Functional poly[(ethylene oxide)-co-(β-benzyl-L-aspartate)] polymeric micelles: block copolymer synthesis and micelles formation

Well-defined α-methoxy-ω-amino and α-hydroxy-ω-amino poly(ethylene oxides) (PEOs), obtained by chemical modifications of α-hydroxy-ω-amino PEO, were studied for block copolymerization with β-benzyl-L -aspartate-N-carboxy anhydride (BLA-NCA); the block copolymers were obtained via polymerization of BLA-NCA with the primary amino end-groups of the PEOs as initiator in the mixture CHCl₃/N,N-dimethylformamide (DMF) (vol. ratio10/1). Gel-permeation chromatography (GPC) of both block copolymers showed the presence of BLA oligomers. α-Methoxy PEO/PBLA and α-hydroxy PEO/PBLA block copolymers were submitted to selective precipitation in 2-propanol; this method allowed total elimination of oligomers as shown by GPC of the purified block copolymers. Moreover, for each block copolymer, the number of BLA units determined by ¹H NMR spectroscopy (in CDCl₃) was in good agreement with the number calculated from the ratio BLA-NCA/amino end-groups of PEO. The polymeric micelles having hydroxy functions or methoxy groups on the outer-shell were prepared by dialysis against water of the corresponding solution of the pure block copolymers. These polymeric micelles were characterized by dynamic light scattering (diameter) and by fluorescence spectroscopy (critical micellar concentration, cmc) using pyrene as a fluorescence probe. Both polymeric micelles have a small diameter (<50nm) and a very low cmc (<20 mg/L in water).     

A Novel,Amphiphilic Ethyl Cellulose Grafting Copolymer with Poly(2‐Hydroxyethyl Methacrylate) Side Chains and Its Micellization

Ethyl cellulose‐graft‐poly(2‐hydroxyethyl methacrylate) (EC‐graft‐PHEMA) graft copolymers were synthesized by atom‐transfer radical polymerization (ATRP) in methanol. The graft copolymers were characterized by means of gel‐permeation chromatography (GPC) and ¹H NMR spectroscopy. The kinetic study indicated that the polymerization was controllable. The EC‐graft‐PHEMA copolymers self‐assembled in water into spherical micelles. The morphology of the micelles was characterized by dynamic light scattering (DLS) and transmission electric microscopy (TEM) and the formation process of the micelles was discussed.

     

Radical telomerization of vinyl acetate with chloroform. Application to the synthesis of poly(vinyl acetate)‐block‐polystyrene copolymers by consecutive telomerization and atom transfer radical polymerization

This paper demonstrates that radical telomerization and atom transfer radical polymerization (ATRP) can be combined in a two‐step procedure to prepare poly‐(vinyl acetate)‐block‐polystyrene (PVOAc‐b‐PSt) diblock copolymers. The first step consists in telomerizing VOAc with chloroform, leading to trichloromethyl‐terminated VOAc telomers CCl₃(VOAc)_nH. A detailed ¹H NMR analysis shows that nearly pure telomer structures are obtained over a broad range of DP_n values (up to at least 60 units). When ATRP of styrene is initiated with a model telomer adduct (CCl₃CH₂CH₂OAc), molecular weights increase linearly with monomer conversion and match theoretical values. Moreover, polydispersities are consistently low (1.22 < M_w/M_n < 1.38) throughout polymerization. Similarly, VOAc telomers (DP_n = 9 and 62) are good ATRP macroinitiators. The high purity of the resulting diblock copolymers is confirmed by GPC using RI/UV dual detection.     

Block copolymers by transformation of living anionic polymerization into controlled/“living” atom transfer radical polymerization

A method for the transformation of living anionic polymerization (LAP) to controlled/“living” atom transfer radical polymerization (ATRP) is reported and utilized for the preparation of block copolymers. The macroinitiators, polystyrene and polystyrene-block-polyisoprene containing the 2-bromoisobutyryl end group (PS-Br, M_n = 12 200, M_w/M_n = 1.04; PS-b-PIP-Br, M_n = 16 800, M_w/M_n = 1.03), were prepared by LAP of styrene and styrene/isoprene, correspondingly, and suitable termination agents. These compounds were used as macroinitiators for controlled/“living” ATRP to prepare block copolymers with methyl acrylate (PS-b-PMA), butyl acrylate (PS-b-PBA), methyl methacrylate (PS-b-PMMA), a mixture of styrene and acrylonitrile (PS-b-P(S-r-AN)) and also chain extension with styrene (PS-b-PS and PS-b-PIP-b-PS). The block copolymers were characterized by means of size exclusion chromatography, ¹H NMR and FT-IR spectroscopy.     

Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging

We report on the fabrication of multifunctional polymeric unimolecular micelles as an integrated platform for cancer targeted drug delivery and magnetic resonance imaging (MRI) contrast enhancement under in vitro and in vivo conditions. Starting from a fractionated fourth-generation hyperbranched polyester (Boltorn H40), the ring-opening polymerization of ?-caprolactone (CL) from the periphery of H40 and subsequent terminal group esterification with 2-bromoisobutyryl bromide afforded star copolymer-based atom transfer radical polymerization (ATRP) macroinitiator, H40-PCL-Br. Well-defined multiarm star block copolymers, H40-PCL-b-P(OEGMA-co-AzPMA), were then synthesized by the ATRP of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and 3-azidopropyl methacrylate (AzPMA). This was followed by the click reaction of H40-PCL-b-P(OEGMA-co-AzPMA) with alkynyl-functionalized cancer cell-targeting moieties, alkynyl-folate, and T(1)-type MRI contrast agents, alkynyl-DOTA-Gd (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid), affording H40-PCL-b-P(OEGMA-Gd-FA). In aqueous solution, the amphiphilic multiarm star block copolymer exists as structurally stable unimolecular micelles possessing a hyperbranched polyester core, a hydrophobic PCL inner layer, and a hydrophilic P(OEGMA-Gd-FA) outer corona. H40-PCL-b-P(OEGMA-Gd-FA) unimolecular micelles are capable of encapsulating paclitaxel, a well-known hydrophobic anticancer drug, with a loading content of 6.67 w/w% and exhibiting controlled release of up to 80% loaded drug over a time period of ～120 h. In vitro MRI experiments demonstrated considerably enhanced T(1) relaxivity (18.14 s(-1) mM(-1)) for unimolecular micelles compared to 3.12 s(-1) mM(-1) for that of the small molecule counterpart, alkynyl-DOTA-Gd. Further experiments of in vivo MR imaging in rats revealed good accumulation of unimolecular micelles within rat liver and kidney, prominent positive contrast enhancement, and relatively long duration of blood circulation. The reported unimolecular micelles-based structurally stable nanocarriers synergistically integrated with cancer targeted drug delivery and controlled release and MR imaging functions augur well for their potential applications as theranostic systems.     

Mixed Hyperbranched/Triblock Copolymer Micelle Assemblies: Physicochemical Properties and Potential for Drug Encapsulation

Mixed micelles have numerous advantages while requiring little to no effort in preparation. This study aims to produce mixed micelle nanostructures from a linear triblock copolymer and a hyperbranched random copolymer, and is able to be loaded with the weakly water-soluble drugs curcumin and indomethacin. Different preparation techniques are employed to produce mixed micelles comprised of Pluronic F127 block copolymer, and hyperbranched poly[(ethylene glycol) methyl ether methacrylate-co-lauryl methacrylate], H-[P(OEGMA-co-LMA)], copolymer. Few studies have dabbled in these types of coassemblies, which provides insight into how structural differences of each copolymer can affect the formation of micelles. To determine the properties of the emerging nanostructures in aqueous environments, including their size, homogeneity, and surface charge, different physicochemical techniques are used, such as light scattering and spectroscopic methods. The results reveal that the copolymers combine, and spontaneously self-assemble into mixed micelle-like nanostructures in aqueous environments, whereas both systems of neat and drug-loaded nanostructures exhibit desirable properties such as small average micelle hydrodynamic radii and low size polydispersity indices. The nanostructures that result from the effective encapsulation of curcumin exhibit outstanding stability over 169 days. The fluorescent qualities of curcumin persist after encapsulation, making the novel nanostructures excellent candidates for bioimaging applications.     

Micelle Behavior of Copolymers Composed of Linear and Hyperbranched Blocks in Aqueous Solution

Multi‐arm poly(THF)‐b‐polyglycerol linear‐hyperbranched copolymers consisting of a linear hydrophobic poly(THF) block and a hyperbranched hydrophilic polyglycerol block were synthesized by ring opening polymerization of tetrahydrofuran with silver trifluoromethane sulfonate as a catalyst and the consecutive polymerization of glycidol. Initiators with different geometries that propagated into different numbers of arms (e.g., 1, 2 or 4) were used to investigate the dependence of the micelle properties of the copolymers on the number of arms. The critical micelle concentration (CMC) first decreased and then increased with increasing numbers of arms showing a minimum CMC at an arm number of 2. A minimum CMC was difficult to obtain using multi‐arm block copolymers composed of linear polymers with the small number of arms investigated in this study. DLS showed that the 4‐arm poly(THF)‐b‐polyglycerol copolymer had a micelle size of approximately 83 nm under aqueous conditions, and the micelle size of the copolymers with different numbers of arms was similar. Unimolecular micelles could eventually be obtained using this system by increasing the number of arms, they are considered an ideal drug delivery carrier due to the concentration‐independent stability in the blood stream.

