The role of miktoarm star copolymers in drug delivery systems

Abstract

Miktoarm star copolymers are relatively considered to be a new and unique class of macromolecules, and are a new topical area due to the unique properties by varying their polymer arms. This macromolecules with the A_mB_n architecture, have m arms of polymer A and n arms of polymer B connected at one central junction point. Over the past decade, miktoarms have been used in biomedical applications such as drug delivery, gene delivery, tissue engineering, diagnosis, and antibacterial/antifouling biomaterials. The intensified interest in miktoarms is attributed to their unique topological structures and attractive physical/chemical properties, including low critical micelle concentration (CMC) in solutions, encapsulation capability, internal and peripheral functionality, and enhanced stimuli-responsiveness. This review outlines the advances in the use of miktoarms in drug delivery for their good performance in biocompatibility, biodegradability and sustained, controlled and targeted drug delivery during the past decade and some unique self-assembly behaviors of miktoarm star copolymers have been reported.     

Super-nucleation in nanocomposites and confinement effects on the crystallizable components within block copolymers, miktoarm star copolymers and nanocomposites

In this paper we reexamine recent results obtained by our group on the crystallization of nanocomposites and linear and miktoarm star copolymers in order to obtain some general features of their crystallization properties. Different nanocomposites have been prepared where a close interaction between the polymer matrix and the nano-filler has been achieved: in situ polymerized high density polyethylene (HDPE) on carbon nanotubes (CNT); and polycaprolactone (PCL) and poly(ethylene oxide) (PEO) covalently bonded to carbon nanotubes. In all these nanocomposites a “super-nucleation” effect was detected where the CNTs perform a more efficient nucleating action than the self-nuclei of the polymer matrix. It is believed that such a super-nucleation effect stems from the fact that the polymer chains are tethered to the surface of the CNT and can easily form nuclei. For polystyrene (PS) and PCL block copolymers, miktoarm star copolymers (with two arms of PS and two arms of PCL) were found to display more compact morphologies for equivalent compositions than linear PS-b-PCL diblock copolymers. As a consequence, the crystallization of the PCL component always experienced much higher confinement in the miktoarm stars case than in the linear diblock copolymer case. The consequences of the topological confinement of the chains in block copolymers and nanocomposites on the crystallization were the same even though the origin of the effect is different in each case. For nanocomposites a competition between super-nucleation and confinement was detected and the behavior was dominated by one or the other depending on the nano-filler content. At low contents the super-nucleation effect dominates. In both cases, the confinement increases as the nano-filler content increases or the second block content increases (in this case a non-crystallizable block such as PS). The consequences of confinement are: a reduction of both crystallization and melting temperatures, a strong reduction of the crystallinity degree, an increase in the supercooling needed for isothermal crystallization, a depression of the overall crystallization rate and a decrease in the Avrami index until values of one or lower are achieved indicating a nucleation control on the overall crystallization kinetics.     

Synthesis and characterization of miktoarm star copolymer of styrene and butadiene using multifunctional macromolecular initiator

A new kind of multifunctional macromolecular initiator with Sn-C bonds and polydiene arms was synthesized by living anionic polymerization.At first,polydiene-stannum chloride(PD-SnCl_3) was prepared by the reaction of n-butyl-Li(n-BuLi),stannic chloride(SnCl_4) and diene.Then PD-SnCl_3 was used to react with the dilithium initiator to prepare the multifunctional organic macromolecular initiators.The result suggested that the initiators had a remarkable yield by GPC,nearly 90%.By using these multifunction...     

