Syntheses of amphiphilic biodegradable copolymers of poly(ethyl ethylene phosphate) and poly(3-hydroxybutyrate) for drug delivery

Biodegradable and amphiphilic triblock copolymers poly(ethyl ethylene phosphate)-poly(3-hydroxy-butyrate)-poly(ethyl ethylene phosphate) (PEEP-b-PHB-b-PEEP) have been successfully synthesized through ring-opening polymerization. The structures are confirmed by gel permeation chromatography and NMR analyses. Crystallization investigated by X-ray diffraction reveals that the block copolymer with higher content of poly(ethyl ethylene phosphate) (PEEP) is more amorphous, showing decreased crystallizability. The obtained copolymers self-assemble into biodegradable nanoparticles with a core-shell micellar structure in aqueous solution, verified by the probe-based fluorescence measurements and transmission electronic microscopy (TEM) observation. The hydrophobic poly(3-hydroxybutyrate) (PHB) block serves as the core of the micelles and the micelles are stabilized by the hydrophilic PEEP block. The size and size distribution are related to the compositions of the copolymers. Paclitaxel (PTX) has been encapsulated into the micelles as a model drug and a sustained drug release from the micelles is observed. MTT assay also demonstrates that the block copolymers are biocompatible, rendering these copolymers attractive for drug delivery. Supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No.20060358036)     

Drug and plasmid DNA co-delivery nanocarriers based on abctype polypeptide hybrid miktoarm star copolymers

We report on the fabrication of self-assembled micelles from ABC-type miktoarm star polypeptide hybrid copolymers consisting of poly(ethylene oxide), poly(L-lysine), and poly(ε-caprolactone) arms, PEO(-b-PLL)-b-PCL, and their functional applications as co-delivery nanocarriers of chemotherapeutic drugs and plasmid DNA. Miktoarm star copolymer precursors, PEO(-b-PZLL)-b-PCL, were synthesized at first via the combination of consecutive "click" reactions and ring-opening polymerizations (ROP), where PZLL is poly(ε-benzyloxycarbonyl-L-lysine). Subsequently, the deprotection of PZLL arm afforded amphiphilic miktoarm star copolymers, PEO(-b-PLL)-b-PCL. In aqueous media at pH 7.4, PEO(-b-PLL)-b-PCL self-assembles into micelles consisting of PCL cores and hydrophilic PEO/PLL hybrid coronas. The hydrophobic micellar cores can effectively encapsulate model hydrophobic anticancer drug, paclitaxel; whereas positively charged PLL arms within mixed micellar corona are capable of forming electrostatic polyplexes with negatively charged plasmid DNA (pDNA) at N/P ratios higher than ca. 2. Thus, PEO(-b-PLL)-b-PCL micelles can act as co-delivery nanovehicles for both chemotherapeutic drugs and genes. Furthermore, polyplexes of pDNA with paclitaxel-loaded PEO(-b-PLL)-b-PCL micelles exhibited improved transfection efficiency compared to that of pDNA/blank micelles. We expect that the reported strategy of varying chain topologies for the fabrication of co-delivery polymeric nanocarriers can be further applied to integrate with other advantageous functions such as targeting, imaging, and diagnostics.     

A new design for light-breakable polymer micelles

A new and general design strategy is presented for amphiphilic block copolymers whose micellar aggregates can be dissociated by light. A diblock copolymer composed of hydrophilic poly(ethylene oxide) (PEO) and a hydrophobic polymethacrylate bearing pyrene pendant groups (PPy) was synthesized using ATRP. Upon UV light irradiation of polymer micellar solutions, the photosolvolysis of pyrene moieties results in their detachment from the polymer and converts the hydrophobic PPy block into hydrophilic poly(methacrylic acid). This effect leads to complete dissociation of polymer micelles.     