     

Thermosensitive AB4 four-armed star PNIPAM-b-HTPB multiblock copolymer micelles for camptothecin drug release

Thermo-sensitive poly(N-isoproplacrylamide)_m-block-hydroxyl-terminated polybutadiene-block-poly(N-isoproplacrylamide)_m (PNIPAM_m-b-HTPB-b-PNIPAM_m, m = 1 or 2) block copolymers, AB₄ four-armed star multiblock and linear triblock copolymers, were synthesized by ATRP with HTPB as central blocks, and characterization was performed by ¹H NMR, Fourier transform infrared, and size exclusion chromatography. The multiblock copolymers could spontaneously assemble into more regular spherical core–shell nanoscale micelles than the linear triblock copolymer. The physicochemical properties were detected by a surface tension, nanoparticle analyzer, transmission electron microscope (TEM), dynamic light scattering, and UV–vis measurements. The multiblock copolymer micelles had lower critical micelle concentration than the linear counterpart, TEM size from 100 to 120 nm, and the hydrodynamic diameters below 150 nm. The micelles exhibited thermo-dependent size change, with low critical solution temperature of about 33–35 °C. The characteristic parameters were affected by the composition ratios, length of PNIPAM blocks, and molecular architectures. The camptothecin release demonstrated that the drug release was thermo-responsive, accompanied by the temperature-induced structural changes of the micelles. MTT assays were performed to evaluate the biocompatibility or cytotoxicity of the prepared copolymer micelles.     

Well‐Defined Cyclohexene Oxide Mid‐Chain Functional Polystyrene Macromonomer: Synthesis,Characterization and Photoinitiated Cationic Homo‐ and Copolymerization

In this article, we present the results of a study of the preparation of a cyclohexene oxide (CHO) mid‐chain functional macromonomer via ATRP of styrene (St) and epoxidation on work‐up with 3‐chloroperoxybenzoic acid. The ATRP initiator, Br? CH? Br, was synthesized by the condensation of 3‐cyclohexene‐1,1‐dimethanol with 2‐bromopropanoyl bromide. The ATRP of St with Br? CH? Br and Cu(I)/bpy yielded well‐defined polystyrene with a cyclohexene mid‐chain group (PSt? CH? PSt). Epoxidation of the PSt? CH? PSt was performed using 3‐chloroperoxybenzoic acid. GPC, IR and ¹H NMR analyses revealed that a low polydispersity macromonomer of polystyrene with CHO functionality at the mid‐chain (PSt? CHO? PSt) was obtained. The photoinduced cationic polymerization of PSt? CHO? PSt yielded comb‐shaped and graft copolymers.

     

Amphiphilic multi-arm-block copolymer conjugated with doxorubicin via pH-sensitive hydrazone bond for tumor-targeted drug delivery

Folate-conjugated unimolecular micelles based on amphiphilic hyperbranched block copolymer, Boltorn^® H40-poly(l-aspartate-doxorubicin)-b-poly(ethylene glycol)/FA-conjugated poly(ethylene glycol) (H40-P(LA-DOX)-b-PEG-OH/FA), were synthesized as a carrier for tumor-targeted drug delivery. The anticancer drug DOX was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms by pH-sensitive hydrazone linkage. The size of the unimolecular micelles was determined as 17–36 and 10–20 nm by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The release profiles of the DOX from the H40-P(LA-DOX)-b-PEG-OH/FA micelles showed a strong dependence on the environmental pH values. The DOX release rate increased in the acidic medium due to the acid-cleavable hydrazone linkage between the DOX and micelles. Cellular uptake of the H40-P(LA-DOX)-b-PEG-OH/FA micelles was found to be higher than that of the H40-P(LA-DOX)-b-PEG-OH micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. Degradation studies showed that the H40-P(LA-DOX)-b-PEG-OH/FA copolymer hydrolytically degraded into polymer fragments within six weeks. These results suggest that H40-P(LA-DOX)-b-PEG-OH/FA micelles could be a promising nanocarrier with excellent in vivo stability for targeting the drugs to cancer cells and releasing the drug molecules inside the cells by sensing the acidic environment of the endosomal compartments.     

