Stimuli‐Induced Core–Corona Inversion of Micelle of Poly(acrylic acid)‐block‐Poly(N‐isopropylacrylamide) and Its Application in Drug Delivery

Core–corona inversion of micelles of diblock copolymer poly(acrylic acid)‐block‐poly(N‐isopropylacrylamide) (PAA‐b‐PNIPAM), has been successfully realized by switching either pH or temperature. The strong interaction of doxorubicin with the PAA block and the pH‐sensitive drug release from the polymer make the system very useful as a controlled drug delivery system. The encapsulation of hydrophobic Nile Red molecules above the lower critical solution temperature of PNIPAM suggests that this polymer may be useful for removing hydrophobic pollutants.

     

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.     

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.     

pH‐Sensitive Micelles Formed by Interchain Hydrogen Bonding of Poly(methacrylic acid)‐block‐Poly(ethylene oxide) Copolymers

pH‐sensitive micelles formed by interchain hydrogen bonding of poly(methacrylic acid)‐block‐poly(ethylene oxide) copolymers were prepared and investigated at pH < 5. Both and R_h of the micelles increase with decreasing pH of the solution, displaying an asymptotic tendency at low pH values. The observed micelles are well‐defined nanoparticles with narrow size distributions (polydispersity ΔR_h/R_h ≤ 0.05) comparable with regular diblock copolymer micelles. The CMCs occur slightly below c = 1 × 10^?4 g · mL^?1. The micelles are negatively charged and their time stability is lower than that of regular copolymer micelles based purely on hydrophobic interactions.

     

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.

     

Expulsion of Unimers from Polystyrene‐block‐poly(acrylic acid) Micelles

Summary: The pH response of the micelles of polystyrene‐block‐poly(acrylic acid) (PS₂₀₀‐b‐PAA₇₈) in water is studied using a combination of techniques: static light scattering (SLS), dynamic light scattering (DLS), and transmission electron microscopy (TEM). The structure of the micelles in dilute aqueous solution is dependent on pH. At pH values <2.5, the micelles precipitate. At pH values from 2.5 to 3.5, the micelles associate to form micellar clusters. At pH values ranging from 3.5 to 8.0, the micelles are dynamically frozen. At pH > 8.1, some PS₂₀₀‐b‐PAA₇₈ unimers gradually escape from the micelles and subsequently re‐associate to form smaller micelles.

The pH‐responsive behavior of the PS₂₀₀‐b‐PAA₇₈ micelles in solution.     

Allyl End‐Functionalized Poly(ethylene oxide)‐block‐poly(methylidene malonate 2.1.2) Block Copolymers: Synthesis,Characterization, and Chemical Modification

Summary: Poly(ethylene oxide)‐block‐poly(methylidene malonate 2.1.2) block copolymer (PEO‐b‐PMM 2.1.2) bearing an allyl moiety at the poly(ethylene oxide) chain end was synthesized by sequential anionic polymerization of ethylene oxide (EO) and methylidene malonate 2.1.2 (MM 2.1.2). This allyl functional group was subsequently modified by reaction with thiol‐bearing functional groups to generate carboxyl and amino functionalized biodegradable block copolymers. These end‐group reactions, performed in good yields both in organic media and in aqueous micellar solutions, lead to functionalized PEO‐b‐PMM 2.1.2 copolymers which are of interest for cell targeting purposes.

Synthetic route to α‐allyl functionalized PEO‐b‐PMM 2.1.2 copolymers.     

Optically Active Poly[{methyl(1‐naphthyl)silylene}(o‐phenylene)methylene]‐Poly(ethylene glycol) Block Copolymer Micelles

Summary: Optically pure (+) and isotactic poly[{methyl(1‐naphthyl)silylene}(o‐phenylene)methylene] terminated with methylphenylchlorosilyl was obtained by the Pt‐catalyzed ring‐opening polymerization of optically pure 1‐methyl‐1‐(1‐naphthyl)‐2,3‐benzosilacyclobut‐2‐ene in the presence of methylphenylchlorosilane as a chain transfer agent. The polymer formed was transformed into a block copolymer by reacting the terminal chlorosilyl group with a commercial poly(ethylene glycol) monomethyl ether. The formation of micelles by the block copolymer in THF‐water mixtures was investigated by fluorescence and UV. More detailed information about the aggregation of the polymer in the micelles was obtained by circular dichroism spectroscopy. It was found that dense aggregates were formed at a concentration higher than the critical micelle concentration. This concentration was higher for lower molecular weight polymer, at higher temperatures, and in more hydrophobic solvent systems. The highly aggregated structure was altered by changing the solvent system.