Synthesis of ABCD‐type miktoarm star copolymers and transformation into zwitterionic star copolymers

ABCD‐type 4‐miktoarm star copolymers of styrene (St), α‐methylstyrene (αMSt), tert‐butyl methacrylate (tBuMA), and 4‐vinylpyridine (4VP) were synthesized via anionic polymerization using 1,3‐bis(1‐phenylvinyl)benzene (m‐DDPE) as the linking molecule. The synthetic route was rationally designed with respect to the reactivity of individual propagating anion towards the double bond of m‐DDPE. Thus the synthesis includes several consecutive key reactions, for example, the monoaddition of polystyryllithium towards m‐DDPE, the polymerization of tBuMA initiated by the resulting monoadduct to produce a diblock macromonomer, the coupling of the macromonomer with poly(α‐methylstyryl)lithium to form a 3‐arm star anion, and the polymerization of 4‐vinylpyridine initiated by the star anion. These reactions were conducted either in a one‐pot process, in which the diblock macromonomer was in situ coupled with poly(α‐methylstyryl)lithium, or in a batch polymerization process, in which the same diblock macromonomer was separated. The final product was hydrolyzed to produce a zwitterionic miktoarm star copolymer, which was soluble at lower pH but insoluble in neutral and basic solution. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4818–4828, 2007     

Synthesis of miktoarm star (block) polymers based on a heterofunctional initiator via combination of ROP, ATRP and functional group transformation

Versatile miktoarm three-arm star polymers, (polystyrene)(polyε-caprolactone)₂ ((PS)(PCL)₂), (PS-b-poly(n-butyl acrylate))(PCL-b-PS-b-poly(n-butyl acrylate))₂ ((PS-b-PnBA)(PCL-b-PS-b-PnBA)₂) and (PtBA-b-PS)(PCL-b-PtBA-b-PS)₂ were synthesized via combination of atom-transfer radical polymerization (ATRP), functional group transformation technique and ring opening polymerization (ROP) using 1,1-dihydroxymethyl-1-(2-bromoisobutyryloxy)methyl ethane (DHB) as a heterofunctional initiator. In the synthesis of (PS)(PCL)₂ by combination of ROP of ε-caprolactone (ε-CL) and ATRP, the implementation sequence, ROP followed by ATRP, was proved to be effective to get a well-defined miktoarm star polymer than the reverse one. The two miktoarm star block polymers, (PS-b-PnBA)(PCL-b-PS-b-PnBA)₂ and (PtBA-b-PS)(PCL-b-PtBA-b-PS)₂, were prepared by one ROP step, one group transformation and ATRP steps using the same initiator. All the polymers have defined structures and their molecular weights are adjustable with good controllability.     

星形聚氧乙烯及星形杂臂氧化乙烯-苯乙烯共聚物的合成

以原子转移自由基偶联法合成了多臂星形聚合物S-PEO和星形杂臂共聚物PEO-PS。以傅立叶红外光谱(FT-IR)和核磁共振(1H NMR)分析方法确定了产物的结构。以GPC分析测试了产物的分子量和分子量分布。GPC分析结果表明所得聚合物分子量增大,分子量分布窄,偶联反应效率可高达99%以上。     

Synthesis of ABC-type miktoarm star polymers by “click” chemistry, ATRP and ROP

ABC-type miktoarm star polymers, poly(ethylene oxide)-block-polystyrene-block-poly (ε-caprolactone)s (PEO-b-PS-b-PCL) were synthesized via combination of “click” chemistry, atom-transfer radical polymerization (ATRP) and ring opening polymerization (ROP). Azide ended PEO arms, PEO-N₃, and a trifunctional molecule, propargyl 2-hydroxylmethyl-2-(α-bromoisobutyraloxymethyl)-propionate (PHBP), were prepared first, respectively. A “click” reaction of PEO-N₃ and PHBP generated a PEO macroinitiator, PEO-(Br)(OH) with two functionalities, one is hydroxyl group and the other is α-bromoisobutyraloxyl group. Consecutive ATRP of styrene (St) and ROP of ε-caprolactone (ε-CL) from the PEO macroinitiator produced the PEO-b-PS-b-PCL miktoarm stars. All the structures of the polymers were determined.     