Water-dispersible, uniform nanospheres by heating-enabled micellization of amphiphilic block copolymers in polar solvents

Uniform nanospheres with tunable size down to 30 nm were prepared simply by heating amphiphilic block copolymers in polar solvents. Unlike reverse micelles prepared in nonpolar, oily solvents, these nanospheres have a hydrophilic surface, giving them good dispersibility in water. Furthermore, they are present as individual, separated, rigid particles upon casting from the solution other than continuous thin films of merged micelles cast from micellar solution in nonpolar solvents. These nanospheres were generated by a heating-enabled micellization process in which the affinity between the solvent and the polymer chains as well as the segmental mobility of both hydrophilic and hydrophobic blocks was enhanced, triggering the micellization of the glassy copolymers in polar solvents. This heating-enabled micellization produces purely well-defined nanospheres without interference of other morphologies. The micelle sizes and corona thickness are tunable mainly by changing the lengths of the hydrophobic and hydrophilic blocks, respectively. The heating-enabled micellization route for the preparation of polymeric nanospheres is extremely simple, and is particularly advantageous in producing rigid, micellar nanospheres from block copolymers with long glassy, hydrophobic blocks which are otherwise difficult to prepare with high efficiency and purity. Furthermore, encapsulation of hydrophobic molecules (e.g., dyes) into micelle cores could be integrated into the heating-enabled micellization, leading to a simple and effective process for dye-labeled nanoparticles and drug carriers.     

Synthesis of fluorine-18 functionalized nanoparticles for use as in vivo molecular imaging agents

Nanoparticles containing fluorine-18 were prepared from block copolymers made by ring opening metathesis polymerization (ROMP). Using the fast initiating ruthenium metathesis catalyst (H2IMes)(pyr)2(Cl)2Ru=CHPh, low polydispersity amphiphilic block copolymers were prepared from a cinnamoyl-containing hydrophobic norbornene monomer and a mesyl-terminated PEG-containing hydrophilic norbornene monomer. Self-assembly into micelles and subsequent cross-linking of the micelle cores by light-activated dimerization of the cinnamoyl groups yielded stable nanoparticles. Incorporation of fluorine-18 was achieved by nucleophilic displacement of the mesylates by the radioactive fluoride ion with 31% incorporation of radioactivity. The resulting positron-emitting nanoparticles are to be used as in vivo molecular imaging agents for use in tumor imaging.     

Thermoresponsive core cross-linked micelles for selective ratiometric fluorescent detection of Hg2+ ions

We report on the fabrication of core cross-linked (CCL) micelles possessing thermoresponsive cores and their application as sensitive and selective ratiometric Hg(2+) probes with thermo-tunable detection efficiency. Well-defined double hydrophilic block copolymer (DHBC) bearing naphthalimide-based Hg(2+)-reactive moieties (NUMA, 4), PEO-b-P(NIPAM-co-NAS-co-NUMA), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, where PEO, NIPAM, and NAS represent poly(ethylene oxide), N-isopropylacrylamide, and N-acryloxysuccinimide. At 25 °C, PEO-b-P(NIPAM-co-NAS-co-NUMA) unimers in aqueous solution can act as ratiometric Hg(2+) probes with a detection limit of ～10.1 nM. After core cross-linking of the micellar nanoparticles formed at elevated temperatures, structurally stable CCL micelles with well-solvated PEO coronas and thermoresponsive cores embedded with Hg(2+)-reactive NUMA moieties were obtained. Upon Hg(2+) addition, the aqueous dispersion of CCL micelles exhibit a colorimetric transition from yellowish to colorless and a fluorometric emission transition from green to bright blue. Moreover, Hg(2+) detection limits of CCL micelles were considerably enhanced to 3.0 and 1.8 nM at 25 and 40 °C, when the thermoresponsive cores are at their swollen and collapsed state, respectively. The high selectivity of CCL micelles to Hg(2+) over other common cations was also demonstrated. Furthermore, in vitro studies revealed that CCL micelles can effectively enter into living cells and sensitively respond to the presence of Hg(2+) ions via the change of fluorescence emission color. This work represents the first example of DHBC-based CCL micelle acting as highly selective and sensitive ratiometric metal ion probes. The structural stability, water dispersibility, biocompatibility, and most importantly the thermo-tunable detection sensitivity of this novel type of CCL micelle-based sensing systems augur well for their future applications as multifunctional nanocarriers for drug delivery, sensing, imaging, and diagnosis.     

