pH‐Responsive Double‐Hydrophilic Block Copolymers: Synthesis and Drug Delivery Application

A novel double‐hydrophilic block copolymer P(MEO₂MA‐co‐OEGMA)‐b‐PAMA has been successfully synthesized by two‐step RAFT polymerization. Then, the amino groups of PAMA blocks in the copolymers react with 1‐pyrenecarboxaldehyde via a “Schiff‐base” reaction, and the resulting copolymers are self‐assembled to form spherical micelles in aqueous solution. Because the “Schiff‐base” linkage is pH sensitive, the release rate of pyrene depends upon the pH of solution. Complete release is achieved at pH 1, and the control release is much faster at pH 5.5 than that at pH 7.4. With progress of pyrene release, the micelles are disassembled gradually and disappeared completely at last. This double‐hydrophilic copolymer is a promising candidate of drug carrier for the aldehyde‐ containing hydrophobic drugs.     

Amorphous‐Crystalline PSnPEOn Heteroarm Star Copolymers: Crystallinity and Crystallization Kinetics

Summary: The crystallization behavior and kinetics of poly(ethylene oxide) in polystyrene/poly(ethylene oxide) heteroarm star copolymers were studied by differential scanning calorimetry and optical microscopy. A comparison between star and linear amorphous‐crystalline block copolymers showed that the macromolecular architecture is an important factor affecting crystallinity. The following points were observed: the equilibrium melting point is higher in the star copolymers, the crystallinity reduces as the number of arms increases, leading to smaller and ill‐defined spherulites, and crystallization proceeds faster in linear copolymers at low supercooling.

Half crystallization times, t_1/2, calculated from the Avrami analysis of the latent heats, obtained during the isothermal crystallization experiments as a function of supercooling, ΔT, for all copolymers.     

Double Hydrophilic Block Copolymer Self‐Assembly in Aqueous Solution

Self‐assembly of double hydrophilic block copolymers (DHBCs) in water is an emerging area of research. The self‐assembly process can be derived from aqueous two‐phase systems that are composed of hydrophilic homopolymers at elevated concentration. Consecutively, DHBCs form self‐assembled structures like micelles, vesicles, or particles at high concentrations in water and without the use of external triggers that would change solubility of individual blocks. Careful choice of the two hydrophilic blocks and design of the polymer structure allows formation of self‐assembled structures with high efficiency. The present contribution highlights recent research in the area of DHBC self‐assembly, including the polymer types employed and strategies for crosslinking of the self‐assembled structures. Moreover, an overview of aqueous multiphase systems and theoretical considerations of DHBC self‐assembly are presented, as well as an outlook regarding potential future applications in areas such as the biomedical field.     

Double‐Hydrophilic Block Copolymers with Monophosphate Ester Moieties as Crystal Growth Modifiers of CaCO3

The synthesis of double‐hydrophilic block copolymers with a poly(ethylene glycol) block (PEG) and a block with pendant monophosphate ester groups based on a hydroxylated polybutadiene block (poly[2‐(2‐hydroxy ethyl)ethylene] (PHEE) with variable degrees of phosphate substitution (up to 40%) is described. It is shown that these block copolymers are very efficient scale inhibitors for CaCO₃. The efficiency of these polymers is compared with block copolymers with an ionic block based on phosphorylated polyglycidol (PGL) with phosphorylation degrees up to 100%. The phosphorylated polyglycidols were also used to modify the morphology of CaCO₃ crystals. Instead of the typical rhombohedral calcite single crystals, superstructures of nanometer‐sized particles are formed in the presence of these block copolymers when two different techniques were used: the fast double‐jet technique and the slow Kitano‐method. In the double‐jet method, only spherical superstructures are obtained, whereas for the slower growth region covered by the Kitano method, complex cone‐like or flower‐like superstructures are formed.     