     

Synthesis and aqueous phase behavior of thermoresponsive biodegradable poly(D,L‐3‐methylglycolide)‐block‐poly(ethylene glycol)‐block‐poly(D,L‐3‐methylglycolide) triblock copolymers

Novel biodegradable thermosensitive triblock copolymers of poly(D ,L ‐3‐methylglycolide)‐block‐poly(ethylene glycol)‐block‐poly(D ,L ‐3‐methylglycolide) (PMG‐PEG‐PMG) have been synthesized. Ring‐opening polymerization of D ,L ‐3‐methyl‐glycolide (MG) initiated with poly(ethylene glycol) (PEG) and Ca[N(SiMe₃)₂]₂(THF)₂ provided triblock copolymers with alternating lactyl/glycolyl sequences of controlled molecular weight, low polydispersity index and uniform chain structure. At relatively low temperatures (≈ 10 °C) these copolymers formed clear solutions in water up to high concentrations (50 wt.‐%). Depending on molecular mass ratios of PMG and PEG blocks, a sol‐gel transition or an increase in viscosity without gel formation was observed upon increasing the temperature of the aqueous solutions. The temperature‐induced gelation was ascertained by rheology and dynamic differential scanning calorimetry (DDSC).

Phase diagram of PMG‐PEG‐PMG 1 400‐1 450‐1 400 in an aqueous solution.     

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.

     

In Situ Aggregates of Enantiomeric Poly(styrene)‐block‐Poly(lactide) Diblock Copolymers via Stereocomplexation in a Non‐selective Solvent

A comprehensive investigation of in situ aggregation of structurally well‐defined enantiomeric poly(styrene)‐block‐poly(lactide) (PS‐b‐PLLA and PS‐b‐PDLA) in a non‐selective solvent, tetrahydrofuran (THF), is presented. The isolated aggregates are found to form poly(L ‐lactide) (PLLA)/poly(D ‐lactide) (PDLA) racemic crystals by differential scanning calorimetry (DSC), wide‐angle X‐ray diffraction (WAXD), and Fourier transform infrared (FTIR) spectroscopy. The kinetic study reveals that the growth rate of the aggregates depends on the molecular weight of the enantiomeric PLA blocks, as well as the preparation conditions. The proposed mechanism demonstrates a new PS (shell)–PLA (core) structural hierarchy solely driven by stereocomplexation between enantiomeric PLLA and PDLA blocks.

     

Melt Structure and its Transformation by Sequential Crystallization of the Two Blocks within Poly(L‐lactide)‐block‐Poly(ε‐caprolactone) Double Crystalline Diblock Copolymers

Summary: Sequential crystallization of poly(L ‐lactide) (PLLA) followed by poly(ε‐caprolactone) (PCL) in double crystalline PLLA‐b‐PCL diblock copolymers is studied by differential scanning calorimetry (DSC), polarized optical microscopy (POM), wide‐angle X‐ray scattering (WAXS) and small‐angle X‐ray scattering (SAXS). Three samples with different compositions are studied. The sample with the shortest PLLA block (32 wt.‐% PLLA) crystallizes from a homogeneous melt, the other two (with 44 and 60% PLLA) from microphase separated structures. The microphase structure of the melt is changed as PLLA crystallizes at 122 °C (a temperature at which the PCL block is molten) forming spherulites regardless of composition, even with 32% PLLA. SAXS indicates that a lamellar structure with a different periodicity than that obtained in the melt forms (for melt segregated samples). Where PCL is the majority block, PCL crystallization at 42 °C following PLLA crystallization leads to rearrangement of the lamellar structure, as observed by SAXS, possibly due to local melting at the interphases between domains. POM results showed that PCL crystallizes within previously formed PLLA spherulites. WAXS data indicate that the PLLA unit cell is modified by crystallization of PCL, at least for the two majority PCL samples. The PCL minority sample did not crystallize at 42 °C (well below the PCL homopolymer crystallization temperature), pointing to the influence of pre‐crystallization of PLLA on PCL crystallization, although it did crystallize at lower temperature. Crystallization kinetics were examined by DSC and WAXS, with good agreement in general. The crystallization rate of PLLA decreased with increase in PCL content in the copolymers. The crystallization rate of PCL decreased with increasing PLLA content. The Avrami exponents were in general depressed for both components in the block copolymers compared to the parent homopolymers.