Non-ionic amphiphilic block copolymers by RAFT-polymerization and their self-organization

Water-soluble, amphiphilic diblock copolymers were synthesized by reversible addition fragmentation chain transfer polymerization. They consist of poly(butyl acrylate) as hydrophobic block with a low glass transition temperature and three different nonionic water-soluble blocks, namely, the classical hydrophilic block poly(dimethylacrylamide), the strongly hydrophilic poly(acryloyloxyethyl methylsulfoxide), and the thermally sensitive poly(N-acryloylpyrrolidine). Aqueous micellar solutions of the block copolymers were prepared and characterized by static and dynamic light scattering analysis (DLS and SLS). No critical micelle concentration could be detected. The micellization was thermodynamically favored, although kinetically slow, exhibiting a marked dependence on the preparation conditions. The polymers formed micelles with a hydrodynamic diameter from 20 to 100 nm, which were stable upon dilution. The micellar size was correlated with the composition of the block copolymers and their overall molar mass. The micelles formed with the two most hydrophilic blocks were particularly stable upon temperature cycles, whereas the thermally sensitive poly(N-acryloylpyrrolidine) block showed a temperature-induced precipitation. According to combined SLS and DLS analysis, the micelles exhibited an elongated shape such as rods or worms. It should be noted that the block copolymers with the most hydrophilic poly(sulfoxide) block formed inverse micelles in certain organic solvents.     

药物包载对两亲嵌段共聚物胶束形态的影响

以聚(ε-己内酯-b-L-丙交酯)/聚乙二醇单甲醚(P(CL-b-LLA)-b-mPEG)和聚(ε-己内酯-b-D,L-丙交酯)/聚乙二醇单甲醚(P(CL-b-DLLA)-b-mPEG)两种两亲嵌段共聚物为载体,选择了物理状态完全不同、而疏水性相近的吲哚美辛和维生素E为模型药物,研究了药物包载对高分子胶束形态的影响.发现两种药物在高分子胶束内部的增溶均会导致胶束形态发生显著改变,变化行为与胶束内核的结晶性和药物疏水性有关.另外,还研究了两种嵌段共聚物的载药性能,发现非结晶性疏水内核共聚物的药物包载率明显大于可结晶疏水内核的共聚物.     

Dual Responsive Block Copolymer Micelles Functionalized by NIPAM and Azobenzene

A novel amphiphilic diblock copolymer composed of a hydrophilic poly(ethylene oxide) block and a hydrophobic block copolymerized by azobenzene‐containing methacrylate and N‐isopropylacrylamide was synthesized using ATRP. The polymer micelles showed dual responsiveness to heat and light. The size of the micelles was dependent on temperature and the encapsulated substance in the hydrophobic cores was released during heating and cooling processes. The hydrophobicity of the micellar cores appeared as a reversible change in response to light with neither disruption of the micelles nor leakage of the encapsulated substance while H‐aggregation of the azobenzene moieties was detected.

     

Polyether nanoparticles from covalently crosslinked copolymer micelles

Double hydrophilic block copolymers poly(ethylene oxide)-b-polyglycidol were synthesized using living anionic polymerization. The polyglycidol blocks were made hydrophobic by the esterification of a part of hydroxyl groups with cinnamic acid, thus simultaneously attaching UV-sensitive double bonds to the polymer backbone. The block copolymers were found to spontaneously associate in aqueous solution forming well-defined micelles, where the corona of the micelles was formed of EO units and the cores consisted of hydrophobic glycidyl cinnanamate units. The critical micelle concentration was determined by light-scattering measurements and fluorescence spectroscopy. Stabilization of micelles was obtained by covalently crosslinking the cores of polyether micelles formed from amphiphilic block copolymers of the type poly(ethylene oxide)-b-poly(glycidol-co-glycidyl cinnamate) (denoted EO(113)-b-(Gl(33)-co-GlCA(33-x))). To obtain stable nanoparticles double bonds of cinnamate units contained in core were crosslinked under UV irradiation. The kinetics of the stabilization process was investigated using SEC-MALLS and UV spectroscopy. The parameters of the micelles and nanogels were calculated from the light-scattering data.     

