Near-infrared light-triggered dissociation of block copolymer micelles using upconverting nanoparticles

We demonstrate a novel strategy enabling the use of a continuous-wave diode near-infrared (NIR) laser to disrupt block copolymer (BCP) micelles and trigger the release of their "payloads". By encapsulating NaYF(4):TmYb upconverting nanoparticles (UCNPs) inside micelles of poly(ethylene oxide)-block-poly(4,5-dimethoxy-2-nitrobenzyl methacrylate) and exposing the micellar solution to 980 nm light, photons in the UV region are emitted by the UCNPs, which in turn are absorbed by o-nitrobenzyl groups on the micelle core-forming block, activating the photocleavage reaction and leading to the dissociation of BCP micelles and release of co-loaded hydrophobic species. Our strategy of using UCNPs as an internal UV or visible light source upon NIR light excitation represents a general and efficient method to circumvent the need for UV or visible light excitation that is a common drawback for light-responsive polymeric systems developed for potential biomedical applications.     

Rational design of light-controllable polymer micelles

Amphiphilic block copolymer (BCP) micelles are nanocarriers that hold promise for controlled delivery applications. This account highlights our recent works on light-dissociable BCP micelles. We have designed and developed light-responsive amphiphilic BCPs whose micellar aggregates (core-shell micelles and vesicles) can be disrupted by light exposure. The basic strategy is to incorporate a chromophore into the structure of the hydrophobic block, whose photoreaction can result in a conformational or structural change that shifts the hydrophilic/hydrophobic balance toward the destabilization of the micelles. Using various chromophores including azobenzene, pyrene and nitrobenzene, we have achieved both reversible and irreversible dissociation of BCP micelles upon illumination with UV/visible or near infrared light. The demonstrated rational design principle based on light-changeable or light-switchable amphiphilicity is general and can be applied to many polymer/chromophore combinations. This opens the door to developing photocontrollable polymer nanocarriers offering control over when and where the release of loaded agents takes place.     

The research on multi‐responsive azobenzene block copolymer and its self‐assembly behavior

The azobenzene‐based amphiphilic copolymers have drawn significant attention as a kind of multi‐responsive smart materials. The demand on deeper investigation of how the azobenzene group influences the micelles formation and light‐responsive behavior on molecular level is very urgent. In this article, multi‐responsive block copolymers, poly (acrylic acid)‐block‐poly[4'‐[[(2‐Methacryloyloxy)ethyl]ethylainino]azobenzene‐co‐poly (ethylene glycol) methyl ether methacrylate] (PAA‐b‐P (AzoMA‐co‐PEGMA)), with pH‐, light‐ and reduction‐responsiveness were synthesized by the monomers of AzoMA, PEGMA and acrylic acid via reversible addition‐fragmentation chain transfer polymerization (RAFT). The amphiphilic block copolymer presented aggregation‐induced emission effect, and it was pH, light, and reduction responsive. The results showed that the micelle size decreased with the decreasing of pH within a certain range. However, the particle size of micelles increased significantly when the pH was 4. Once adding reduction agent, the micelles were disassembly. Fluorescent molecule of Nile red was selected as a hydrophobic guest molecule to study the properties of encapsulating and releasing abilities of block copolymer micelles for guest molecules. The results showed that the loading capacity of three kinds of copolymer micelles was closely related to the aggregates formed by the hydrophobic block, mainly azobenzene block. Besides, the block copolymer micelles could release a certain amount of Nile red under the irradiation of UV light, the reduction with Na₂S₂O₄ as reductant, and the exposure to alkaline environment. The mechanism of how the different status of azobenzene group influenced the self‐assembly and multi‐responsive behavior was explored on molecular level.     

Self-assembly of a diblock copolymer with pendant disulfide bonds and chromophore groups: a new platform for fast release