Synthesis of miktoarm star and miktoarm star block copolymers via a combination of atom transfer radical polymerization and stable free‐radical polymerization

A trifunctional initiator, 2‐phenyl‐2‐[(2,2,6,6‐tetramethyl)‐1‐piperidinyloxy] ethyl 2,2‐bis[methyl(2‐bromopropionato)] propionate, was synthesized and used for the synthesis of miktoarm star AB₂ and miktoarm star block AB₂C₂ copolymers via a combination of stable free‐radical polymerization (SFRP) and atom transfer radical polymerization (ATRP) in a two‐step or three‐step reaction sequence, respectively. In the first step, a polystyrene (PSt) macroinitiator with dual ω‐bromo functionality was obtained by SFRP of styrene (St) in bulk at 125 °C. Next, this PSt precursor was used as a macroinitiator for ATRP of tert‐butyl acrylate (tBA) in the presence of Cu(I)Br and pentamethyldiethylenetriamine at 80 °C, affording miktoarm star (PSt)(PtBA)₂ [where PtBA is poly(tert‐butyl acrylate)]. In the third step, the obtained St(tBA)₂ macroinitiator with two terminal bromine groups was further polymerized with methyl methacrylate by ATRP, and this resulted in (PSt)(PtBA)₂(PMMA)₂‐type miktoarm star block copolymer [where PMMA is poly(methyl methacrylate)] with a controlled molecular weight and a moderate polydispersity (weight‐average molecular weight/number‐average molecular weight < 1.38). All polymers were characterized by gel permeation chromatography and ¹H NMR. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2542–2548, 2003     

Block and star block copolymers by mechanism transformation X. Synthesis of poly(ethylene oxide) methyl ether/polystyrene/poly(l-lactide) ABC miktoarm star copolymers by combination of RAFT and ROP

Poly(ethylene oxide) methyl ether/polystyrene/poly(l-lactide) (MPEO/PSt/PLLA) ABC miktoarm star copolymers were synthesized by combination of reversible addition-fragmentation transfer (RAFT) polymerization and ring-opening polymerization (ROP) using bifunctional macro-transfer agent, MPEO with two terminal dithiobenzoate and hydroxyl groups. It was prepared by reaction of MPEO with maleic anhydride (MAh), subsequently reacted with dithiobenzoic acid and ethylene oxide. RAFT polymerization of St at 110 °C yielded block copolymer, MPEO-b-PSt [(MPEO)(PSt)CH₂OH], and then it was used to initiate the polymerization of l-lactide in the presence of Sn(OCt)₂ at 115 °C to produce ABC miktoarm star polymers, s-[(MPEO)(PSt)(PLLA)]. The structures of products obtained at each synthetic step were confirmed by NMR and gel permeation chromatography data.     

Synthesis and characterization of model 3‐miktoarm star copolymers of poly(dimethylsiloxane) and poly(2‐vinylpyridine)

3‐Miktoarm star copolymers, 3μ‐D₂V, with two poly(dimethylsiloxane) (PDMS) and one poly(2‐vinylpyridine) (P2VP) arm, were synthesized by using anionic polymerization–high vacuum techniques and (chloromethylphenylethyl)methyl dichlorosilane, heterofunctional linking agent, with two SiCl groups and one CH₂Cl group. The synthetic strategy involves the selective reaction of the two ? SiCl groups with PDMSOLi living chains, followed by reaction of the remaining chloromethyl group with P2VPLi. Combined molecular characterization results (size exclusion chromatography, membrane osmometry, and ¹H NMR spectroscopy) revealed a high degree of structural and compositional homogeneity. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 614–619, 2006     

Entropic effects in mixed micelles formed by star/linear and star/star AB copolymers