Polarized optical micrographs during isothermal crystallization of (a) homo‐PLLA, (b) homo‐PCL, (c) and (d) block copolymer after 30 min at 122 °C and after 15 min at 42 °C.     

pH‐Responsive Micelles Based on Amphiphilic Block Copolymers Bearing Ortho Ester Pendants as Potential Drug Carriers

Amphiphilic block copolymers (PEG‐b‐PEYM) bearing acid‐labile ortho ester pendant chains were synthesized by atom transfer radical polymerization, and the effect of chain‐length of the ortho‐ester‐bearing PEYM block on micelle properties was investigated. The length of the PEYM block affected the critical micelle concentration and pH‐dependent average particle size but not the kinetics of side‐chain hydrolysis. A hydrophobic dye, Nile red, was loaded in the micelles. Both the loading content and the size of the loaded micelles were influenced by the length of the PEYM block, whereas the release kinetics of Nile red was not. Provided that these acid‐labile micelles are completely cell compatible, they are potentially useful bio‐responsive nanocarriers for enhancing the efficacy of hydrophobic drugs.

     

Dual‐Functional PEI–Poly(γ‐Cholesterol‐l‐Glutamate) Copolymer for Drug/Gene Co‐delivery

Novel dual‐functional PEI‐poly(γ‐cholesterol‐l ‐glutamate) (PEI‐PCHLG) copolymers are developed for the first time. A series of PEI‐PCHLG (PEI‐1, PEI‐2, PEI‐3, and PEI‐4) with various PEI percentages and molecular weights are successfully synthesized, among which the poor organic solvent solubility of PEI‐1 precludes its further application. The other three copolymers can spontaneously self‐assemble into micelles; the critical micelle concentration (CMC) values are 0.66, 1.3, and 0.95 μmol L^?1, respectively. PEI‐2 and PEI‐4, with lower CMC, are worth being further developed as promising drug carriers because of their resistance to dilution in circulation after systemic administration. However, PEI‐4 can form smaller‐sized micelles than PEI‐2 and has similar in vitro cytotoxicity to PEI. Thus, PEI‐4 is further investigated. PEI‐4 micelles can not only incorporate docetaxel (DTX) with high encapsulation efficiency (91.0%) and drug loading (4.3%), but also load pDNA efficiently at a ratio of 8:1 (w/w). DTX‐loaded PEI‐4 micelles (DTX‐PEI‐4) can also carry genes with the same gene‐binding capacity as PEI‐4 micelles. The above three micelles (DTX‐PEI‐4, pDNA‐PEI‐4, and pDNA/DTX‐PEI‐4) are sub‐micrometer‐sized and spherical. The results indicate that PEI‐4 containing 28.9% PEI, one of the PEI‐PCHLG copoly­mers, is a potential carrier for gene delivery, drug delivery, or even drug/gene co‐delivery.

     

Fiber‐Like Micelles from the Crystallization‐Driven Self‐Assembly of Poly(3‐heptylselenophene)‐block‐Polystyrene

The crystallization‐driven self‐assembly (CDSA) of crystalline‐coil polyselenophene diblock copolymers represents a facile approach to nanofibers with distinct optoelectronic properties relative to those of their polythiophene analogs. The synthesis of an asymmetric diblock copolymer with a crystallizable, π‐conjugated poly(3‐heptylselenophene) (P3C7Se) block and an amorphous polystyrene (PS) coblock is described. CDSA was performed in solvents selective for the PS block. Based on transmission electron microscopy (TEM) analysis, P3C7Se₁₈‐b‐PS₁₂₅ formed very long (up to 5 μm), highly aggregated nanofibers in n‐butyl acetate (nBuOAc) whereas shorter (ca. 500 nm) micelles of low polydispersity were obtained in cyclohexane. The micelle core widths in both solvents determined from TEM analysis (≈ 8 nm) were commensurate with fully‐extended P3C7Se₁₈ chains (estimated length = 7.1 nm). Atomic force microscopy (AFM) analysis provided characterization of the micelle cross‐section including the PS corona (overall micelle width ≈ 60 nm). The crystallinity of the micelle cores was probed by UV–vis and photoluminescence (PL) spectroscopy and wide‐angle X‐ray scattering (WAXS).     

