chain continuation extension of ofpolyvinyl ether)the synthesis isblock ineffective. withthe exchangepoly(1-ethoxyethylglycidyl Thus, beforeof Li for continuation K or Csether) cations of is the ineffective. synthesisis necessary, the Thus, before continuation of the synthesis the exchange of Li+ for K+ or Cs+ cations is necessary, exchangemaking of Lithe+ for synthesis K+ or Cs more+ cations tedious. is necessary, The problem making was thesolved synthesis when morethe polymerization tedious. The problem of epoxides was promotedmaking the by synthesis phosphazene more tedious. base P(4)- Thet -Buproblem (see Schemewas solved 19) whenstrongly the complexingpolymerization Li+ ofwas epoxides developed solvedpromoted when the by polymerization phosphazene base of epoxidesP(4)-t-Bu (see promoted Scheme by 19) phosphazene strongly complexing base P(4)- Li+t -Buwas (seedeveloped Scheme 19) [43,44]. + strongly[43,44]. complexing Li was developed [43,44].

SchemeScheme 19. 19. Structure Structure of ofthe the P(4)- P(4)-t-But-Bu phosphazene phosphazene base. base. Scheme 19. Structure of the P(4)-t-Bu phosphazene base.

Polymers 2016, 8, 227 11 of 25

Polymers 2016, 8, 227 11 of 24 Addition of P(4)-t-Bu at the beginning of the synthesis of the second block (i.e., at the beginning of the polymerizationAddition of of P(4)- epoxides)t-Bu at the results beginning in the of complexation the synthesis ofof Lithe+ cations.second block Formation (i.e., at the of a beginning Li+/P(4)- t-Bu + complexof the shifts polymerization the equilibrium of epoxides) between results the covalent in the complexation lithium alkoxides of Li andcations. the muchFormation more of reactive a Li+/P(4)-t-Bu complex shifts the equilibrium between the covalent lithium alkoxides and the much ionic species towards the latter ones. This approach allowed for obtaining polystyrene-b-polyglycidol more reactive ionic species towards the latter ones. This approach allowed for obtaining copolymerspolystyrene- withb degrees-polyglycidol of polymerization copolymers with ranging degrees from of polymerization 40 to 160 and ranging from 70 from to 220 40 forto 160 polystyrene and and polyglycidolfrom 70 to 220 blocks, for polystyrene respectively and po [40lyglycidol]. blocks, respectively [40]. MacroinitiatorsMacroinitiators obtained obtained in in the the reaction reaction ofof poly(styrene-poly(styrene-coco-butadiene--butadiene-co-isoprene)–OHco-isoprene)–OH with with potassiumpotassium hydride hydride were were used used forfor thethe synthesissynthesis of of copolymers copolymers containing containing polyvinyl polyvinyl and and poly(1-ethoxyethylglycidylpoly(1-ethoxyethylglycidyl ether) ether) blocks. blocks. The The successful successful deprotection deprotection with with concentrated concentrated HCl HCl yielded copolymersyielded withcopolymers polyglycidol with polyglycidol blocks [45 blocks]. [45]. EspeciallyEspecially interesting interesting are are copolymerscopolymers containi containingng the thehydrophobic hydrophobic biodegradable biodegradable polyester polyester and the hydrophilic polyglycidol blocks. These copolymers are considered candidates for the and the hydrophilic polyglycidol blocks. These copolymers are considered candidates for the preparation of drug carriers. To this class belong poly(ethylene preparation of drug carriers. To this class belong poly(ethylene oxide)-b-polyglycidol-b-poly(L-lactide) oxide)-b-polyglycidol-b-poly(L-lactide) tri-block copolymers, which were synthesized by a tri-blocksequential copolymers, polymerization which wereof ethylene synthesized oxide, 1-ethoxyethylglycidyl by a sequential polymerization ether and L-lactide of ethylene and by oxide, 1-ethoxyethylglycidyldeprotection converting ether acetal and grLoups-lactide in poly(1-ethoxyethylglycidyl and by deprotection ether) converting into hydroxyl acetal groups groups in poly(1-ethoxyethylglycidyl(Scheme 20) [46]. ether) into hydroxyl groups (Scheme 20)[46].