An amphiphilic block copolymer comprising poly(ethylene glycol) (PEG) and poly(2-(methacryloyl)oxyethyl-2'-hydroxyethyl disulfide) (PMAOHD) blocks was synthesized by atom transfer radical polymerization (ATRP). Pyrenebutyric acid was conjugated to the block copolymer by esterification, and a block copolymer with pendant disulfide bonds and pyrenyl groups (PEG-b-P(MAOHD-g-Py)) was obtained. (1)H NMR and gel permeation chromatography (GPC) results demonstrated the successful synthesis of the block copolymer. The cleavage of the disulfide bonds and the degrafting of the pyrenyl groups were investigated in THF and a THF/methanol mixture. Fluorescence spectroscopy, GPC, and (1)H NMR results demonstrated fast cleavage of the disulfide bonds by Bu(3)P in THF. Fluorescence results showed the ratio of the intensity of the excimer peak to the monomer peak decreased rapidly within 20 min. GPC traces of the block copolymer moved to a long retention time region after addition of Bu(3)P, indicating the cleavage of the disulfide bonds and the degrafting of the pyrenyl groups. PEG-b-P(MAOHD-g-Py) can self-assemble into micelles with poly(MAOHD-g-Py) cores and PEG coronae in a mixture of methanol and THF (9:1 by volume). The dissociation of the micelles in the presence of Bu(3)P was investigated. After cleavage of the disulfide bonds in the micellar cores, a pyrene-containing small molecular compound and a block copolymer with pendant thiol groups were produced. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and (1)H NMR were employed to track the dissociation of the polymeric micelles. All the techniques demonstrated the dissociation of the micelles and the fast release of pyrenyl groups from the micelles.     

聚乙二醇-b-聚(D,L-丙交酯-co-碳酸丙二酯)的胶束化及其药物控释研究

通过开环共聚合成了由D,L-丙交酯、碳酸丙二酯和聚乙二醇构成的两亲性嵌段共聚物(PETLA),研究了PETLA胶束化及药物控释行为.嵌段共聚物和胶束通过核磁共振(1H-NMR)、荧光分光光度计、凝胶渗透色谱(GPC)、动态光散射(DLS)、透射电镜(TEM)和紫外光谱(UV)表征.实验结果发现临界胶束浓度随共聚物疏水链段长度增加而减小,胶束直径随疏水链段长度增加而增大.透射电镜照片表明载药胶束MT1直径为30~40nm,呈规则球形.体外释药表明9-NC以可控方式释放,突释后药物释放速率接近零级恒速.     

Conventional synthesis of amphiphilic block copolymer utilized for polymeric micelle by mechanochemical solid-state polymerization

The first example is presented here of an amiphiphilic block copolymer synthesized by mechanochemical solid-state polymerization and used to form polymeric micelles. A model amphiphilic block copolymer was synthesized first, possessing galactose as a hydrophilic side chain and theophylline as a hydrophobic side chain, by mechanochemical solid-state polymerization. The resulting copolymer had a narrow molecular weight distribution. Polymeric micelle formation was subsequently carried out with the copolymer by a dialysis method. To gain insight into the physicochemical properties of the polymeric micelle, dynamic light scattering (DLS) measurements were performed. A narrow distribution of diameters was observed in the polymeric micelle solution, and these micelles were disrupted by the addition of sodium dodecyl sulfate (SDS). It was also confirmed by DLS measurements that the polymeric micelles were spherical. These results suggested that the block copolymer synthesized by mechanochemical solid-state polymerization was as suitable for the preparation of polymeric micelles as materials obtained by living polymerization.     

Stimuli-responsive supramolecular assemblies of linear-dendritic copolymers

With the goal of developing a pH-responsive micelle system, linear-dendritic block copolymers comprising poly(ethylene oxide) and either a polylysine or polyester dendron were prepared and hydrophobic groups were attached to the dendrimer periphery by highly acid-sensitive cyclic acetals. These copolymers were designed to form stable micelles in aqueous solution at neutral pH but to disintegrate into unimers at mildly acidic pH following loss of the hydrophobic groups upon acetal hydrolysis. Micelle formation was demonstrated by encapsulation of the fluorescent probe Nile Red, and the micelle sizes were determined by dynamic light scattering. The structure of the dendrimer block, its generation, and the synthetic method for linking the acetal groups to its periphery all had an influence on the critical micelle concentration and the micelle size. The rate of hydrolysis of the acetals at the micelle core was measured for each system at pH 7.4 and pH 5, and it was found that all systems were stable at neutral pH but underwent significant hydrolysis at pH 5 over several hours. The rate of hydrolysis at pH 5 was dependent on the structure of the copolymer, most notably the hydrophobicity of the core-forming block. To demonstrate the potential of these systems for controlled release, the release of Nile Red as a "model payload" was examined. At pH 7.4, the fluorescence of micelle-encapsulated Nile Red was relatively constant, indicating it was retained in the micelle, while at pH 5, the fluorescence decreased, consistent with its release into the aqueous environment. The rate of release was strongly correlated with the rate of acetal hydrolysis and was therefore controlled by the chemical structure of the copolymer. The mechanism of Nile Red release was investigated by monitoring the change in size of the micelles over time at acidic pH. Dynamic light scattering measurement showed a size decrease over time, eventually reaching the size of a unimer, thus providing evidence for the proposed micelle disintegration.     

