Poly(hydroxyl propyl methacrylate)‐b‐Poly(oligo ethylene glycol methacrylate) Thermoresponsive Block Copolymers by RAFT Polymerization

Thermoresponsive amphiphilic poly(hydroxyl propyl methacrylate)‐b‐poly(oligo ethylene glycol methacrylate) block copolymers (PHPMA‐b‐POEGMA) are synthesized by RAFT polymerization, with different compositions and molecular weights. The copolymers are molecularly characterized by size‐exclusion chromophotography, and ¹H NMR spectroscopy. Dynamic light scattering (DLS) and static light scattering (SLS) experiments in aqueous solutions show that the copolymers respond to temperature variations via formation of self‐organized nanoscale aggregates. Aggregate structural characteristics depend on copolymer composition, molecular weight, and ionic strength of the solution. Fluorescence spectroscopy experiments confirm the presence of less hydrophilic domains within the aggregates at higher temperatures. The thermoresponsive behavior of the PHPMA‐b‐POEGMA block copolymers is attributed to the particular solubility characteristics of the hydrophilic, water insoluble PHPMA block that are modulated by the presence of the water soluble POEGMA block.     

Biocompatible Poly(D,L‐lactide)‐block‐Poly(2‐methacryloyloxyethylphosphorylcholine) Micelles for Drug Delivery

Well‐defined amphiphilic PLA‐b‐PMPC diblock copolymers were synthesized. Bimimetic micelles were prepared and applied for release of anti‐cancer drugs (DOX). TEM and DLS analysis revealed a regular spherical shape with small diameter (less than 50 nm) of the micelle. The biocompatibility of PLA‐b‐PMPC micelles was studied, and it was found that the micelles possessed excellent cytocompatibility due to the zwitterionic phosphorylcholine group. DOX could be efficiently loaded into the micelles with a loading efficiency of 44–67%. The DOX‐loaded micelles showed lower cytotoxicity than free drugs and efficiently delivered and released the drug into cancer cells. With these properties, the PLA‐b‐PMPC polymer micelles are attractive as drug carriers for pharmaceutical application.

     

Janus Micelle Formation Induced by Protonation/Deprotonation of Poly(2‐vinylpyridine)‐block‐Poly(ethylene oxide) Diblock Copolymers

A novel approach to amphiphilic polymeric Janus micelles based on the protonation/deprotonation process of poly(2‐vinylpyridine)‐block‐poly(ethylene oxide) (P2VP‐b‐PEO) diblock copolymers in THF is presented. It is found that addition of HCl to the micelles solution of P2VP‐b‐PEO copolymers leads to the formation of vesicles. Subsequently mixing a small amount of hydrazine monohydrate with the vesicle solution can induce the dissociation and reorganization of the vesicles into Janus micelles. When HCl is replaced by HAuCl₄ precursors, composite Janus particles containing gold in P2VP blocks are obtained.

     

Hydrolyzed Poly(2‐plenyl‐2‐oxazoline)s in Aqueous Media and Biological Fluids

Hydrolyzed poly(2‐phenyl‐2‐oxazoline)s (PPhOx) are synthesized by partial hydrolysis of PPhOx in order to produce self‐assembling copolymers with chargeable and hydrophobic units. The resulting poly(ethylene imine‐co‐2‐phenyl‐2‐oxazoline) [P(EI‐co‐PhOx)] amphiphilic copolymers contain phenyl‐oxazoline and ethylene imine segments in a random sequence and their chemical structure is confirmed by ¹H NMR and attenuated total reflection‐Fourier transform infrared spectroscopy. Static and dynamic light scattering experiments show that in aqueous solutions the random copolymers associate into aggregates of sizes in the range between 50 and 200 nm depending on the solution conditions and hydrophobic content. The positive charge of the nanoaggregates that is caused by protonation of the amine nitrogen is confirmed by zeta potential measurements. Self‐assembly in phosphate buffered saline results in large aggregates. The aggregates are proved to interact with fetal bovine serum proteins. This investigation shows that hydrolyzed phenyl oxazoline‐based copolymers provide stable amphiphilic nanoparticles able to interact with biological macromolecules for biotechnological and pharmaceutical applications.     