Scheme 20. Synthesis of tri-block copolymer with poly(ethylene oxide), polyglycidol and polylactide Scheme 20. Synthesis of tri-block copolymer with poly(ethylene oxide), polyglycidol and blocks. polylactide blocks. A linear tri-block copolymer with central polyglycidol and side polylactide blocks was Asynthesized linear tri-blockby one-pot copolymer polymerization with central of 1-ethoxyethylglycidyl polyglycidol and ether side polylactideinitiated with blocks wasHOC(CH synthesized3)2CH2CH by2C(CH one-pot3)2O−K polymerization+ (a derivative ofof 2,4-dimethylhexane-2,4-diol), 1-ethoxyethylglycidyl etherwith subsequent initiated with (when the first monomer was´ consumed)+ polymerization of L-lactide [30]. Due to the proton HOC(CH3)2CH2CH2C(CH3)2O K (a derivative of 2,4-dimethylhexane-2,4-diol), with subsequent exchange, L-lactide polymerized at both ends. Deprotection of hydroxyl groups, carried out using (when the first monomer was consumed) polymerization of L-lactide [30]. Due to the proton exchange, AlCl3∙6H2O, was highly selective. Only the acetal groups were cleaved, leaving the ester groups in L-lactide polymerized at both ends. Deprotection of hydroxyl groups, carried out using AlCl3¨6H2O, the poly(L-lactide) blocks intact. was highly selective. Only the acetal groups were cleaved, leaving the ester groups in the poly(L-lactide) It should be noted that in the synthesis of linear copolymers with polyglycidol and polylactide blocksblocks intact. the sequence of block synthesis is important. At least for K+ counterions, the Itpoly(1-ethoxyethylglycidyl should be noted that in the ether) synthesis block of linearshould copolymers be synthesized with polyglycidol first. This andis polylactidebecause the blocks + the sequence…-CH[CH of2OCH(CH block synthesis3)OCH2CH is important.3]O−K+ growing At least forspecies, K counterions, located at the the poly(1-ethoxyethylglycidyl ends of living ´ + ether)poly(1-ethoxyethylglycidyl block should be synthesized ether), first. Thisinitiate is becausethe thepolymerization... -CH[CH 2OCH(CHof L-lactide,3)OCH whereas2CH3]O K growing…-C(O)CH(CH species, located3)O-K+ species at the of living ends polylactide of living are poly(1-ethoxyethylglycidyl inefficient as initiators of the ether),polymerization initiate the of 1-ethoxyethylglycidyl ether. However, such a limitation does+ not apply to the copolymerization of polymerization of L-lactide, whereas ... -C(O)CH(CH3)O-K species of living polylactide are inefficient as initiatorstert-butyl of glycidyl the polymerization eter with ε-caprolactione, of 1-ethoxyethylglycidyl initiated with ether. benzyl However, alcohol/such P(4)- at-Bu limitation system, doesfor not which it was possible to obtain random copolymers [47]. Molar masses of synthesized copolymers apply to the copolymerization of tert-butyl glycidyl eter with ε-caprolactione, initiated with benzyl were in the range of 13,000 to 49,200. Hydrolysis of t-Bu–O–CH2– groups in copolymers yielded alcohol/ P(4)-t-Bu system, for which it was possible to obtain random copolymers [47]. Molar masses of polyglycidol units. synthesized copolymers were in the range of 13,000 to 49,200. Hydrolysis of t-Bu–O–CH2– groups in copolymers yielded polyglycidol units.

Pluronic-type copolymers in which polyglycidol constituted the external blocks were also synthesized [48]. The synthesis began with activation of both ends of the hydroxyl-terminated Polymers 2016, 8, 227 12 of 24 Polymers 2016, 8, 227 12 of 25 Pluronic-type copolymers in which polyglycidol constituted the external blocks were also synthesized [48]. The synthesis began with activation of both ends of the hydroxyl-terminated poly(propylene oxide) with CsOH¨ H O. Water produced at this stage was removed by the poly(propylene oxide) with CsOH·H2O.2 Water produced at this stage was removed by the addition additionof dry benzene of dry benzene and azeotropic and azeotropic distillation, distillation, yielding yielding a apoly(propylene poly(propylene oxide) oxide) di-functionaldi-functional + macroinitiator containing Cs Cs+ alcoholatealcoholate active active enters. enters. The The macroinitiator macroinitiator initiated initiated polymerization polymerization of of1-ethoxyethylglycidyl 1-ethoxyethylglycidyl ether ether andand the tri-blockthe tri-block copolymer—poly(1-ethoxyethylglycidyl copolymer—poly(1-ethoxyethylglycidyl ether)-b- poly(propyleneether)-b-poly(propylene oxide)-b -poly(1-ethoxyethylglycidyloxide)-b-poly(1-ethoxyethylglycidyl ether) was ether) obtained. was obtained. Acetal groupsAcetal groups in poly(1- in ethoxyethylglycidyl ether) were cleaved with AlCl ¨6H O, yielding the polyglycidol- b-poly(propylene poly(1-ethoxyethylglycidyl ether) were 3cleaved2 with AlCl3∙6H2O, yielding the oxide)-polyglycidol-b-polyglycidolb-poly(propylene tri-block copolymer.oxide)-b-polyglycidol tri-block copolymer. There are reports onon thethe synthesissynthesis ofof polyglycidol-containingpolyglycidol-containing graft copolymers with branched polyglycidol grafts or with branchedbranched polyglycidolpolyglycidol corescores [[49,50].49,50]. A polystyrene main chain was synthesized by RAFT copolymerization of styrene and α α α 4-acetoxystyrene initiated by S-1-dodecyl-S’’S”-(α,α’-dimethyl-α’’-acetic”-acetic acid) trithiocarbonate as a chain-transfer agent agent [49]. [49]. Hydrolysis Hydrolysis of ofacetoxy acetoxy groups groups yielded yielded poly( poly(p-hydroxystyrene)p-hydroxystyrene) units. units. The Theactivation activation of hydroxyl of hydroxyl groups groups with with diphenylmethyl diphenylmethyl potassium potassium (DPMK) (DPMK) yielded yielded a a macroinitiator initiating polymerization polymerization of of glycidol. glycidol. At At this this step step the the branched branched polyglycidol polyglycidol grafts grafts were were formed. formed. The Theprocess process is illustrated is illustrated in Scheme in Scheme 21. 21.