Double Hydrophilic Poly(ethylene oxide)‐block‐Poly(dehydroalanine) Block Copolymers: Comparison of Two Different Synthetic Routes

Two different synthetic pathways give access to the amphiphilic block copolymer poly(ethylene oxide)‐block‐poly(tert‐butoxycarbonylaminomethylacrylate). In the first approach, two end‐functionalized segments are linked via click chemistry; and in the second approach, a poly(ethylene oxide) (PEO) based macroinitiator is chain extended via atom transfer radical polymerization (ATRP). In both cases the linking unit consists of an amide group, which is necessary to effectively deprotect the corresponding polymer precursor without cleavage of both segments. For this, amide‐containing ATRP initiators are employed and successful synthesis by nuclear magnetic resonance (NMR) and size exclusion chromatography (SEC) analyses before comparing both pathways is demonstrated. After deprotection, a novel double hydrophilic block copolymer, poly(ethylene oxide)‐block‐poly(dehydroalanine), is obtained, which is investigated using SEC (aqueous and DMSO) and ¹H‐NMR spectroscopy. Containing a potentially zwitterionic PDha segment and a high density of both amino and carboxylic groups, pH‐dependent aggregation of the block copolymer is expected and is studied using dynamic light scattering, revealing interesting solution properties. The corresponding polymers are applied in various areas including drug delivery systems or in biomineralization.     

Salt‐ and pH‐Responsive Semirigid/Flexible Double‐Hydrophilic Block Copolymers

Double‐hydrophilic block copolymers (DHBCs) of poly((4‐diethylamino)‐(E)‐stilbene)‐alt‐maleic acid)‐block‐acryloyl morpholine (DEASti‐alt‐MA)‐b‐ACMO), semirigid‐b‐flexible coil structures, form polyion complexes (PICs) in aqueous solutions. The pH and salt responsiveness of the PICs are studied using dynamic light scattering (DLS). PIC complex formation is dependent on block segment lengths and pH. The particle size increases as the pH approaches the IEP (isoelectric point) of the DHBC. The salt responsiveness is also measured by using DLS to monitor PIC size for four examples with different segment molar masses. These PICs exhibit an antipolyelectrolyte effect with increasing hydrodynamic diameter as ionic strength (NaCl) increases from 0.01 to 2.0 m . PICs are more stable at higher ionic strengths with higher ACMO molar mass.

     

Tetraphenylsilane‐Cored Star‐Shaped Amphiphilic Block Copolymers for pH‐Responsive Anticancer Drug Delivery

Four‐arm star‐shaped poly[2‐(diethylamino)ethyl methacrylate]‐b‐poly[2‐hydroxyethyl methacrylate]s block copolymers using tetraphenylsilane (TPS) as a core with adjustable arm lengths are synthesized through two‐step atom transfer radical polymerizations. For comparison, a linear block copolymer with similar molecular weight is also prepared. The assembled star‐shaped copolymer micelles exhibit sizes of 102–139 nm and critical micelle concentrations of 1.49–3.93 mg L^?1. Moreover, the bulky and rigid TPS core is advantageous for propping up the four star‐shaped arms to generate large intersegmental space. As a result, the drug‐loading capacity in the micelles is up to 33.97 wt%, much surpassing the linear counterpart (8.92 wt%) and the previously reported star‐shaped copolymers prepared using pentaerythritol as the core. Furthermore, the micelles show sensitive pH‐responsive drug release when the pH changes from 7.4 to 5.0. The in vitro cytotoxicity to Hela cells indicates that the doxorubicin (DOX)‐loaded micelles have similar anticancer activity to the pristine DOX. The combination of excellent micelle stability, high drug‐loading, sensitive pH response, and good anticancer activity endows the copolymers with promising application in drug control delivery for anticancer therapy.     