Multicomponent nanoparticles via self-assembly with cross-linked block copolymer surfactants

We describe a simple and versatile protocol to prepare water-soluble multifunctional nanostructures by encapsulation of different nanoparticles in shell cross-linked, block copolymer micelles. This method permits simultaneous incorporation of different nanoparticle properties within a nanoscale micellar container. We have demonstrated the co-encapsulation of magnetic (gamma-Fe2O3 and Fe3O4), semiconductor (CdSe/ZnS), and metal (Au) nanoparticles in different combinations to form multicomponent micelles that retain the precursor particles' distinct properties. Because these multifunctional hybrid nanostructures spontaneously assemble from solution by simultaneous desolvation of nanoparticles and amphiphilic block copolymer components, we anticipate that this can be used as a general protocol for preparing multifunctional nanostructures without explicit multimaterial synthesis or surface functionalization of nanoparticles.     

Synthesis and applications of shell cross-linked thermoresponsive hybrid micelles based on poly(N-isopropylacrylamide-co-3-(trimethoxysilyl)propyl methacrylate)-b-poly(methyl methacrylate)

Shell cross-linked (SCL) thermoresponsive hybrid micelles consisting of a cross-linked thermoresponsive hybrid hydrophilic shell and a hydrophobic core domain were synthesized from poly(N-isopropylacrylamide-co-3- (trimethoxysilyl)propyl methacrylate)-b-polymethyl methacrylate (P(NIPAAm-co-MPMA)-b-PMMA) amphiphilic block copolymers. Transmission electron microscopy (TEM) images showed that the SCL micelles formed regularly globular nanoparticles. The SCL micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 degrees C, observed by turbidity measurements and dynamic light scattering (DLS). The drug loading and in vitro drug release properties of the SCL micelles bearing a silica-reinforced PNIPAAm shell were further studied, which showed that the SCL micelles exhibited a much improved entrapment efficiency (EE) as well as a slower release rate which allowed the entrapped molecules to be slowly released over a much longer period of time as compared with pure PNIPAAm-b-PMMA micelles.     

用于基因传输及磁共振显像的聚乙烯亚胺-g-聚己内酯共聚物的合成与表征

采用可生物降解的聚己内酯改性聚乙烯亚胺,得到两亲性的接枝共聚物(PEI-g-PCL).该共聚物通过溶剂挥发法在水中自组装形成纳米粒子,其内部负载有超顺磁性四氧化三铁纳米粒子(SPIO)及质粒DNA(pDNA).研究表明,PEI-g-PCL聚合物自组装形成的颗粒为胶束状,无论是否负载SPIO纳米粒子都可以有效地负载pDNA,并对293细胞具有较高的转染效率.此类载体有望在基因转染的过程中利用磁共振手段进行实时、无创观测.     

A giant surfactant of polystyrene-(carboxylic Acid-functionalized polyhedral oligomeric silsesquioxane) amphiphile with highly stretched polystyrene tails in micellar assemblies

A novel giant surfactant possessing a well-defined hydrophilic head and a hydrophobic polymeric tail, polystyrene-(carboxylic acid-functionalized polyhedral oligomeric silsesquioxane) conjugate (PS-APOSS), has been designed and synthesized via living anionic polymerization, hydrosilylation, and thiol-ene "click" chemistry. PS-APOSS forms micelles in selective solvents, and the micellar morphology can be tuned from vesicles to wormlike cylinders and further to spheres by increasing the degree of ionization of the carboxylic acid. The effect of APOSS-APOSS interactions was proven to be essential in the morphological transformation of the micelles. The PS tails in these micellar cores were found to be highly stretched in comparison with those in traditional amphiphilic block copolymers, and this can be explained in terms of minimization of free energy. This novel class of giant surfactants expands the scope of macromolecular amphiphiles and provides a platform for the study of the basic physical principles of their self-assembly behavior.     