Scheme 21. Synthesis of polystyrene with branched polyglycidol grafts. Scheme 21. Synthesis of polystyrene with branched polyglycidol grafts.

The branched polyglycidol core of copolymer with poly(L-lactide) multi-arms was synthesized L by ring-openingThe branched polymerization polyglycidol core of of glycidol copolymer catalyzed/initiated with poly( -lactide) with multi-arms Sn(Oct)2 was. The synthesized addition byof ring-openingD-lactide after polymerization complete conversion of glycidol of glycidol catalyzed/initiated leads to formation with Sn(Oct) of the2. The external addition poly( of LD-lactide)-lactide afterarms complete[50]. This copolymerizat conversion ofion glycidol conforms leads toto route formation g in Scheme of the 18, external with M poly( denotingL-lactide) D-lactide. arms [50]. This copolymerization conforms to route g in Scheme 18, with M denoting D-lactide. 2.7. Functionalized Polyglycidol and Polyglycidol-Containing Copolymers 2.7. Functionalized Polyglycidol and Polyglycidol-Containing Copolymers Functionalized polyglycidol could be obtained by the introduction of required functional Functionalized polyglycidol could be obtained by the introduction of required functional groups groups during initiation, termination, or as a result of reactions with polyglycidol –CH2OH side during initiation, termination, or as a result of reactions with polyglycidol –CH OH side groups. groups. 2 For example, the synthesis of branched polyglycidol with primary amine groups was performed For example, the synthesis of branched polyglycidol with primary amine groups was in a process that consisted of the following steps [51]: performed in a process that consisted of the following steps [51]: ‚• initiationinitiation ofof thethe polymerizationpolymerization ofof ethyleneethylene oxideoxide withwith cesiumcesium dibenzyl-2-aminoethanolate;dibenzyl-2-aminoethanolate; ‚• using obtainedobtained macroinitiator macroinitiator for for initiation initiation of theof polymerizationthe polymerization of 1-ethoxyethylglycidyl of 1-ethoxyethylglycidyl ether; ‚ deblockingether; of hydroxyl groups in poly(1-ethoxyethylglycidyl ether), activation of hydroxyl groups • withdeblocking CsOH; of hydroxyl groups in poly(1-ethoxyethylglycidyl ether), activation of hydroxyl ´ + ‚ polymerizationgroups with CsOH; of glycidol initiated with . . . –CH2O Cs ; • 2 − + ‚ conversionpolymerization of the of dibenzyl-2-aminoethyl-O– glycidol initiated with …–CH . . . groupsO Cs ; into the NH2CH2CH2O– . . . groups. • conversion of the dibenzyl-2-aminoethyl-O–… groups into the NH2CH2CH2O–… groups. DetailsDetails of the of synthesis the synthesis are shown are shown in Scheme in Scheme 22. 22.