The entropic effects in the comicellization behavior of amphiphilic AB copolymers differing in chain architecture of solvophilic A or solvophobic B parts are studied by means of molecular dynamics simulations. In particular, we studied linear/star and star/star copolymer mixtures. The properties of interest were the critical micelle concentration, the mean aggregation number, the shape of the micelle, which is expressed by the shape anisotropy, the thickness of the corona, and the solvophobic core radius. We found that the critical micelle concentration values for linear/star and copolymer mixtures show a positive deviation from the analytical predictions of the molecular theory of comicellization for chemically identical copolymers. This could be attributed to the effective interactions between copolymers originated from the architectural asymmetry. The effective interactions induce a small decrease in the aggregation number of preferential micelles in linear/star mixtures triggering the nonrandom mixing between the solvophilic moieties in the corona for all mixtures. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 442–452     

Synthesis of well‐defined miktoarm star polymers of poly(dimethylsiloxane) by the combination of chlorosilane and benzyl chloride linking chemistry

A series of novel four‐arm A₂B₂ and A₂BC and five‐arm A₂B₂C miktoarm star polymers, where A is poly(dimethylsiloxane) (PDMS), B is polystyrene (PS), and C is polyisoprene (PI), were successfully synthesized by the combination of chlorosilane and benzyl chloride linking chemistry. This new and general methodology is based on the linking reaction of in‐chain benzyl chloride functionalized poly(dimethylsiloxane) (icBnCl–PDMS) with the in‐chain diphenylalkyl (icD) living centers of PS‐DLi‐PS, PS‐DLi‐PI, or (PS)₂‐DLi‐PI. icBnCl–PDMS was synthesized by the selective reaction of lithium PDMS enolate (PDMSOLi) with the chlorosilane groups of dichloro[2‐(chloromethylphenyl)ethyl]methylsilane, leaving the benzyl chloride group intact. The icD living polymers, characterized by the low basicity of DLi to avoid side reactions with PDMS, were prepared by the reaction of the corresponding living chains with the appropriate chloro/bromo derivatives of diphenylethylene, followed by a reaction with BuLi or the living polymer. The combined molecular characterization results of size exclusion chromatography, ¹H NMR, and right‐angle laser light scattering revealed a high degree of structural and compositional homogeneity in all miktoarm stars prepared. The power of this general approach was demonstrated by the synthesis of a morphologically interesting complex miktoarm star polymer composed of two triblock terpolymer (PS‐b‐PI‐b‐PDMS) and two diblock copolymer (PS‐b‐PI) arms. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6587–6599, 2006     

Influence of the block hydrophilicity of AB2 miktoarm star copolymers on cluster formation in solutions

We investigated the formation of various micelle shapes of lipid-like amphiphilic AB(2) miktoarm star copolymers in a solution, by performing dissipative particle dynamics simulations. AB(2) miktoarm star copolymer molecules are modeled with coarse-grained structures that consist of a relatively hydrophilic head (A) group with a single arm and a hydrophobic tail (B) group with double arms. A decrease in the hydrophilicity of the head group leads to a reduction of the polymer-solvent contact area, causing cluster structure changes from spherical micelles to vesicles. Consequently, a spherical exterior with multi-lamellar or cylindrical phase interior structures forms under poor solvent conditions without the introduction of spherical hard-wall containers. Furthermore we observed that, for small head group lengths, vesicles were formed in much wider range of solvent-head interaction strength than for long head groups, indicating that molecules with short head group offer a superior vesicle forming property. A phase diagram, the structure and kinetics of the cluster formation, a density profile, and a detailed shape analysis are presented to discuss the molecular characteristics of potential candidates for drug carriers that require superior and versatile vesicle forming properties. We also show that, under certain solvent-hydrophilic head group interaction conditions, initially formed cylindrical micelles transform to bilayer fragments through redistribution of copolymers within the cluster.     