PNIPAM-b-聚碳酸酯温敏胶束的制备及用作药物控制释放载体的研究

以多孔硅球固定化猪胰脂肪酶(IPPL)为催化剂,温敏性HO-PNIPAM为大分子引发剂,5-甲基-5-烯丙氧羰基-三亚甲基碳酸酯(MAC)和5,5-二甲基三亚甲基碳酸酯(DTC)为共聚单体,通过开环聚合合成了不同结构比例的两亲性嵌段型共聚物P(MAC-co-DTC) -b-PNIPAM.该嵌段型共聚物在水中可自组装形成...     

两亲嵌段共聚物胶束用作医用材料

两亲嵌段共聚物可以在水溶液中自组装形成亲水性链段为外壳、疏水性链段为内核的胶束,这种胶束能够用作药物载体而引起人们极大的关注。本文综述了两亲嵌段共聚物胶束用作医用材料的研究进展,主要内容包括医用两亲嵌段共聚物的种类,胶束化,以及用作诊断试剂载体、药物缓释载体、靶向载体等。两亲嵌段共聚物胶束用作磁共振造影剂载体有利于肿瘤的诊断,用作药物缓释载体可以有效增溶难溶性抗肿瘤药物,延长药物在体内的血液循环时间。此外,通过对胶束表面进行修饰或者施加外场,还可以实现靶向功能。因此,两亲嵌段共聚物胶束在医用材料领域有着广阔的发展前景。     

Enhanced DOX loading in star-like benzyl functionalized polycaprolactone micelles

The self-assembly of functionalized polycaprolactone amphiphilic diblock copolymers is explored for carrier-mediated doxorubicin delivery for cancer treatment. In this report, functionalized polycaprolactone-based amphiphilic block copolymers with controlled branching architecture are investigated. Star-like copolymers, namely 4-arm and 6-arm poly(γ-benzyloxy-ε-caprolactone)-b-poly{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone} (PBCL-b-PMEEECL) were synthesized by living ring-opening block copolymerization (ROP) of γ-(2-benzyloxy)-ε-caprolactone and γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone using multifunctional initiators. A systematic investigation of the effect of branching points on polymer properties and micellar carrier properties was carried out. The star-like PBCL-b-PMEEECL micelles displayed better thermodynamic stability, size reduction, and enhanced doxorubicin encapsulation than the linear PBCL-b-PMEEECL. Furthermore, the π–π stacking between the benzyl group of the hydrophobic PBCL core and the doxorubicin, the anti-cancer drug, also increases the stability and loading capacity of the micelles. The star-polymers display tunable thermoresponsivity in the range of 40–42°C. When the DOX-loaded micelles are accumulated in the tumor, the shell of the polymeric micelles dehydrates upon heating (at a temperature above its LCST), causing disassembling of the micelles and releasing of DOX. Compared with DOX-loaded linear and 4-arm micelles, DOX-loaded 6-arm micelles exhibited higher in vitro anti-tumor activity. Thus, the 6-arm benzyl substituted polycaprolactone-based micellar systems are promising candidates for drug delivery applications.     

Self-assembled micellar nanoparticles of a novel star copolymer for thermo and pH dual-responsive drug release

An amphiphilic star block copolymer comprised of a hydrophobic PMMA block and a hydrophilic tri-arm poly(NIPAAm-co-DMAEMA) block was synthesized by copolymerization of NIPAAm and DMAEMA, with Ce(4+) ions and tris(hydroxymethyl)methylamine as a redox initiatory system. The star copolymer undergoes self-assembly to the micellar nanoparticles with a core-shell structure and the thermo/pH dual-response, originated from the thermo-sensitivity of PNIPAAm and the pH-sensitivity of PDMAEMA. A fluorescence probe study showed the pH-dependent low CMCs (7.5 to 11.2 mg/L) of the micelles, confirming the formation of stable micelles. Morphological investigations showed that the blank and drug-loaded micelles both had spherical and uniform shapes. The sizes of the blank and drug-loaded nanoparticles were between 80 and 120 nm, depending on the given pH. The LCSTs of the star copolymer were determined to be 32 degrees C, 36.6 degrees C and 39.5 degrees C, corresponding to pH 5, pH 7.4 and pH 9, respectively, demonstrating a pH-dependent thermo-response. As a drug delivery, the micellar nanoparticles showed the dual-responsive release profiles in vitro, which were confirmed by the drug release studies. The obtained results showed the thermo-triggered accelerated release at pH 7.4, and the pH-triggered accelerated release at 37 degrees C, indicating the micelles nanoparticles would be a promising site-specific drug delivery for enhancing the accumulation of drug in targeting pathological areas.     