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Scheme 22. Synthesis of branched polyglycidol with primary amine groups. SchemeScheme 22. 22.Synthesis Synthesisof of branchedbranched polyglycidol with with primary primary amine amine groups. groups. It was also possible to obtain the sulfonate derivative of the abovementioned polymer [51]. It wasTheIt was alsoamine also possible possiblegroups to into obtain branchedobtain the the sulfonatepolyglycidol, sulfonate derivativederivative shown of in the theScheme abovementioned abovementioned 22, were further polymer polymer modified [51]. [51 ]. by reactionTheThe amine with amine 1-pyrene-butyric groups groups in in branched branched acid pentafluorophenyl polyglycidol,polyglycidol, shown ester. in in TheScheme Scheme reaction 22, 22 ,resultedwere were further further in the modified addition modified byof by reactionthereaction pyrene with with moiety. 1-pyrene-butyric 1-pyrene-butyric The pyrene acidacid labels pentafluorophenyl pentafluorophenyl promoted adsorption ester. ester. Theof The the reaction reactionstrongly resulted resultedhydrophilic, in the in addition the branched addition of the pyrene moiety. The pyrene labels promoted adsorption of the strongly hydrophilic, branched ofpolyglycidol the pyrene moiety. onto the The multi-walled pyrene labels carbon promoted nanotube adsorptions, ensuringof their the solubilization strongly hydrophilic, with water branched [51]. polyglycidol onto the multi-walled carbon nanotubes, ensuring their solubilization with water [51]. polyglycidolEnd-capping onto the of multi-walled the living poly(1-ethoxyethylglycidyl carbon nanotubes, ensuring ether) their solubilizationwith p-chloromethyl with water styrene [51]. End-capping of the living poly(1-ethoxyethylglycidyl ether) with p-chloromethyl styrene yieldedEnd-capping α-t-butoxy- of theω-vinylbenzyl-poly(1-ethoxyethylglycidyl living poly(1-ethoxyethylglycidyl ether) ether), with whichp-chloromethyl after deprotection styrene yieldedwith yielded α-t-butoxy-ω-vinylbenzyl-poly(1-ethoxyethylglycidyl ether), which after deprotection with α-tformic-butoxy- acidω -vinylbenzyl-poly(1-ethoxyethylglycidylgave α-t-butoxy-ω-vinylbenzyl-polyglycidol ether), [52]. whichThe macromonomer after deprotection was withused formicas a formic acid gave α-t-butoxy-ω-vinylbenzyl-polyglycidol [52]. The macromonomer was used as a surfmer,α stabilizing ωmicrospheres synthesized in the radical emulsion polymerization of styrene acidsurfmer, gave stabilizing-t-butoxy- microspheres-vinylbenzyl-polyglycidol synthesized in [the52]. radical The macromonomer emulsion polymerization was used asof astyrene surfmer, stabilizing[53]. microspheres synthesized in the radical emulsion polymerization of styrene [53]. [53]. Functionalization of polyglycidol blocks in the tri-block copolymers (see Scheme 20) was Functionalization of polyglycidol blocks in the tri-block copolymers (see Scheme 20) was convenientlyFunctionalization performed of by polyglycidol esterification blocks of its hyin droxymethylthe tri-block groupscopolymers with acid(see chloridesScheme 20)or withwas conveniently performed by esterification of its hydroxymethyl groups with acid chlorides or with cyclicconveniently anhydrides performed [54]. These by esterification functionalization of its processes hydroxymethyl are illustrated groups in with Scheme acid 23.chlorides or with cycliccyclic anhydrides anhydrides [54 [54].]. These These functionalization functionalization processesprocesses are illustrated illustrated in in Scheme Scheme 23. 23 .

Scheme 23. Synthesis of tri-block copolymer with poly(ethylene oxide), polyglycidol and polylactide Scheme 23. Synthesis of tri-block copolymer with poly(ethylene oxide), polyglycidol and polylactide Schemeblocks 23.withSynthesis carboxylic of acid tri-block and 4-(phenyl-azo-phenyl) copolymer with poly(ethylene groups . oxide), polyglycidol and polylactide blocks with carboxylic acid and 4-(phenyl-azo-phenyl) groups . blocks with carboxylic acid and 4-(phenyl-azo-phenyl) groups. In 2010 Möller developed an elegant route for the synthesis of polyglycidol with some blocks In 2010 Möller developed an elegant route for the synthesis of polyglycidol with some blocks labeled with side C12, C14, and C16 alkyl chains [55]. The route was based on observation that in acidic In 2010 Möller developed an elegant route for the synthesis of polyglycidol with some blocks conditionslabeled with sidethe C 12, C14deblocking, and C16 alkyl chainsof [55].hydroxyl The route groupswas based onin observationpoly(t-butylglycidyl that in acidic labeled with side C ,C , and C alkyl chains [55]. The route was based on observation ether)-conditionsb-poly(1-ethoxyethylglycidyl the 12 deblocking14 16ether)of doeshydroxyl not proc eed groupsat the samein rate. Hydrolysispoly(t-butylglycidyl of acetal thatether)- in acidicb-poly(1-ethoxyethylglycidyl conditions the deblocking ether) of does hydroxyl not proc groupseed at inthe poly( samet-butylglycidyl rate. Hydrolysis ether)- of acetalb-poly