Block and star block copolymers by mechanism transformation. IV. Synthesis of S‐(PSt)2(PDOP)2 miktoarm star copolymers by combination of ATRP and CROP

A new tetrafunctional initiator, di(hydroxyethyl)‐2,9‐dibromosebacate (DHEDBS) [HOCH₂CH₂OOCCHBr(CH₂)₆CHBrCOOCH₂CH₂OH], was synthesized and used in preparation of A₂B₂ miktoarm star copolymers, (polystyrene)₂/ [poly(1,3‐dioxepane)]₂ [S‐(PSt)₂(PDOP)₂], by transformation of atom transfer radical polymerization (ATRP) to cationic ring‐opening polymerization (CROP). First, two‐armed PSt with two primary hydroxyl groups sited at the center of macromolecule [(PStBr)₂(OH)₂] was obtained by ATRP of St with the initiation system of DHEDBS/CuBr/bpy, and used as a chain‐transfer agent in the CROP of DOP with triflic acid as the initiator. Therefore, A₂B₂ miktoarm star copolymer S‐(PSt)₂(PDOP)₂ was formed. Its structure was confirmed by the ¹H NMR spectrum. Gel permeation chromatography (GPC) curves show that the polymers obtained have a relatively narrow molecular weight distribution. The hydrolysis product of S‐(PSt)₂(PDOP)₂ was also characterized by ¹H NMR and GPC. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 437–445, 2001     

Novel ABC miktoarm star terpolyphosphoesters: Facile construction and high‐flame retardant property

A combination of ring‐opening metathesis polymerization (ROMP), ring‐opening polymerization (ROP), and acyclic diene metathesis (ADMET) polymerization approach was first time utilized in the preparation of novel ABC miktoarm star terpolyphosphoesters (PPEs). Acrylate‐terminated monotelechelic PPE was first prepared through ROMP of 7‐membered cyclic phosphate monomer in the presence of a terminating agent, and then terminal acrylate group was readily converted, by thiol‐Michael addition click reaction and esterification, to a heterodifunctional PPE with hydroxyl and acrylate groups, which was a key precursor for the preparation of ABC miktoarm terpolymers. ROP of the cyclic phosphoester monomer initiated by this PPE was successively carried out to generate the acrylate‐functionalized block PPE, which utilized as a selective macromolecular chain stopper in subsequent ADMET polymerization of α,ω‐diene phosphate monomer, finally producing miktoarm terpolyphosphoester. These prepared miktoarm star terpolyphosphoesters demonstrated superior thermal and flame retardant properties via TGA, limiting oxygen index, and microscale combustion calorimetry tests. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 692–701     

Synthesis, characterization and self-assembly of ion-bonded amphiphilic A2B miktoarm star copolymers containing an azobenzene unit at the core

An azobenzene-containing supramolecular copolymers, consisted of two polystyrene (PSt) arms and one poly(ethylene oxide) (PEO) arm linked via ionic bond, has been designed and successfully synthesized. Monomethoxy PEO with phenylazobenzenesulfonic acid as the terminus (PEO-NN-SO₃H) was utilized to react with polystyrene carrying tertiary amino group at the middle of the polymer chain (PSt₂-N(CH₃)₂) to form ion-bonded supramolecular star copolymers (PSt₂-NN-PEO) with an azobenzene group at the core based on the interaction between sulfonic acid group and amino group. The obtained copolymers were characterized by ¹H nuclear magnetic resonance (¹H NMR) and gel permeation chromatography (GPC) techniques. The self-assembly behavior of the copolymers with different molecular weight of PSt was investigated, which shows solid spherical aggregates in water. The aggregation leads to the lower isomerization degree (54%) at the photostationary state in water compared with that in 1,4-dioxane (82%).     

Effect of inorganic salts on the micellar behaviour of ethylene oxide-propylene oxide block copolymers in aqueous solution

The aggregation behaviour of two ethylene oxide-propylene oxide block copolymers (PEO-PPO-PEO) in aqueous solution has been investigated in the presence of added salts (KCNS, KI, KBr, KCl and KF) by viscosity, cloud point, light scattering, pulse gradient spin echo NMR, and solubilization measurements. The salts have a strong effect on the cloud points of the pluronics. Both P-85 and L-64 form micelles which increase in size and change into elongated shapes when the cloud point is approached. The changes of size and shape of the micelles, revealed by the intrinsic viscosity and rheological properties, seem to occur at the same temperature relative to the cloud point, independent of the nature of the salt. The onset of micelle formation is also shifted in the same direction as the cloud point by the salts, but by a much smaller amount.     