Reversible Hydrogels from an Ampholytic An(B‐b‐C)n Heteroarm Star Block Terpolymer

An asymmetric, amphiphilic, A_n(B‐b‐C)_n heteroarm star block terpolymer bearing polystyrene and poly(2‐vinyl pyridine)‐block‐poly(acrylic acid) arms, was synthesized by anionic polymerization, using an extending “in‐out” method and a post polymerization deprotection reaction. Due to the pH‐dependent protonation/deprotonation equilibrium of the P2VP/PAA blocks, a rich phase behavior was observed as a function of pH. At pH = 2, the star terpolymers form a physical hydrogel through a solvent‐induced sol/gel transition in a DMF/water solvent mixture. The gelation mechanism was attributed to a jamming effect mediated by increasing the dielectric permittivity of the medium.

     

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.

     

Star Block Copolymers Through Nitroxide‐Mediated Radical Polymerization From Polyhedral Oligomeric Silsesquioxane (POSS) Core

A series of star block copolymers were prepared through nitroxide‐mediated radical polymerization (NMRP) from polyhedral oligomeric silsesquioxanes (POSS) nanoparticle by core‐first polymerization. Eight N‐alkoxyamine groups were incorporated onto the eight corners of a POSS cube through quantitative hydrosilylation through addition of octakis(dimethylsiloxy)silsesquioxane (Q₈M POSS) with 1‐(2‐(allyloxy)‐1‐phenylethoxy)‐2,2,6,6‐tetramethylpiperidine (allyl‐TEMPO) and Karstedt's agent (a platinum divinylsiloxane complex) was used as a catalyst. Octa‐N‐alkoxyamines POSS (OT‐POSS) were used as platform to synthesize star polystyrene‐POSS ((PS)₈‐POSS) homopolymer and diblock copolymers of poly(styrene‐block‐4‐vinylpyridine)‐POSS ((PS‐b‐P4VP)₈‐POSS) and poly(styrene‐block‐acetoxystyrene) ((PS‐b‐PAS)₈‐POSS) through NMRP. In addition, subsequent selective hydrolysis of the acetyl protective group of (PS‐b‐PAS)₈‐POSS, the poly(styrene‐block‐vinyl phenol) ((PS‐b‐PVPh)₈‐POSS) with strong hydrogen bonding group was obtained. The detailed chemical structure and self‐assembled structures of these star block copolymers based on POSS were characterized by ¹H NMR, FTIR, SEC, TEM, and SAXS analyses.

     

Multi‐Responsive Supramolecular Double Hydrophilic Diblock Copolymer Driven by Host‐Guest Inclusion Complexation between β‐Cyclodextrin and Adamantyl Moieties

Well‐defined β‐CD‐terminated poly(N‐isopropylacrylamide) (β‐CD‐PNIPAM) was synthesized via a combination of atom transfer radical polymerization (ATRP) and click chemistry. Moreover, adamantyl‐terminated poly(2‐(diethylamino)ethyl methacrylate) (Ad‐PDEA) was synthesized by ATRP using an adamantane‐containing initiator. Host‐guest inclusion complexation between β‐CD and adamantyl moieties drives the formation of supramolecular double hydrophilic block copolymers (DHBC) from β‐CD‐PNIPAM and Ad‐PDEA. The obtained supramolecular PNIPAM‐b‐PDEA diblock copolymer exhibits intriguing multi‐responsive and reversible micelle‐to‐vesicle transition behavior in aqueous solution by dually playing with solution pH and temperatures.

     

Micellization Kinetics of a Novel Multi‐Responsive Double Hydrophilic Diblock Copolymer Studied by Stopped‐Flow pH and Temperature Jump