Acid‐Labile Copolymer Micelles Cross‐Linked by a Twin Ortho Ester Cross‐Linking Agent: Synthesis,Characterization, and Evaluation

In this work, a series of poly(ethylene glycol)‐block‐poly(N‐succinimidyl methacrylate) (PEG‐b‐PNSM) micelles with different length of PNSM are prepared by self‐assembly in phosphate buffer. In situ cross‐linked micelles (CLM) with high stability at neutral pH are obtained by adding a pH‐sensitive cross‐linker bearing two five‐membered ortho ester rings, 2‐{4‐[2‐(2‐amino‐ethoxy)‐[1,3]dioxolan‐4‐ylmethoxymethyl]‐[1,3]dioxolan‐2‐yloxy}‐thylamine. Nile Red as a model drug is easily loaded into CLM, and the release rate accelerate at acidic environments (pH 5). Cytotoxicity of PEG‐b‐PNSM and CLM against NIH3T3 cells is determined and favorable biocompatibility is possessed. Confocal laser scanning microscopy study shows that Nile Red‐loaded CLM has excellent cellular uptake by MCF‐7 cells. Paclitaxel (PTX) is successfully encapsulated into the cross‐linked micelles. In vitro cytotoxicity of free PTX, and PTX‐loaded CLM causes almost the same potency in killing MCF‐7 cells. These results suggest that cross‐linked micelles can be a potential vehicle for delivering hydrophobic anticancer drugs to tumors.

     

Effect of Arrangement of L‐Lactide and D‐Lactide in Poly[(L‐lactide)‐co‐(D‐lactide)] on its Resistance to Hydrolysis Studied by Molecular Modeling

Molecular modeling is used to explain how the resistance of poly[(L ‐lactide)‐co‐(D ‐lactide)] to hydrolysis is affected by the percentages of L ‐ and D ‐lactide and their arrangements in blocks or random arrangements in the polymer. Previous studies on improving the hydrolysis resistance of PLA have involved forming either poly(L ‐lactide)/poly(D ‐lactide) (PLLA/PDLA) polyblends or copolymers of L ‐ and D ‐lactide. In this study, molecular modeling was used to study the hydrolysis resistance of PLA containing various arrangements of L ‐ and D ‐lactide in the polymers. PLA copolymers are found to have less resistance to hydrolysis than a PLLA/PDLA polyblend having the same percentages of L ‐ and D ‐lactide because a polyblend can form more stereocomplexes, which is the most stable structure PLA can form.

     

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.

     

Salt‐Induced Micelle Behavior of Poly(sodium acrylate)‐block‐Poly(N‐isopropylacrylamide) by ATRP

Temperature‐ and pH‐sensitive diblock copolymers PAANa₇₅‐b‐PNIPAM_m are prepared by a combination of reverse and normal ATRP in aqueous solution at room temperature. The block copolymer is also stimuli‐sensitive with respect to salt in the aqueous solution, and forms spherical star‐like micelles with a PNIPAM core and an expanded PAANa shell for PAANa₇₅‐b‐PNIPAM₇₆ as well as spherical crew‐out micelles with a PNIPAM core for PAANa₇₅‐b‐PNIPAM₅₁₁₀, as indicated by a fluorescence probe technique and TEM. A three‐stage model mechanism of phase transition driven by small molecule salt is proposed.

     

In Situ Forming Poly(ethylene glycol)‐ Poly(L‐lactide) Hydrogels via Michael Addition: Mechanical Properties,Degradation, and Protein Release

Chemically crosslinked hydrogels are prepared at remarkably low macromonomer concentrations from 8‐arm poly(ethylene glycol)‐poly(L ‐lactide) star block copolymers bearing acrylate end groups (PEG‐(PLLA_n)₈‐AC, n = 4 or 12) and multifunctional PEG thiols (PEG‐(SH)_n, n = 2, 4, or 8) through a Michael‐type addition reaction. Hydrogels are obtained within 1 min after mixing PEG‐(PLLA₄)₈ ‐AC and PEG‐(SH)₈ in phosphate buffered saline, quickly reaching a high storage modulus of 17 kPa. Lysozyme and albumin are released for 4 weeks from PEG‐(PLLA₁₂)₈‐AC/PEG‐(SH)₈ hydrogels. Lysozyme release from PEG‐(PLLA₁₂)₈‐AC/PEG‐(SH)₂ and PEG‐(PLLA₁₂)₈‐AC/PEG‐(SH)₄ hydrogels is significantly faster with complete release in 3 and 12 d, respectively, as a result of a combination of degradation and diffusion.