Dual Stimuli-Responsive Self-Assembly Behavior of a Tailor-Made ABC-Type Amphiphilic Tri-Block Copolymer

This investigation describes the synthesis of a dual stimuli-responsive, amphiphilic ABC tri-block copolymer (BCP) based on the functional monomers via RAFT polymerization. In this case, ABC-type BCP was prepared based on N-isopropylacrylamide, n-butyl acrylate, and 4-vinylpyridine in DMF solvent using cyanomethyl dodecyl trithiocarbonate as the RAFT agent and azobisisobutyronitrile as a thermal initiator in a subsequent macro-RAFT approach, respectively. The BCPs were characterized by SEC, ¹H-NMR, FTIR spectroscopy, and DSC analyses. Temperature and pH-dependent properties of the smart BCP micelles in aqueous medium were investigated using dynamic light scattering. Transmission electron microscopic images were taken at cryogenic and dry conditions to study the morphology of molecular assemblies of block copolymers in an aqueous medium. The phase and topographical images were captured by atomic force microscopy to understand the assembly of block copolymers in solvents of different polarities. The morphology of BCP micelles was transformed from flower-like to spherical in the presence of solvents with different polarities (H₂O or CHCl₃).     

Investigation of a new thermosensitive block copolymer micelle: hydrolysis, disruption, and release

Thermosensitive polymer micelles are generally obtained with block copolymers in which one block exhibits a lower critical solution temperature in aqueous solution. We investigate a different design that is based on the use of one block bearing a thermally labile side group, whose hydrolysis upon heating shifts the hydrophilic-hydrophobic balance toward the destabilization of block copolymer micelles. Atom transfer radical polymerization was utilized to synthesize a series of diblock copolymers composed of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(2-tetrahydropyranyl methacrylate) (PTHPMA). We show that micelles of PEO-b-PTHPMA in aqueous solution can be destabilized as a result of the thermosensitive hydrolytic cleavage of tetrahydropyranyl (THP) groups that transforms PTHPMA into hydrophilic poly(methacrylic acid). The three related processes occurring in aqueous solution, namely, hydrolytic cleavage of THP, destabilization of micelles, and release of loaded Nile Red (NR), were investigated simultaneously using 1H NMR, dynamic light scattering, and fluorescence spectroscopy, respectively. At 80 degrees C, the results suggest that the three events proceed with a similar kinetics. Although slower than at elevated temperatures, the disruption of PEO-b-PTHPMA micelles can take place at the body temperature (approximately 37 degrees C), and the release kinetics of NR can be adjusted by changing the relative lengths of the two blocks or the pH of the solution.     

Probing paeonol-pluronic polymer interactions by 1H NMR spectroscopy

By using a combination of 1H NMR spectroscopy, two-dimensional heteronuclear single-quantum coherence-resolved (1)H{(13)C} and homonuclear rotating-frame Overhauser enhancement NMR correlation experiments with diffusion ordered spectroscopy (DOSY), the location and distribution of a hydrophobic drug, paeonol, have been established with respect to the methyl groups of the poly(ethylene oxide)-poly(propylene oxide) -poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer. The interaction between them is adjustable according to the different temperature-dependent hydrophilicities or hydrophobicities of the triblock copolymer components. On the other hand, such interactions influence the self-assembly properties of the block copolymer amphiphiles in solution. The amount of anhydrous methyl groups of PPO segments shows an increase with increasing paeonol concentration. It was also demonstrated that the shell-crosslinking of the Pluronic polymer has an effect in increasing the amount of anhydrous methyl groups and thus increasing the hydrophobicity of Pluronic micelles. This might be the deeper reason underlying the increase in drug-loading capacity and prolongation in release time of Pluronic micelles for drug delivery after the shell-crosslinking. Changes in self-diffusion coefficients of paeonol with varying copolymer concentrations and types were also determined by the diffusion-based NMR DOSY technique, and values of K(a), DeltaG, and n were calculated.     

Block copolymer micelles with enzyme molecules at the interfaces

This research provides an efficient method for the fabrication of hybrid micelles with enzyme molecules at the interfaces. Amphiphilic block copolymer is synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization, and thiol‐modified porcine pancreatic lipase (PPL‐SH) is obtained by treatment of native PPL with Traut's reagent. PPL‐SH is conjugated to the block copolymer chains by thiol‐disulfide exchange reaction. In phosphate buffered saline, the bioconjugate self‐assembles into micelles with enzyme molecules at the interfaces between hydrophobic cores and hydrophilic coronae. The bioactivity of the enzyme molecules on the micelles are compared with the native enzyme. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 2047–2052     