The Aggregation Behavior of Poly(ethylene oxide)‐Poly(methyl methacrylate) Diblock Copolymers in Organic Solvents

Poly(ethylene oxide)‐poly(methyl methacrylate) and poly(ethylene oxide)‐poly(deuteromethyl methacrylate) block copolymers have been prepared by group transfer polymerization of methyl methacrylate (MMA) and deuteromethyl methacrylate (MMA‐d₈), respectively, using macroinitiators containing poly(ethylene oxide) (PEO). Static and dynamic light scattering and surface tension measurements were used to study the aggregation behavior of PEO‐PMMA diblock copolymers in the solvents tetrahydrofuran (THF), acetone, chloroform, N,N‐dimethylformamide (DMF), 1,4‐dioxane and 2,2,2‐trifluoroethanol. The polymer chains are monomolecularly dissolved in 1,4‐dioxane, but in the other solvents, they form large aggregates. Solutions of partially deuterated and undeuterated PEO‐PMMA block copolymers in THF have been studied by small‐angle neutron scattering (SANS). Generally, large structures were found, which cannot be considered as micelles, but rather fluctuating structures. However, ¹H NMR measurements have shown that the block copolymers form polymolecular micelles in THF solution, but only when large amounts of water are present. The micelles consist of a PMMA core and a PEO shell.     

Dual pH‐Sensitive DOX‐Conjugated Cyclodextrin‐Core Star Nano‐Copolymer Prodrugs

Herein this study reports dual pH‐sensitive doxorubicin (DOX)‐conjugated β‐cyclodextrin‐core star copolymers with tailoring properties such as direct water‐solubility and stability prior to reaching target sites. For these purposes, three kinds of novel well‐defined β‐cyclodextrin‐core poly(2‐(diethylamino)ethyl methacrylate‐co‐4‐formylphenyl methacrylate)‐b‐poly(poly(ethylene glycol) methyl ether methacrylate) star copolymers (CD‐star‐P(DEA‐co‐FPMA)‐b‐PPEGMA, SPDFP1–3) with different poly(ethylene glycol) methyl ether methacrylate contents are designed and synthesized by atom transfer radical polymerization (ATRP) strategy. 4‐Formylphenyl methacrylate is introduced into the inner arm block of the star copolymers for conjugating DOX by imine bond formation. Interestingly, the DOX‐conjugated β‐cyclodextrin‐core star copolymers not only can directly dissolve in aqueous buffer solution of pH 7.0 to form unimolecular micelles without any aid of organic solvent, but also exhibit strong pH‐dependent DOX release. At normal pH 7.4 the DOX amount released is very small, whereas at pH 5.0 DOX can be released. By selecting SPDFP2–DOX as a representative, it is found that the SPDFP2–DOX micelles show less cytotoxicity compared to carrier‐free DOX and can be internalized by HeLa cells. It is expected that the exploration can provide new strategy for preparing drug delivery system.

     

Effects of pH‐Sensitive Groups on Poly(ethylene oxide)‐block‐poly(ϵ‐caprolactone) Block Copolymer Micelles Used as Drug Carriers

A new type of drug delivery system consisting of an amphiphilic polymer micelle with pH‐sensitive groups is reported. The polymer comprises mPEG [poly(ethylene glycol) monomethyl ether], PCL [poly(?‐caprolactone)], and either PAA [poly(acrylic acid)] or PMAA [poly(methacrylic acid)]. Both mPEG‐b‐PCL and mPEG‐b‐PCL‐b‐PAA/PMAA are characterized by ¹H NMR, FTIR, and gel permeation chromatography (GPC). The diameters of the mPEG‐b‐PCL‐b‐PAA/PMAA micelles are found to increase with increases in pH and studies show that in vitro release of nifedipine from mPEG‐b‐PCL‐b‐PAA/PMAA micelles becomes faster as the pH value of phosphate‐buffered saline (PBS) increases. This new type of pH‐sensitive polymeric micelle can potentially be used as a drug carrier for oral administration of water‐insoluble drugs.     