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Polymers 2016, 8, 227 14 of 24 (1-ethoxyethylglycidyl ether) does not proceed at the same rate. Hydrolysis of acetal groups is much groupseasier than is much hydrolysis easier of thant-butyl hydrolysis ether groups. of t-butyl However, ether it isgroups. worth notingHowever, that selectiveit is worth deprotection noting that of selectivehydroxyl groupsdeprotection in random of hydroxyl copolymers groups of t-butylglycidyl in random copolymers ether and 1-ethoxyethylglycidyl of t-butylglycidyl ether ether wasand 1-ethoxyethylglycidylnot successful [56]. Apparently, ether was the not neighboring successful group [56]. effect Apparently, facilitated the the neighboring hydrolysis of groupt-butyl effect ether facilitatedgroups adjacent the hydrolysis to the solvated of t-butyl hydroxyls, ether whichgroups were adjacent formed to bythe fast solvated hydrolysis hydroxyls, of acetal which groups were [56]. formedThus, the by synthesis fast hydrolysis of polyglycidol, of acetal in groups which the[56]. units Thus, labeled the synthesis with alkyl of chains polyglycidol, constituted in which a separate the unitsblock, labeled was performed with alkyl by thechains following constituted sequence a se ofparate reactions: block, was performed by the following sequence of reactions: ‚ sequential polymerization of 1-ethoxyethylglycidyl ether and t-butylglycidyl ether initiated with ´ + • Csequential6H5–(CH 2polymerization)3O K ; of 1-ethoxyethylglycidyl ether and t-butylglycidyl ether initiated ‚ deblockingwith C6H5–(CH of hydroxyl2)3O−K+; groups in poly(1-ethoxyethylglycidol ether) with hydrochloric acid (the • concentrationdeblocking of ofhydroxyl HCl and groups time ofindeblocking poly(1-ethoxyethylglycidol were optimized); ether) with hydrochloric acid (the ‚ labelingconcentration of polyglycidol of HCl and with time alkyl of deblocking chains in reactionwere optimized); between –CH2OH groups of polyglycidol • andlabeling alkyl of chains polyglycidol with isocyanate with alkyl end-groups; chains in reaction between –CH2OH groups of polyglycidol ‚ deprotectionand alkyl chains of hydroxyl with isocyanate groups inend-groups; poly(t-butylglycidyl ether) block using trifluoroacetic acid. • deprotection of hydroxyl groups in poly(t-butylglycidyl ether) block using trifluoroacetic acid. The processThe process of synthesis of synthesis is illustrated is illustrated in Scheme in Scheme 24. 24.

Scheme 24. Synthesis fof polyglycidol with C12, C14, and C16 alkyl side chains. Scheme 24. Synthesis fof polyglycidol with C12,C14, and C16 alkyl side chains. Polyglycidol and polyglycidol-containing copolymers could also be conveniently functionalizedPolyglycidol by andclick polyglycidol-containing reaction [56]. The process copolymers consists of could the addition also be conveniently of propargyl functionalized moieties in a reactionby click of reaction propargyl [56]. bromide The process with consistsKOH-activated of the addition–CH2OH ofgroups propargyl of polyglycidol. moieties in The a reaction obtained of poly(glycidylpropargyl bromide propargyl with KOH-activatedether-co-glycidol) –CH is 2readyOH groups for further of polyglycidol. functionalization The obtained by Cu(I) poly(glycidyl controlled (2propargyl + 3) cycloaddition ether-co-glycidol) of compounds is ready with for azide further groups. functionalization Scheme 25 gives by an Cu(I) example controlled of the addition (2 + 3) ofcycloaddition a sugar moiety. of compounds with azide groups. Scheme 25 gives an example of the addition of a sugar moiety.

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Scheme 25. Polyglycidol labeled with sugar moieties.

The above-described modifications of polyglycidol and polyglycidol-containing copolymers The above-described modifications of polyglycidol and polyglycidol-containing copolymers yielded a variety of amphiphilic polymers, which, depending on the details of the structure of the yielded a variety of amphiphilic polymers, which, depending on the details of the structure of the hydrophilic and hydrophobic components, are often able to self-organize into nanoparticles, hydrophilic and hydrophobic components, are often able to self-organize into nanoparticles, liposomes, liposomes, and other polymer aggregates suitable for encapsulation or solubilization of hydrophobic andcompounds. other polymer The aggregatespresence of suitable reactive for groups encapsulation in polyglycidol or solubilization and polyglycidol-functionalized of hydrophobic compounds. Thederivatives presence allows of reactive their labeling groups inwith polyglycidol fluorescent and labels polyglycidol-functionalized [51,54]. derivatives allows theirThe labeling functional with fluorescent derivatives labels of polyglycidol [51,54]. can be used as building blocks for the preparation of nano-objectsThe functional useful derivativesfor various applications of polyglycidol in medicine. can be used as building blocks for the preparation of nano-objects useful for various applications in medicine. 3. Applications of Polyglycidol and Polyglycidol-Containing Polymers in Medicine 3. Applications of Polyglycidol and Polyglycidol-Containing Polymers in Medicine