两亲性嵌段共聚物的合成及其在离子液体中的自组装行为

采用阴离子开环聚合法合成了两亲性嵌段共聚物PLA-PEG-PLA.用FT-IR,1H NMR和GPC等手段对嵌段共聚物的结构组成进行了表征.两亲性嵌段共聚物在离子液体1-丁基-3-甲基咪唑六氟磷酸盐中能自组装成胶束,用透射电子显微镜观察了聚合物在离子液体中形成胶束的纳米结构.当疏水链长固定时,胶束的自组装形状主要依赖于亲水链的长度.两亲性共聚物在离子液体中可自组装成可控制结构的纳米胶束,这种纳米结构胶束在很多领域具有广泛的应用前景.     

in vitro biological evaluation of folate-functionalized block copolymer micelles for selective anti-cancer drug delivery

The main objective of this study was to evaluate the ability of folic acid-functionalized diblock copolymer micelles to improve the delivery and uptake of two poorly water-soluble anti-tumor drugs, tamoxifen and paclitaxel, to cancer cells through folate receptor targeting. The diblock copolymer used in this study comprised a hydrophilic poly[2-(methacryloyloxy)ethyl phosphorylcholine] (MPC) block, carrying at the chain end the folate targeting moiety, and a pH-sensitive hydrophobic poly[2-(diisopropylamino)ethyl methacrylate] (DPA) block (FA-MPC-DPA). The drug-loading capacities of tamoxifen- and paclitaxel-loaded micelles were determined by high performance liquid chromatography and the micelle dimensions were determined by dynamic light scattering and transmission electron microscopy. Cell viability studies were carried out on human chronic myelogenous leukaemia (K-562) and colon carcinoma cell lines (Caco-2) in order to demonstrate that drug-loaded FA-MPC-DPA micelles exhibited higher cytotoxicities toward cancer cells than unfunctionalized MPC-DPA micelles. Uptake studies confirmed that folate-conjugated micelles led to increased drug uptake within cancer cells, demonstrating the expected selectivity toward these tumor cells.     

Spontaneous generation of amphiphilic block copolymer micelles with multiple morphologies through interfacial Instabilities

We introduce a method for the formation of block copolymer micelles through interfacial instabilities of emulsion droplets. Amphiphilic polystyrene-block-poly(ethylene oxide) (PS-PEO) copolymers are first dissolved in chloroform; this solution is then emulsified in water and chloroform is extracted by evaporation. As the droplets shrink, the organic solvent/water interface becomes unstable, spontaneously generating a new interface and leading to dispersion of the copolymer as micellar aggregates in the aqueous phase. Depending on the composition of the copolymer, spherical or cylindrical micelles are formed, and the method is shown to be general to polymers with several different hydrophobic blocks: poly(1,4-butadiene), poly(-caprolactone), and poly(methyl methacrylate). Using this method, hydrophobic species dissolved or suspended in the organic phase along with the amphiphilic copolymer can be incorporated into the resulting micelles. For example, addition of PS homopolymer, or a PS-PEO copolymer of different composition and molecular weight, allows the diameter and morphology of wormlike micelles to be tuned, while addition of hydrophobically coated iron oxide nanoparticles enables the preparation of magnetically loaded spherical and wormlike micelles.     

Redox‐responsive core cross‐linked micelles of poly(ethylene oxide)‐b‐poly(furfuryl methacrylate) by Diels‐Alder reaction for doxorubicin release

Redox‐responsive core cross‐linked (CCL) micelles of poly(ethylene oxide)‐b‐poly(furfuryl methacrylate) (PEO‐b‐PFMA) block copolymers were prepared by the Diels‐Alder click‐type reaction. First, the PEO‐b‐PFMA amphiphilic block copolymer was synthesized by the reversible addition‐fragmentation chain transfer polymerization. The hydrophobic blocks of PFMA were employed to encapsulate the doxorubicin (DOX) drug, and they were cross‐linked using dithiobismaleimidoethane at 60 °C without any catalyst. Under physiological circumstance, the CCL micelles demonstrated the enhanced structural stability of the micelles, whereas dissociation of the micelles took place rapidly through the breaking of disulfide bonds in the cross‐linking linkages under reduction environment. The core‐cross‐linked micelles showed fine spherical distribution with hydrodynamic diameter of 68 ± 2.9  nm. The in vitro drug release profiles presented a slight release of DOX at pH 7.4, while a significant release of DOX was observed at pH 5.0 in the presence of 1,4‐dithiothreitol. MTT assays demonstrated that the block copolymer did not have any practically cytotoxicity against the normal HEK293 cell line while DOX‐loaded CCL micelles exhibited a high antitumor activity towards HepG2 cells. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3741–3750     