Synthesis and Micellization of Star‐Shaped Poly(ethylene glycol)‐block‐Poly(ε‐caprolactone)

Summary: The relationship between the architecture of block copolymers and their micellar properties was investigated. Diblock, 3‐arm star‐shaped and 4‐arm star‐shaped block copolymers based on poly(ethylene glycol) and poly(ε‐caprolactone) were synthesized. Micelles of star‐shaped block copolymer in an aqueous solution were then prepared by a solvent evaporation method. The critical micelle concentration and the size of the micelles were measured by the steady‐state pyrene fluorescence method and dynamic light scattering, respectively. The CMC decreased in the order di‐, 3‐arm star‐shaped and 4‐arm star‐shaped block copolymer. The size of the micelles increased in the same order as the CMC. Theory also predicts that the formation of micelles becomes easier for 4‐arm star‐shaped block copolymers than for di‐ and 3‐arm star‐shaped block copolymers, which qualitatively agrees with the experiments.

     

The Temperature‐Responsive Nanoassemblies of Amphiphilic Random Copolymers Carrying Poly(siloxane) and Poly(oxyethylene) Pendant Chains

Novel amphiphilic random copolymers carrying poly(oxyethylene) and poly(siloxane) pendant chains are synthesized by atom transfer radical polymerization starting from either a fluorescent, julolidine‐based initiator, or a nonfluorescent initiator. For both copolymer systems, dynamic light scattering measurements carried out on aqueous solutions as a function of temperature reveal the occurrence of a sharp and fully reversible transition between two different self‐associative states of individual, single‐chain self‐folded nanoassemblies, so‐called unimer micelles, (D_h = 8–10 nm) and collapsed multichain aggregates (D_h = 700–1400 nm) at a critical temperature T_c. Covalently linked julolidine terminal and added ethidium bromide are separately used as fluorescent probes and both prove the temperature‐dependence of the different self‐association of the copolymers in water.     

Self‐Assembly and Responsive Behavior of Poly(peptide)‐Based Copolymers

Well‐defined copolymers synthesized by combining poly(ethylene glycol) (PEG) and amino acid based building blocks are investigated with regard to their helical rigidity and self‐assembly. Optical active block copolymers reported here are designed to have a pendant amino acid and polymerizable group, that is, isonitrile in order to induce helix formation and reduce the mobility of polymer chains by forming a hydrogen bond network so that a helix with reasonable rigidity can be obtained. Due to the amphiphilicity and a relatively shorter PEG as a coil, these polymers form micelles as observed under transmission electron microscopy in which copolymers PEG₁₀₈‐b‐PPIC₇₆₄ and PEG₁₀₈‐b‐PPIC₁₀₂₀ appear to be evolving into nanoparticles with a size distribution of 100–200 nm. Circular dichroism spectroscopy is employed to study the nature of the helix and its rigidity. The folding and unfolding of polymer helix as a result of the ability of a selective solvent to form/disrupt hydrogen bonds with the peptide linkage is also discussed to highlight the responsive nature of the polymer.     

Amphiphilic Block Copolymers Containing Regioregular Poly(3‐hexylthiophene) and Poly(2‐ethyl‐2‐oxazoline)

Poly(3‐hexylthiophene)‐block‐poly(2‐ethyl‐2‐oxazoline) amphiphilic rod–coil diblock copolymers have been synthesized by a combination of Grignard metathesis (GRIM) and ring‐opening cationic polymerization. Diblock copolymers containing 5, 15, and 30 mol‐% poly(2‐ethyl‐2‐oxazoline) have been synthesized and characterized. The synthesized rod–coil block copolymers display nanofibrillar morphology where the density of the nanofibrills is dependent on the concentration of the poly(2‐ethyl‐2‐oxazoline) coil segment. The conductivity of the diblock copolymers was lowered from 200 to 35 S · cm^?1 with an increase in the content of the insulating poly(2‐ethyl‐2‐oxazoline) block. By contrast, the field‐effect mobility decreased by 2–3 orders of magnitude upon the incorporation of the poly(2‐ethyl‐2‐oxazoline) insulating segment.