ABC type miktoarm star copolymers through combination of controlled polymerization techniques with thiol‐ene and azide‐alkyne click reactions

ABC type miktoarm star copolymer with polystyrene (PS), poly(ε‐caprolactone) (PCL) and poly(ethylene glycol) (PEG) arms was synthesized using controlled polymerization techniques in combination with thiol‐ene and copper catalyzed azide‐alyne “click” reactions (CuAAC) and characterized. For this purpose, 1‐(allyloxy)‐3‐azidopropan‐2‐ol was synthesized as the core component in a one‐step reaction with high yields (96%). Independently, ω‐thiol functionalized polystyrene (PS‐SH) was synthesized in a two‐step protocol with a very narrow molecular weight distribution. The bromo end function of PS obtained by atom transfer radical polymerization was first converted to xanthate function and then reacted with 1, 2‐ethandithiol to yield desired thiol functional polymer (PS‐SH). The obtained polymer was grafted onto the core by thiol‐ene click chemistry. In the following stage, ε‐caprolactone monomer was polymerized from the core by ring opening polymerization (ROP) using tin octoate as catalyst through hydroxyl groups to form the second arm. Finally, PEG‐acetylene, which was simply synthesized by the esterification of Me‐PEG and 5‐pentynoic acid, was clicked onto the core through azide groups present in the structure. The intermediates at various stages and the final miktoarm star copolymer were characterized by ¹H NMR, FTIR, and GPC measurements. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

End functionalization of hyperbranched poly(siloxysilane): Novel crosslinking agents and hyperbranched–linear star block copolymers

Functionalized hyperbranched poly(siloxysilane)s have been prepared by hydrosilylation reactions involving the multiple silicon hydride (SiH) groups of the polymer to introduce other reactive groups such as epoxy, amine, and hydroxyl groups. The possible use of these modified polymers as novel crosslinking agents is discussed. The same hydrosilylation reaction is used to attach preformed linear poly(isobutylene) (PIB) or poly(ethylene oxide) (PEO) onto the hyperbranched polymer to afford unusual hyperbranched–linear star block copolymers. The PIB‐derived copolymer is shown to be very hydrophobic, whereas its PEO‐derived counterpart is amphiphilic. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 2970–2978, 2000     

A strategy for synthesis of ion‐bonded amphiphilic miktoarm star copolymers via supramolecular macro‐RAFT agent

Amphiphilic supramolecular miktoarm star copolymers linked by ionic bonds with controlled molecular weight and low polydispersity have been successfully synthesized via reversible addition‐fragmentation chain transfer (RAFT) polymerization using an ion‐bonded macromolecular RAFT agent (macro‐RAFT agent). Firstly, a new tetrafunctional initiator, dimethyl 4,6‐bis(bromomethyl)‐isophthalate, was synthesized and used as an initiator for atom transfer radical polymerization (ATRP) of styrene to form polystyrene (PSt) containing two ester groups at the middle of polymer chain. Then, the ester groups were converted into tertiary amino groups and the ion‐bonded supramolecular macro‐RAFT agent was obtained through the interaction between the tertiary amino group and 2‐dodecylsulfanylthiocarbonylsulfanyl‐2‐methyl propionic acid (DMP). Finally, ion‐bonded amphiphilic miktoarm star copolymer, (PSt)₂‐poly(N‐isopropyl‐acrylamide)₂, was prepared by RAFT polymerization of N‐isopropylacrylamide (NIPAM) in the presence of the supramolecular macro‐RAFT agent. The polymerization kinetics was investigated and the molecular weight and the architecture of the resulting star polymers were characterized by means of ¹H‐NMR, FTIR, and GPC techniques. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5805–5815, 2008