Synthesis and characterization of temperature‐sensitive block‐graft PNiPAAm‐b‐(PαN3CL‐g‐alkyne) copolymers by ring‐opening polymerization and click reaction

This study synthesized thermo‐sensitive amphiphilic block‐graft PNiPAAm‐b‐(PαN₃CL‐g‐alkyne) copolymers through ring‐opening polymerization of α‐chloro‐ε‐caprolactone (αClCL) with hydroxyl‐terminated macroinitiator poly(N‐isopropylacrylamide) (PNiPAAm), substituting pendent chlorides with sodium azide. This was then used to graft various kinds of terminal alkynes moieties by means of the copper‐catalyzed Huisgen's 1,3‐dipolar cycloaddition (“click” reaction). ¹H NMR, FTIR, and gel permeation chromatography (GPC) was used to characterize these copolymers. The solubility of the block‐graft copolymers in aqueous media was investigated using turbidity measurement, revealing a lower critical solution temperature (LCST) in the polymers. These solutions showed reversible changes in optical properties: transparent below the LCST, and opaque above the LCST. The LCST values were dependant on the composition of the polymer. With critical micelle concentrations (CMCs) in the range of 2.04–9.77 mg L^?1, the block copolymers formed micelles in the aqueous phase, owing to their amphiphilic characteristics. An increase in the length of hydrophobic segments or a decrease in the length of hydrophilic segments amphiphilic block‐graft copolymers produced lower CMC values. The research verified the core‐shell structure of micelles by ¹H NMR analyses in D₂O. Transmission electron microscopy was used to analyze the morphology of the micelles, revealing a spherical structure. The average size of the micelles was in the range of 75–145 nm (blank), and 105–190 nm (with drug). High drug entrapment efficiency and drug loading content were observed in the drug micelles. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

New amphiphilic diblock copolymers: surfactant properties and solubilization in their micelles

Several series of amphiphilic diblock copolymers are investigated as macrosurfactants in comparison to reference low-molar-mass and polymeric surfactants. The various copolymers share poly(butyl acrylate) as a common hydrophobic block but are distinguished by six different hydrophilic blocks (one anionic, one cationic, and four nonionic hydrophilic blocks) with various compositions. Dynamic light scattering experiments indicate the presence of micelles over the whole concentration range from 10(-4) to 10 g x L(-1). Accordingly, the critical micellization concentrations are very low. Still, the surface tension of aqueous solutions of block copolymers decreases slowly but continuously with increasing concentration, without exhibiting a plateau. The longer the hydrophobic block, the shorter the hydrophilic block, and the less hydrophilic the monomer of the hydrophilic block is, the lower the surface tension is. However, the effects are small, and the copolymers reduce the surface tension much less than standard low-molar-mass surfactants. Also, the copolymers foam much less and even act as anti-foaming agents in classical foaming systems composed of standard surfactants. The copolymers stabilize O/W emulsions made of methyl palmitate as equally well as standard surfactants but are less efficient for O/W emulsions made of tributyrine. However, the copolymer micelles exhibit a high solubilization power for hydrophobic dyes, probably at their core-corona interface, in dependence on the initial geometry of the micelles and the composition of the block copolymers. Whereas micelles of copolymers with strongly hydrophilic blocks are stable upon solubilization, solubilization-induced micellar growth is observed for copolymers with moderately hydrophilic blocks.