     

Micelles with a Loose Core Self‐Assembled from Coil‐g‐Rod Graft Copolymers Displaying High Drug Loading Capacity

High drug loading capacity is one of the critical demands of micellar drug‐delivery vehicles; however, it is a challenging work. Herein, it is demonstrated that micelles self‐assembled from poly(ethylene glycol)‐graft‐poly(γ‐benzyl‐l ‐glutamate) (PEG‐g‐PBLG) coil‐g‐rod graft copolymers display high drug‐loading capacity for doxorubicin (DOX) model drugs. As revealed by a combination study of experiments and dissipative particle dynamics simulations, the high drug‐loading capacity of the micelles is related to the loose core structure of the micelles. In these micelles, the hydrophobic PBLG grafts randomly disperse in the micelle core due to their rigid nature and the coil‐g‐rod topology of the graft copolymers, which results in a loose core of the micelles. The structure of the graft copolymer, including the length of rod grafts, the length of coil backbone, and the grafting ratio of the rod grafts affecting the arrangement of the rod grafts in the micelle core has influence on the drug‐loading capacity of the micelles. Besides, the strong π–π stacking interaction between graft copolymers and DOX also plays an important part in achieving high drug‐loading capacity. In vitro studies reveal that these drug‐loaded micelles show good biocompatibility, and the DOX can be gradually released from the micelles.     

A Convenient Method for the Synthesis of the Amphiphilic Triblock Copolymer Poly(L‐lactic acid)‐block‐Poly(L‐lysine)‐block‐Poly(ethylene glycol) Monomethyl Ether

The amphiphilic triblock copolymer PLA‐b‐PLL‐b‐MPEG is prepared in three steps through acylation coupling between the terminal amino groups of PLA‐b‐PZLL‐NH₂ and carboxyl‐terminal MPEG, followed by the deprotection of amines. The block copolymers are characterized via FT‐IR, ¹H NMR, DSC, GPC, and TEM. TEM analysis shows that the triblock polymers can form polymeric micelles in aqueous solution with a homogeneous spherical morphology. The cytotoxicity assay indicates that the final triblock polymer micelles after deprotection show low cytotoxicity against Bel7402 human hepatoma cells. MPEG and PLL were introduced into the main chain of PLA affording a kind of ideal bioabsorbable polymer materials, which is expected to be useful in drug and gene delivery.

     

One‐Step Preparation of Reduction‐Responsive Biodegradable Polymers as Efficient Intracellular Drug Delivery Platforms

Reduction‐responsive biodegradable polymeric micelles based on functional 2‐methylene‐1,3‐dioxepane (MDO) copolymers are developed and investigated for triggered doxorubicin (DOX) release. The MDO‐based copolymers P(MDO‐co‐PEGMA‐co‐PDSMA) are synthesized via the simple one‐step radical ring‐opening copolymerization of MDO, poly(ethylene glycol) methyl ether methacrylate (PEGMA), and pyridyldisulfide ethylmethacrylate (PDSMA). The copolymers can self‐assemble to form micelles in aqueous solution. DOX, a model anticancer drug, is loaded into the micelles with the drug loading content (DLC) of 11.3%. The micelles can be disassembled under a reductive environment (10 × 10^?3m glutathione), which results in a triggered drug release behavior. The glutathione‐mediated intracellular drug release of DOX‐loaded micelles is investigated against A549 cells. Confocal laser scanning microscopy (CLSM) results demonstrated that DOX‐loaded micelles exhibits faster drug release in glutathione monoester (GSH‐OEt)‐pretreated A549 cells, compared with untreated and buthionine sulfoximine (BSO)‐pretreated A549 cells. Based on the facile synthetic strategy, the reduction‐sensitive biodegradable micelles with triggered intracellular drug release are promising for anticancer drug delivery.