Synthesis and Characterization of Styrene/Butyl Acrylate Linear and Star Block Copolymers via Atom Transfer Radical Polymerization

Summary: Well‐defined styrene (S) and butyl acrylate (BA) linear and star‐like block copolymers are synthesized via atom transfer radical polymerization (ATRP) using di‐ and trifunctional alkyl halide initiators employing the Cu/PMDETA (N,N,N′,N″,N″‐pentamethyldiethylenetriamine) catalyst system. Initial addition of Cu^II deactivator and utilization of halogen exchange techniques suppresses the coupling of radicals and improves cross‐propagation to a large extent, which results in better control over the polymerization. Two types of star‐like PBA/PS block copolymers are prepared by using core‐first techniques: a trifunctional PBA or PS macroinitiator extended with the other monomer. Block copolymers with a well‐defined structure and low polydispersity (PDI = ) are obtained in both cases. A trifunctional PBA₃ macroinitiator with = 136 000 g · mol^?1 and PDI = 1.15 is extended to (PBA‐PS)₃ star‐like block copolymer with = 171 100 g · mol^?1 and PDI = 1.15. A trifunctional PS₃ macroinitiator with = 27 000 g · mol^?1 and PDI = 1.16 g · mol^?1 is extended to (PS‐PBA)₃ with = 91 500 g · mol^?1 and PDI = 1.40. The individual star‐like macromolecules as well as their aggregates are visualized by atomic force microscopy (AFM) where the PS and PBA adopt the globular and extended conformation, respectively. For the PBA core star block copolymers, PS segments tend to aggregate either intramolecularly or intermolecularly. PS core star block copolymers form aggregates with a PS core and emanating PBA chains. Most aggregates have ‘n × 3’ arms but minor amounts of ‘defective’ stars with 4, 5, 8, or 11 arms are also observed. The AFM analysis shows that PS core star block copolymers contain about 92% three‐arm block copolymers, and the efficiency of cross‐propagation is 97.3%.

Schematic representation of the synthesis of BA/S star‐like block copolymers by ATRP, and their resultant AFM images.     

Poly(oligoethylene glycol methacrylate) Star-Shaped Copolymers with Hydroxypropyl Methacrylate Cores

Star-shaped copolymers with crosslinked hyperbranched cores, varying in both number and length of the arms, are prepared by the reversible addition-fragmentation chain transfer (RAFT) polymerization technique. Star synthesis is conducted via a simple, “core-first” method. Hydroxypropyl methacrylate monomer is used for the formation of the hyperbranched/crosslinked core, with ethylene glycol dimethacrylate used as a bifunctional monomer in the role of the cross-linker. Two different cross-linker/chain transfer agent ratios are chosen to manipulate the number of the arms in the final star nanostructure. Oligoethylene glycol methacrylate (OEGMA₅₀₀) is used as a biocompatible and hydrophilic component for the creation and extension of the arms. Arm length is controlled by the amount of OEGMA monomer used in the second polymerization step. Molecular characterization of the four synthesized stars is achieved via size exclusion chromatography and nuclear magnetic resonance, which provides information regarding the molar mass, dispersity, and composition of each star-shaped copolymer. Dynamic light scattering (DLS) studies of copolymers in N,N-dimethyl formamide solutions provide sizes of individual copolymer molecules in the size range of 8–20 nm. Aqueous dispersions of copolymers are investigated by DLS, cryogenic transmission electron microscopy, and atomic force microscopy, which show the formation of spherical aggregates with diameters of 60–350 nm, dependent on the arm number and length of star copolymers. The obtained sizes and size distributions, along with the hydroxyl-group-bearing cores, indicate that the star copolymer can be used as potential nanocarriers for drugs or bioimaging agents.     