Micellization in solutions of hybrid block copolymer of poly(methyl methacrylate) and hyperbranched perfluorinated poly(phenylene germane)

Fractions of the product resulting from the polymerization of methyl methacrylate in the presence of hyperbranched perfluorinated poly(phenylene germane) have been studied by dynamic and static light scattering and capillary viscometry in methyl ethyl ketone solutions. The hybrid product is obtained via the reaction of the chain transfer of methyl methacrylate propagating radicals to pentafluorophenyl groups. Eight fractions have been isolated by fractional precipitation, including fractions of the linear-dendrite block copolymer. Light scattering studies have shown that hybrid macromolecules containing 15–20 wt % hyper-branched fragments form micelles in solutions.     

Monodisperse Cylindrical Micelles of Controlled Length with a Liquid‐Crystalline Perfluorinated Core by 1D “Self‐Seeding”

Precise control over the morphology and dimensions of block copolymer (BCP) micelles has attracted interest due to the potential of this approach to generate functional nanostructures. Incorporation of liquid crystalline (LC) block can provide additional ways to vary micellar morphologies, but the formation of uniform micelles with controllable dimensions from LC BCPs has not yet been realized. Herein, we report the preparation of monodisperse cylindrical micelles with a LC poly(2‐(perfluorooctyl)ethyl methacrylate (PFMA) core via a fragmentation‐thermal annealing (F‐TA) process, resembling the “self‐seeding” process of crystalline BCP micelles. The average length of the cylinders increases with annealing temperature, with a narrow length distribution (L_w/L_n<1.1). We also demonstrate the potential application of the cylinders with LC cores as a cargo‐carrier by the successful incorporation of a hydrophobic fluorescent dye tagged with a fluorooctyl group.     

Structural diversity in poly(disulfide)s

This article reports a synthetic methodology for single step preparation of telechelic poly(disulfide)s (PDS) by step‐growth polymerization between a di‐thiol and a commercially available monomer 2,2′‐dithiodipyridine in presence of a functional group appended pyridyl disulfide moiety as the “mono‐functional impurity” (MFI). Redox‐destructible well‐defined segmented PDSs with functional chain terminal, predicted and tunable degree of polymerization and narrow polydispersity index (<2.0) could be synthesized under a mild reaction condition. Using an appropriate MFI, PDS could be synthesized with trithiocarbonate chain terminals in a single step, which could be further used as macro chain‐transfer agent (CTA) for chain growth polymerization under RAFT mechanism producing ABA type tri‐block copolymer wherein the B block consists of the degradable PDS chain. By copolymerization between a hydrophobic di‐thiol monomer and a hydroxyl group appended di‐thiol monomer, PDS could be prepared with pendant hydroxyl functional group which was utilized to initiate ring opening polymerization of cyclic lactide monomers producing well‐defined degradable graft‐copolymer. The pendant hydroxyl groups were further utilized to anchor a polar carboxylic group to the degradable PDS backbone which under basic condition showed aqueous self‐assembly generating micelle‐like structure with hydrophobic guest encapsulation ability and glutathione responsive sustained release. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 194–202     

Effect of block molecular weight distribution on the structure formation in block copolymer/homopolymer blends

The effect of homopolymer (hP) addition on the structure formation in lamellar amorphous block copolymers (BCP) with narrow‐ and broad‐molecular weight distribution (MWD) was studied using small‐angle X‐ray scattering and transmission electron microscopy. The systems in our study consist of blends of a poly(styrene‐b‐methyl acrylate) copolymer with block‐selective broad MWD of the poly(methyl acrylate) domain as well as polystyrene and poly(methyl acrylate) hPs with molecular weight less than the corresponding block of the copolymer. Homopolymer addition to the broad MWD domain of the BCP is found to induce structural changes similar to narrow MWD BCP/hP blend systems. Conversely, addition of hP to the narrow MWD domain is found to induce a more pronounced expansion of lamellar domains due to the segregation of the hP to the center region within the host copolymer domain. With increasing hP concentration, the formation of a stable two‐phase regime with coexisting lamellar/gyroid microphases is observed that is bounded by uniform lamellar phase regimes that differ in the distribution of hP within the corresponding narrow MWD block domain. The segregation of low‐molecular weight hP to the center region of the narrowdisperse domains of a broad MWD BCP is rationalized as a consequence of the more stretched chain conformations within the narrowdisperse block that are implied by the presence of a disperse adjacent copolymer domain. The increase of chain stretching reduces the capacity of the narrowdisperse block to solubilize hP additives and thus provides a driving force for the segregation of hP chains to the center of the host copolymer domain. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 50: 106–116, 2012