     

Synthesis and Self‐Assembly Behavior of Organic–Inorganic Poly(ethylene oxide)‐block‐Poly(MA POSS)‐block‐Poly(N‐isopropylacrylamide) Triblock Copolymers

In this work, the synthesis of 3‐methacryloxypropylheptaphenyl POSS, a new POSS macromer (denoted MA‐POSS) is reported. The POSS macromer is used to synthesize PEO‐b‐P(MA‐POSS)‐b‐PNIPAAm triblock copolymers via sequential atom transfer radical polymerization (ATRP). The organic‐inorganic, amphiphilic and thermoresponsive ABC triblock copolymers are characterized by means of nuclear magnetic resonance spectroscopy (NMR) and gel permeation chromatography (GPC). Differential scanning calorimetry (DSC) and atomic force microscopy (AFM) show that the hybrid ABC triblock copolymers are microphase‐separated in bulk. Cloud point measurements show that the effect of the hydrophiphilic block (i.e. PEO) on the LCSTs is more pronounced than the hydrophobic block (i.e. P(MA‐POSS)). Both transmission electron microscopy (TEM) and dynamic light scattering (DLS) show that all the triblock copolymers can be self‐organized into micellar aggregates in aqueous solutions. The sizes of the micellar aggregates can be modulated by changing the temperature. The temperature‐tunable self‐assembly behavior is interpreted using a combination of the highly hydrophobicity of P(MA‐POSS), the water‐solubility of PEO and the thermoresponsive property of PNIPAAm in the triblock copolymers.     

Solution Self‐Assembly of Poly(ferrocenylphenylphosphine)‐block‐polydimethylsiloxane: Formation of Spherical Micelles with an Organometallic Poly(ferrocenylphenylphosphine) Core

The novel organometallic‐inorganic diblock copolymer, poly(ferrocenylphenylphosphine)‐block‐polydimethylsiloxane (PFP‐b‐PDMS), with narrow molecular weight distribution has been synthesized by living anionic polymerization through sequential monomer addition. These block copolymers self‐assemble into “star‐like” spherical micelles in hexane with a dense organometallic PFP core surrounded by a swollen corona of the PDMS chains. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to characterize these micellar aggregates. It was found that the block copolymer micelles have a relatively narrow core size distribution, but an overall broader distribution of hydrodynamic size in hexane. Significantly, the preparation method of the micelle solution was also found to have an influence on the size and size distribution of the resulting micellar structures.     

Tunable Morphologies From Bulk Self‐Assemblies of Poly(acryloxypropyl triethoxysilane)‐b‐poly(styrene)‐b‐poly(acryloxypropyl triethoxysilane) Triblock Copolymers

Reactive poly(acryloxypropyl triethoxysilane)‐b‐poly(styrene)‐b‐poly(acryloxypropyl triethoxysilane) (PAPTES‐b‐PS‐b‐PAPTES) triblock copolymers are prepared through nitroxide‐mediated polymerization (NMP). The bulk morphologies formed by this class of copolymers cast into films are examined by small‐angle X‐ray scattering (SAXS) and transmission electron microscopy (TEM). The films morphology can be tuned from spherical structures to lamellar structures by increasing the volume fraction of PS in the copolymer. Thermal annealing at temperatures above 100 °C provides sufficient PS mobility to improve ordering.     