3.1. Biocompatibility Biocompatibility of polymers is indispensable for using these materials in medicine as drugdrug carriers, implantsimplants (regardless (regardless whether whether permanent permanen or resorbable),t or resorbable), and various and elementsvarious ofelements equipment. of Thus,equipment. the issue Thus, of thethe biocompatibilityissue of the biocompatibility of polyglycidol of polyglycidol is of primary is importance. of primary importance. EfficientEfficient proteinprotein adsorption,adsorption, accompanied by conformational changes resulting in thethe denaturation of adsorbed proteins,proteins, usually triggerstriggers undesired effectseffects includingincluding immuneimmune responseresponse and clot formation, and has a deleterious influenceinfluence on the biological functions of adsorbed proteins. Extensive studiesstudies carriedcarried out out in in our our laboratory laboratory revealed revealed that that the the incorporation incorporation of polyglycidolof polyglycidol into into the interfacialthe interfacial layer layer of the of polystyrenethe polystyrene microspheres microspheres and surfacesand surfaces of carbon of carbon glass, glass, gold, gold, and stainlessand stainless steel flatsteel substrates flat substrates leads toleads a strong to a reduction strong reductio of proteinn of adsorption protein [adsorption57–62]. However, [57–62]. the However, activation the of polyglycidolactivation of hydroxylpolyglycidol groups hydroxyl with 1,3,5-trichlorotriazine groups with 1,3,5-trichlorotriazine allows for efficient allows covalent for efficient protein covalent binding (seeprotein Scheme binding 26)[ (see57,59 Scheme,61,62]. 26) [57,59,61,62].

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Scheme 26. Attachment of protein to polyglycidol. Scheme 26. Attachment of protein to polyglycidol. Studies of interactions of linear and branched polyglycidols and polyglycidol-containing copolymersStudies with of interactions cell cultures ofand linear living and organisms branched revealed polyglycidols that these andcompounds: polyglycidol-containing copolymers with cell cultures and living organisms revealed that these compounds: • do not interact with the DNA of the Chinese hamster B14 cell line (linear and arborescent ‚ dopolymers not interact with with poly(ethylene the DNA of oxide) the Chinese and polyglycidol hamster B14 units) cell line [63]; (linear and arborescent polymers • withare not poly(ethylene toxic towards oxide) peripherial and polyglycidol blood mononuclear units) [63]; cells (hyperbranched) [64]; • ‚ areare nothemocompatible toxic towards peripherial(hyperbranched blood polyglycidol mononuclear and cells hyperbranched (hyperbranched) copolymer [64]; of glycerol ‚ areand hemocompatible sebacic acid) [65,66]; (hyperbranched polyglycidol and hyperbranched copolymer of glycerol and • sebacicand are acid)well [tolerated65,66]; even if injected in high doses [65]. ‚ andIt was are wellalso tolerated found eventhat ifdendritic injected inpolyglycidol high doses [65with]. terminal sulfate end groups has anti-inflammatory properties [67]. These observations support the attempts to use polyglycidols with Itvarious was architectures also found thatas well dendritic as their copolymers polyglycidol as materials with terminal for medical sulfate applications. end groups has anti-inflammatory properties [67]. These observations support the attempts to use polyglycidols with3.2. Polyglycidol-Based various architectures Drug as Carriers well as their copolymers as materials for medical applications.

3.2. Polyglycidol-BasedMany papers on drug Drug carriers Carriers based on polyglycidol and polyglycidol derivatives have already been published. A comprehensive discussion of particular systems exceeds the scope of this paper. Many papers on drug carriers based on polyglycidol and polyglycidol derivatives have already We will only present a list providing brief information on encapsulated bioactive compounds, the been published. A comprehensive discussion of particular systems exceeds the scope of this paper. chemical composition of nano- or micro-carriers, and methods used for their preparation. The data We will only present a list providing brief information on encapsulated bioactive compounds, the are listed in Table 1. chemical composition of nano- or micro-carriers, and methods used for their preparation. The data are listed in Table1. Table 1. Drug carriers based on polyglycidol and polyglycidol derivatives.

Encapsulator Carrier Method of encapsulation Reference bioactive compound Proteins BSA Polylactide-hyperbranched polyglycidol nanoparticles Nanoprecipitation [68,69] Insulin β-cyclodextrin labeled polyglycidol nanoparticles Coprecipitation [70] Insulin β-cyclodextrin labeled polyglycidol hydrogel Gelation [71] Nanogels from dendritic polyglycidols with azide and Asparaginase Inverse nanoprecipitation [72] -p-propargyloxy-benzacetale Poly(N-isopropylacrylamide)- Nanogel swelling in transglutaminase 1 [73] polyglycerol-based nanogels protein solution Nucleic acids

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Table 1. Drug carriers based on polyglycidol and polyglycidol derivatives.