The role of non-covalent interactions in anticancer drug loading and kinetic stability of polymeric micelles

A new series of acid- and urea-functionalized polycarbonate block copolymers were synthesized via organocatalytic living ring-opening polymerization using methoxy poly(ethylene glycol) (PEG) as a macroinitiator to form micelles as drug delivery carriers. The micelles were characterized for critical micelle concentration, particle size and size distribution, kinetic stability and loading capacity for a model anticancer drug, doxorubicin (DOX) having an amine group. The acid/urea groups were placed in block forms (i.e. acid as the middle block or the end block) or randomly distributed in the polycarbonate block to investigate molecular structure effect. The micelles formed from the polymers in both random and block forms provided high drug loading capacity due to strong ionic interaction between the acid in the polymer and the amine in DOX. However, the polymers with acid and urea groups placed in the block forms formed micelles with wider size distribution (two size populations), and their DOX-loaded micelles were less stable. The number of acid/urea groups in the random form was further varied from 5 to 8, 13 and 19 to study its effects on self-assembly behaviors and DOX loading. An increased number of acid/urea groups yielded DOX-loaded micelles with smaller size and enhanced kinetic stability because of improved inter-molecular polycarbonate-polycarbonate (urea-urea and urea-acid) hydrogen-bonding and polycarbonate-DOX (acid-amine) ionic interactions. However, when the number of acid/urea groups was 13 or higher, micelles aggregated in a serum-containing medium, and freeze-dried DOX-loaded micelles were unable to re-disperse in an aqueous solution. Among all the polymers synthesized in this study, 1b with 8 acid/urea groups in the random form had the optimum properties. In vitro release studies showed that DOX release from 1b micelles was sustained over 7 h without significant initial burst release. MTT assays demonstrated that the polymer was not toxic towards HepG2 and HEK293 cells. Importantly, DOX-loaded micelles were potent against HepG2 cells with IC₅₀ of 0.26 mg/L, comparable to that of free DOX (IC₅₀: 0.20 mg/L). In addition, DOX-loaded 1b micelles yielded lower DOX content in the heart tissue of the tested mice as compared to free DOX formulation after i.v. injection. These findings signify that 1b micelles may be a promising carrier for delivery of anticancer drugs that contain amine groups.     

Effect of Nanoclay on in situ Preparation of “All Acrylate” ABA Triblock Copolymers via ATRP and Their Morphology

The preparation and characterization of a series of poly(methyl methacrylate)‐block‐poly(butyl acrylate)‐block‐poly(methyl methacrylate) ABA triblock copolymers and their clay nanocomposites via in situ ATRP is reported. The molecular weights and the chemical structures of these nanocomposites are characterized by means of GPC, FTIR, and NMR analyses. DSC, AFM, and SAXS analyses prove a nanophase‐separated morphology in the block copolymer/clay nanocomposites. DMA analysis demonstrates an additional reinforcing effect of nanoclay in the block copolymer nanocomposites. AFM analysis indicates that the bulk polymer has a cylindrical morphology that is unaffected in the nanocomposite, as corroborated by SAXS analysis.     

Synthesis and Association Behaviour of Linear Block Copolymers with Different Microstructures but the Same Composition

The di‐ and triblock copolymers, P(MAA)‐b‐P(MMA), P(MAA)‐b‐P(BMA), P(MAA)‐b‐P(MAA‐co‐MMA)‐b‐P(MMA) and P(MAA)‐b‐P(MAA‐co‐BMA)‐b‐P(BMA), were synthesised via ATRP in order to study the association behaviour in water via polyelectrolyte titration, fluorescence spectroscopy, dynamic light scattering and scanning force microscopy. P(BMA) block copolymers spontaneously self‐associate into micelles whereas for P(MMA) block copolymers addition of salt is necessary to induce aggregation. Principally, the hydrodynamic radius of the micelles decreases from di‐ to triblock copolymer which was attributed to a different conformation of the random middle block at the core/corona interface.

     

Aggregation Behavior of Polystyrene/Poly(acrylic acid) Heteroarm Star Copolymers in 1,4‐Dioxane and Aqueous Media

Ionic heteroarm star copolymers bearing polystyrene (PS) and poly(acrylic acid) (PAA) arms (PS_nPAA_n) were prepared by quantitative hydrolysis of the poly(tert‐butyl acrylate) (PtBA) arms of the corresponding PS_nPtBA_n star copolymer. The aggregation properties of these copolymers were studied in various solvents. In 1,4‐dioxane PS₁₂PAA₁₂ (with nearly symmetrical PS and PAA arms) forms reverse micelles of low aggregation number (N_agg) and spherical morphology. In an 80 : 20 (v/v) 1,4‐dioxane/water mixture these micelles are transformed to regular micelles with an unexpectedly high N_agg and an elongated rod‐like structure. An abnormal behavior was observed in aqueous solutions of charged PS₂₄PANa₂₄ (with asymmetrical PS and PAA arms, W_PS = 19 wt.‐%) at low concentrations. A non‐equilibrium physical gel is formed, characterized by a very high viscosity and an elastic response upon oscillatory shearing.     