Double hydrophilic diblock copolymer, poly(N‐isopropylacrylamide)‐block‐poly(2‐diethylamino ethyl methacrylate) (PNIPAM‐b‐PDEA), was synthesized via reversible addition‐fragmentation chain transfer (RAFT) polymerization. Containing the well‐known thermo‐responsive PNIPAM block and pH‐responsive PDEA block, this novel diblock copolymer exhibits intriguing “schizophrenic” micellization behavior in aqueous solution, forming PDEA‐core micelles at alkaline pH and room temperature, and PNIPAM‐core micelles at acidic pH and elevated temperatures. The kinetics of the pH‐ and thermo‐responsive micellization processes were studied in detail using a stopped‐flow apparatus equipped with a newly developed millisecond temperature jump (mT‐jump) accessory. Upon a pH jump from 4 to 12 at 25 °C, the early stages of relaxation curves monitoring the formation PDEA‐core micelles can be well‐fitted using a double‐exponential function, leading to two characteristic relaxation time constants, τ₁ and τ₂. As τ₂ decreases with increasing polymer concentration, the slow process is thus expected to proceed via micelle fusion/fission mechanism, approaching the final equilibrium state. Upon a temperature jump from 20 to 45 °C at pH 4, the relaxation curves monitoring the formation PNIPAM‐core micelles can also be well‐fitted using a double‐exponential function. The fast process (τ₁) is associated with the quick association of unimers into a large amount of small micelles and the formation of quasi‐equilibrium micelles. τ₂ is almost independent of polymer concentration, suggesting that unimer insertion/expulsion is the main mechanism for the slow process. The protonated PDEA corona of quasi‐equilibrium micelles renders the micelle fusion/fission mechanism less favorable due to electrostatic repulsion.

     

Aggregation and Crosslinking of Poly(N,N‐dimethylacrylamide)‐b‐pullulan Double Hydrophilic Block Copolymers

The self‐assembly of polymers is a major topic in current polymer chemistry. In here, the self‐assembly of a pullulan based double hydrophilic block copolymer, namely pullulan‐b‐poly(N,N‐dimethylacrylamide)‐co‐poly(diacetone acrylamide) (Pull‐b‐(PDMA‐co‐PDAAM)) is described. The hydrophilic block copolymer induces phase separation at high concentration in aqueous solution. Additionally, the block copolymer displays aggregates at lower concentration, which show a size dependence on concentration. In order to stabilize the aggregates, crosslinking via oxime formation is described, which enables preservation of aggregates at high dilution, in dialysis and in organic solvents. With adequate stability by crosslinking, double hydrophilic block copolymer (DHBC) aggregates open pathways for potential biomedical applications in the future.     

Well‐defined N‐Isopropylacrylamide Dual‐Sensitive Copolymers with LCST ≈38 °C in Different Architectures: Linear,Block and Star Polymers

Reversible addition‐fragmentation chain transfer (RAFT) polymerization is used to prepare temperature‐ and pH‐sensitive statistical copolymers with lower critical solution temperature (LCST) close to 38 °C at pH 7.4 based on N‐isopropylacrylamide and methacrylic acid derivative comonomers with a pK_a close to 6. Statistical copolymers are re‐activated to prepare amphiphilic block copolymers and star polymers with cross‐linked core. The LCST is maintained by varying the architecture; however, the LCST originated behaviour changes due to self‐aggregation. Statistical copolymers and short block copolymers show complex aggregation, whereas mid‐size block copolymers and star polymers show shrinkage of aggregate dimensions. The pH of the medium has a profound impact on the self‐assembling behaviour of the different polymer architectures.     

Synthesis and Self‐Assembly of Novel Amphiphilic Six‐Armed Star Copolymers TP[PDMAEMA‐b‐PSt]6

A triphenylene (TP)‐based hexafunctional initiator was prepared and used in successive ATRP of DMAEMA and St. Well‐defined six‐armed star block copolymers TP[PDMAEMA‐b‐PSt]₆ bearing hydrophilic backbones inside and hydrophobic blocks outside were successfully synthesized. The self‐assembly behaviors of the novel amphiphilic copolymer were further investigated. Co‐existing spherical and bowl‐shaped aggregates were observed from their neutral aqueous solution, while large spherical structures with different dimensions were obtained from their diluted HCl and CF₃COOH aqueous solution, respectively. Dynamic light scattering in different aqueous solutions were conducted to give further confirmation. The possible mechanism of the morphology formation was proposed.