Encapsulator Carrier Method of encapsulation Reference bioactive compound Proteins BSA Polylactide-hyperbranched polyglycidol nanoparticles Nanoprecipitation [68,69] Insulin β-cyclodextrin labeled polyglycidol nanoparticles Coprecipitation [70] Insulin β-cyclodextrin labeled polyglycidol hydrogel Gelation [71] Nanogels from dendritic polyglycidols with azide and Asparaginase Inverse nanoprecipitation [72] -p-propargyloxy-benzacetale Poly(N-isopropylacrylamide)- Nanogel swelling in transglutaminase 1 [73] polyglycerol-based nanogels protein solution Nucleic acids DNA Quarternized a poly(glycidol-co-ethylene oxide) Nanoprecipitation [74] Quarternized branched Incubation of polymer and nucleic pDNA poly(glycidol-co-2,3-epoxypropyldiethyl-amine) [75] acid solution and DNA polyplexes Polyplexes of corona aminated hyperbranched Incubation of polymer and nucleic siRNA [76] polyglycidol and siRNA acid solution Polyplexes of hyperbranched polyglycidol modified with Incubation of polymer and nucleic siRNA [77] glycine and siRNA acid solution Polyplexes of amphiphilic copolymer containing Incubation of polymer and nucleic siRNA hyperbranched polyglycidol end-capped with [78] acid solution amines and siRNA Polyplexes of adamantane-modified hyperbranched Incubation of polymer and nucleic pDNA polyglycerol end-capped with cationic [79] acid solution β-cyclodextrin and pDNA Polyplexes of polyglycidol-pluronic-poly-glycidol with Incubation of polymer and nucleic pDNA 2-(N,N-dimethylaminomethyl)-5-aminomethyl [80] acid solution phenylboronic acid groups and pDNA Polyplexes of poly(ethylene oxide)-(branched Incubation of polymer and nucleic pDNA polyglycidol) with endgroups capped with [81] acid solution tris(2-aminoethyl)amine) nanodiamond particles with immobilized polyglycidol Incubation of nanocarrier and pDNA [82] modified with grafted poly(arg-co-lys-co-his) nucleic acid solution pDNA and Vesicles composed of cyclodextrin labeled with branched doxorubicin polyglycidol end-capped with tris(2-aminoethyl)amine) Nanoprecipitation [83] hydrochloride and bearing aliphatic chains DNA Lamin A/C) Polyplexes of hyperbranched polyglycidol modified by Incubation of polymer and nucleic and 51-CTGGACTTC [84] addition of oligoamines via the photo-cleavable linkages acid solution CAGAAGAACATT-3´ Anticancer drugs Covalent immobilization via the Doxorubicin Hyperbranched polyglycidol [85] enzymatically cleavable linkage Hyperbranched polyglycidol with grafted Covalent immobilization via the Doxorubicin [86] poly(ethylene oxide) enzymatically cleavable linkage Covalent immobilization via pH Doxorubicin Poly(ethylene oxide)-[hyperbranched polyglycidol] [87] sensitive hydrazone linkage Hyperbranched polyglycidol with grafted Covalent immobilization via pH Doxorubicin poly(ethylene oxide) and targeting antibodies agains [88] sensitive hydrazone linkage epidermal growth factor Covalent immobilization of drug Doxorubicin, and dye via cleavable linkage. indodicarbocyanine Hyperbranched polyglycidol [89] Monitoring of drug release dye by fluorescence Nanodiamond particles with grafted hyperbranched Covalent immobilization via pH Doxorubicin [90] polyglycidol end-capped with RGD tripeptide sensitive hydrazone linkage Hyperbranched polyglycidol modified with Covalent immobilization via Cisplatin [91] succinic anhydride carboxyl groups Nanodiamond particles with grafted hyperbranched Covalent immobilization via Cisplatin polyglycidol end-capped with RGD tripeptide and [92] carboxyl groups COOH groups Polymers 2016, 8, 227 18 of 25

Table 1. Cont.

Encapsulator Carrier Method of encapsulation Reference bioactive compound Fe O nanoparticles with immobilized Covalent immobilization via pH Methotrexate 3 4 [93] hyperbranched polyglycidol sensitive hydrazone linkage Hyperbranched polyglycidol with sulfate and Covalent immobilization via Paclitaxel [94] amine end groups cleavable ester linkage Hyperbranched polyglycidol with attached Solubilization of Paclitaxel [95,96] poly(ethylene oxide) and alkyl chains hydrophobic drug Polymeric micelles of hyperbranched polyglycidol labeled Paclitaxel Nanoprecipitation [97] with β-cyclodextrin Hyperbranched polyglycidol with attached Solubilization of Docetaxel [96] poly(ethylene oxide) and alkyl chains hydrophobic drug Docetaxel Hyperbranched polyglycidol with attached alkyl chains Nanoprecipitation [98] Sagopilone Hyperbranched polyglycidol with attached alkyl chains Entrapment during micellization [99] Miscellaneous Hyperbranched polyglycidol with biphenyl groups Solubilization of Nimodipine [100] in the core hydrophobic drug Quercetin Polylactide-(hyperbranched polyglycidol) Nanoprecipitation [101] Hyperbrached polyglycidol modified by addition of Water-in oil-in water Endomorphins [102] poly(lactide-co-glycolide) chains double emulsification