Prolate and Temperature‐Responsive Self‐Assemblies of Amphiphilic Random Copolymers with Perfluoroalkyl and Polyoxyethylene Side Chains in Solution

Two amphiphilic random copolymers, PEGMAx‐co‐FAy (x = 90 and 70 mol%), are synthesized by ATRP and their solutions are investigated as a function of solvent, concentration, and temperature by DLS and SANS analyses. Both copolymers self‐assemble in nanostructures by single‐chain folding in water solutions over a wide range of temperatures. The values of the DLS hydrodynamic radius and the SANS radius of gyration are found to be ≈4 nm and ≈3.4–3.7 nm, respectively. Moreover, SANS shows the self‐folded nanoassemblies to be prolated spheroids with a ratio of polar/equatorial axes of ≈5:1 for PEGMA90‐co‐FA10 and ≈2:1 for PEGMA70‐co‐FA30. On heating above a critical temperature T_c, multichain microassemblies are formed that revert back to nanoassemblies on cooling below T_c. This temperature‐responsive transition is fully and sharply reversible.     

Effect of Block Order of ABA‐ and BAB‐Type NIPAAm/HEMA Triblock Copolymers on Thermoresponsive Behavior of Solutions

ABA and BAB triblock thermoresponsive copolymers (A = N‐isopropylacrylamide, B = 2‐hydroxyethyl methacrylate) have been synthesized by atom transfer radical polymerization (ATRP). BAB is shown to exhibit a higher transition temperature and a good solubility in water compared to ABA with the same composition and concentration. The differences are attributed to the distinct micellar structure, which is regulated by the block order of the copolymers. It is speculated that ABA and BAB copolymers separately form branch and flower micelles in water, which mainly influence the course of phase transition. The moduli of the ABA copolymer solution are higher than those of the BAB above gel point. In terms of hypothesized micelle models, it is proposed that the ‘branch’ micelles of the ABA solution preferably form more physical interconnections.

     

Folate‐Conjugated Poly(N‐(2‐hydroxypropyl) methacrylamide)‐block‐Poly(benzyl methacrylate): Synthesis,Self‐Assembly,and Drug Release

Well‐defined amphiphilic diblock copolymers of poly(N‐(2‐hydroxypropyl)methacrylamide)‐block‐poly(benzyl methacrylate) (PHPMA‐b‐PBnMA) are synthesized using reversible addition–fragmentation chain transfer polymerization. The terminal dithiobenzoate groups are converted into carboxylic acids. The copolymers self‐assemble into micelles with a PBnMA core and PHPMA shell. Their mean size is <30 nm, and can be regulated by the length of the hydrophilic chain. The compatibility between the hydrophobic segment and the drug doxorubicin (DOX) affords more interaction of the cores with DOX. Fluorescence spectra are used to determine the critical micelle concentration of the folate‐conjugated amphiphilic block copolymer. Dynamic light scattering measurements reveal the stability of the micelles with or without DOX. Drug release experiments show that the DOX‐loaded micelles are stable under simulated circulation conditions and the DOX can be quickly released under acidic endosome pH.     

Phase Behavior of Double Zwitterionic Block Copolymers in Water: Morphology Transition through Concentration Dependent Selectivity of Water Partitioning

Phase behavior of double zwitterionic diblock copolymers composed of a poly(carboxybetaine methacrylate) (PCB2) and a poly(sulfobetaine methacrylate) (PSB4) (PCB2_n-b-PSB4_m) has been mapped out in aqueous solutions. Phase diagrams are constructed with polymer concentration, ϕ, ranging from 0.08 to 0.80 and PSB4 volume fraction in the PCB2_n-b-PSB4_ms, f_PSB4, ranging from 0.23 to 0.93 at 25 °C. PCB2_n-b-PSB4_m aqueous solutions show symmetric phase diagram above ϕ = 0.55, indicating that water is nearly neutral with respect to PCB2 and PSB4. The morphology transforms from columnar with PCB2 cylinders to lamellar to columnar with PSB4 cylinders with decreasing ϕ, and the phase boundaries exhibit a negative slope below ϕ = 0.45. The morphology transition is rationalized in terms of interfacial curvature modulation through the volume expansion of the PCB2 phase due to the selective water partitioning. The lyotropic mesophase of double hydrophilic block copolymers is a unique molecular compartment for hydrophilic molecules with low interfacial tension.