     

Characterization of Linear and 3‐Arm Star Block Copolymers by Liquid Chromatography at Critical Conditions

Summary: LCCC for polyMA homopolymers was established in order to analyze the polyMA‐polySt linear and star block copolymers. The validity of the assumption that under the LCCC for polyMA, the polyMA segment in the polyMA‐containing block copolymer is chromatographically “invisible” was verified. It was found that within the scale of investigation ( ), the molecular weight and architecture of the polyMA segments had no evident influence on the retention behavior of the polySt‐polyMA block copolymers and the polyMA block in the copolymer was “invisible”. The critical conditions of polyMA were used for quantitative analysis of the polySt block in the linear and 3‐arm star polyMA‐polySt block copolymers, which were synthesized by AGET ATRP in miniemulsion. It was shown that the copolymer had completely different elution peak from its MI. The calculated molecular weights of polySt blocks in the block copolymers were similar to those obtained from normal SEC analysis. Transferring the eluates from the LCCC (the first dimension) column to a SEC column (the second dimension) produced LCCC × SEC two‐dimensional chromatogram, which contained information on both chemical composition and molecular weight of the synthesized copolymers. The combination of these liquid chromatography methods clearly confirmed the high initiation efficiency of the polyMA MIs during the synthesis of block copolymers and the presence of a byproduct formed by radical‐radical coupling.

     

Water‐Soluble Stoichiometric Polyelectrolyte Complexes Based on Cationic Comb‐Type Copolymers

Summary: The interaction between the cationic comb‐type copolymer poly(acrylamide‐co‐MAPTAC)‐graft‐polyacrylamide, synthesized by free‐radical polymerization, and the anionic homopolymer NaPA has been investigated. Water‐soluble PECs are formed through a charge neutralization process. They adopt a compact structure, and form nanoparticles consisting of a hydrophobic PEC core and a protective hydrophilic PAM corona. By increasing the composition of the graft copolymers in neutral PAM side chains, the aggregation number and the size of the nanoparticles decrease. Moreover, increasing the ionic strength of the solution favours the dissociation of the complexes.

A schematic representation of the PEC nanoparticles formed at N_NaPA = 0.5.     

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.     

Self‐Assembling of Block Copolymers with Alternative Solvents

Block copolymer (BCP) lithography is one of the most technologically intriguing and scientifically interesting strategies for achieving nanometer‐sized features. This method usually exploits toluene as solvent for the deposition of BCPs in all the processing steps. However, this chemical has some technical disadvantages, such as high toxicity and hygroscopicity. The first aspect can limit its use on the industrial scale because of the protocols on the environmental and operator risks, while the second causes aging effects that can alter the results. In order to overcome these intrinsic limitations, a BCP self‐assembly (BCP‐SA) strategy is presented by using alternative deposition solvents in place of toluene. A preliminary study, based on the physical characteristics, such as volatility, polarity, and hygroscopicity, is carried out to explore two new alternative solvents, ethyl acetate and tetrahydrofuran. The effects on the BCP‐SA due to the new solvents are studied by SEM analysis supported by suitable software for the images elaboration. The results achieved show very promising outcomes for the polymer solutions obtained with ethyl acetate, in terms of uniformity of geometrical features, ordered areas extension, and homogeneity of the pattern obtained, making this chemical a good alternative to toluene.     

Segmented Block Copolymers with Terephthalic‐Extended Poly(ethylene oxide) Segments

Segmented block copolymers comprised of flexible PEO segments and monodisperse crystallizable bisestertetraamide segments have been synthesized. The influence of the terephthalic units in the soft phase on the transitions and the thermal mechanical and elastic properties are studied. The presence of terephthalic units in the copolymer increases the glass transition temperature of the soft phase by ≈5 °C. The low‐temperature flexibility of the copolymers is improved because of the lower crystallinity and melting temperature of PEO. With the use of terephthalic‐extended PEO segments, segmented block copolymers with low moduli (G' < 15 MPa) and good elastic properties could be obtained.