3.3. Applications of Polyglycidol and Polyglycidol Derivatives in Diagnostics-Based Drug Carriers Biocompatibility, long circulation time in the blood, the availability of many routes for functionalization, and the suitability for controlled binding of various biomolecules makes polyglycidol and its derivatives interesting for applications in medical diagnostics, both in vivo and in vitro. There is great interest in contrast agents used in tissue imaging. Gd3+-loaded hyperbranched polyglycidol with amine groups containing corona [103] and Fe3O4 superparamagnetic particles protected by a hyperbranched pololyglycidol coating, used to stabilize particle circulation in the blood, were found to be suitable for Magnetic Resonance Imaging (MRI) [104,105]. Hyperbranched polyglycidol with sulfated corona, labeled with indocyanine green or indotricarbocyanine dyes, were excellent agents for near-infrared fluorescence imaging [106,107]. Complex particles comprising a superparamagnetic iron oxide core coated with fluorescent silica and protected with grafted hyperbranched polyglycidol constitute a new contrast agent for MRI and optical imaging [108]. Tri-modal imaging systems were also developed based on hyperbranched polyglycidol labeled with radioactive 111In, fluorescent Alexa dye, and Gd3+ for MRI [109]. Hyperbranched polyglycidol with moieties chelating 67Ga/68Ga were studied as reagents for positron emission tomography (PET) [110]. Gold nanorods coated with hyperbranched polyglycidol with sulfated corona were used as a contrast agent for optoacoustic tomography, for the monitoring of rheumatoid arthritis [111]. Polyglycidol with immobilized glucose oxidase is an essential component of biosensors for the detection of glucose [112]. Basinska et al. developed a new type of diagnostic test based on the changes of electrophoretic mobility in poly(styrene/α-tertbutoxy-ω-vinylbenzyl-polyglycidol) [113]. The test was dedicated for determination of γ-globulins against Helicobacter pylori in the blood serum. The microspheres were synthesized by emulsion copolymerization of styrene and α-tert-butoxy-ω-vinylbenzyl-polyglycidol. Their interfacial layer enriched in polyglycidol allowed the covalent immobilization of antigens complementary to antibodies against Helicobacter pylori, the proteins that are present in the blood of infected patients. The polyglycidol-rich interfacial layer eliminated any adventitious protein adsorption, allowing only attachment of antibodies against Helicobacter pylori by antigen–antibody interactions. Since both microspheres and antibodies are electrically charged, the attachment of antibodies affects the mobility of microspheres in an electric field. Polymers 2016, 8, 227 19 of 25

4. Conclusions Synthesis of polyglycidol with moderate molar mass (about 30,000) and controlled topology (linear, star-like, hyperbranched) does not pose a problem. Many methods were developed for synthesis of various copolymers containing units of polyglycidol, polyethers (mainly poly(ethylene oxide) and poly(propylene oxide)), polyesters (polylactide and poly(ε-caprolactone)), and polyolefins (styrene). These copolymers could be functionalized with alkene and alkyne moieties, sulfate, amine, azide, and carboxyl groups. They could be used for binding proteins and other biomolecules. Polyglycidols modified with hydrophobic segments self-assemble into polymeric micelles, polymeric liposomes, and other kinds of aggregates. When tethered to surfaces they modify the surface properties, making the surfaces hydrophilic and antifouling. Amphiphilic derivatives of polyglycidol are promising candidates for drug carriers and for contrast agents useful for various kinds of tissue imaging. However, in spite of significant achievements in this field, there are still several problems to be solved. Many functionalization processes and synthetic routes of drug carriers are multistep and for large-scale pharmaceutical applications they are probably too expensive. Thus, a further search for simpler modification routes is still needed. Knowledge of relations between topology and chemical composition of polyglycidol-containing copolymers and their self-organization into polymeric micelles and other types of nanoparticles is insufficient and still requires further studies. In spite of numerous reports on protein–polyglycidol interactions, further investigation will be needed to give a detailed explanation of these interactions at a molecular level. The possibility of synthesizing high molar mass polyglycidol and polyglycidol-containing copolymers with biodegradable segments; i.e., copolymers with mechanical properties appropriate for use as temporary implants replacing tendons and other elastic tissue, has been insufficiently explored. The field is still quite far from being fully explored.

Acknowledgments: The financial support of the Ministry of Science and Higher Education (Statutory Fund) is highly appreciated. Conflicts of Interest: The authors declare no conflict of interest.

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