Spherical Compound Micelles with Lamellar Stripes Self‐Assembled from Star Liquid Crystalline Diblock Copolymers in Solution

Detailed investigations on the self‐assembly of amphiphilic star block copolymers composed of three‐arm poly(ethylene oxide) (PEO) and poly(methacrylate) (PMAAz) with an azobenzene side chain (denoted as 3PEO‐b‐PMAAz) into stable spherical aggregates with clear lamellar stripes in solution are demonstrated. Four block copolymers, 3PEO₁₂‐b‐PMA(Az)₃₃, 3PEO₂₂‐b‐PMA(Az)₃₁, 3PEO₂₂‐b‐PMA(Az)₆₂, and linear PEO₆₈‐b‐PMA(Az)₃₁, are synthesized. The liquid crystalline properties of the block copolymers are studied by differential scanning calorimetry, polarized optical microscopy techniques, and wide‐angle X‐ray diffraction. The morphologies of the compound micelles self‐assembled in tetrahydrofuran (THF)/water mixtures are observed by means of transmission electron microscopy and scanning electron microscopy. The size of the spherical micelles is influenced by the self‐assembly conditions and the lengths of two blocks. The well‐defined three‐arm architecture of the hydrophilic blocks is a key structural element to the formation of stable spherical compound micelles. The micelle surface integrity is affected by the lengths of PEO blocks. The lamellar stripes are clearly observed on these micelles. This work provides a promising strategy to prepare functional stable spherical compound micelles self‐assembled by amphiphilic block copolymers in solution.     

Synthesis of Amphiphilic Poly(ethylene oxide‐co‐glycidol)‐graft‐polyacrylonitrile Brush Copolymers and their Self‐assembly in Aqueous Media

An amphiphilic copolymer brush poly(ethylene oxide‐co‐glycidol)‐graft‐polyacrylonitrile [poly(EO‐co‐Gly)‐g‐PAN], is successfully prepared for the first time by a combination of anionic polymerization and redox free radical polymerization. The final products and intermediates are characterized by NMR and GPC. Aggregates made from the brush copolymers, poly(EO‐co‐Gly)‐g‐PAN, with a long hydrophobic graft length in water are studied by TEM and DLS. The effects of hydrophobic graft length and water content on the morphologies are discussed. Some rare morphologies of aggregates are observed, such as lamellae, bicontinuous networks, bowls or nanosheets, and large compound rods with a brittleness that can be ascribed to the orientation of high content semi‐crystalline PAN segments.     

Effects of Poly(N‐isopropylacrylamide) (PNIPAAm) on the Conformational Change of Poly(N 5‐hydroxyalkyl glutamine) (PHAG) in PHAG‐PNIPAAm Block Copolymer with Temperature

Diblock copolymers consisting of poly(N ⁵‐hydroxyalkylglutamine) (PHAG) and poly(N‐isopropylacrylamide) (PNIPAAm) were prepared by aminolysis with aminoalkanols of the side‐chain ester of poly(γ‐benzyl L ‐glutamate) (PBLG) as a part of PBLG‐PNIPAAm block copolymers. The molecular weight ratio of the initial PBLG to the resulting PHAG was nearly 0.35. The effect of PNIPAAm on the conformational change of PHAG in PHAG‐PNIPAAm block copolymers with temperature was investigated by circular dichroism. Poly[N ⁵‐(2‐hydroxyethyl)‐L ‐glutamine] (PHEG) and the PHEG‐PNIPAAm copolymer (GNE) stayed in a randomly coiled conformation whereas poly[N ⁵‐(3‐hydroxypropyl)‐L ‐glutamine] (PHPG), poly(N ⁵‐(4‐hydroxybutyl)‐L ‐glutamine) (PHBG), PHPG‐PNIPAAm copolymer (GNP), and PHBG‐PNIPAAm copolymer (GNB) underwent conformational transitions with temperature. The conformational change of the PHPG block in GNP copolymer occurred from an α‐helix to a random coil after the incorporation of PNIPAAm into the copolymer. The thermodynamic parameters of the thermally induced helix‐coil transition for PHBG and PHBG‐PNIPAAm in aqueous solution were calculated.