Facile, solution-based synthesis of soft, nanoscale janus particles with tunable janus balance

We present a novel, versatile, and simple solution-based routine to produce soft, nanosized Janus particles with tunable structural and physical properties at high volume yield. This process is based on the cross-linking of compartments within precisely defined multicompartment micelles (MCMs), which are themselves formed by the self-assembly of ABC triblock terpolymers. Therein, the C blocks form the stabilizing corona emanating from B compartments, which in turn reside on an A core. Cross-linking of the B compartments allows to permanently fixate the phase-separated state and dissolution in a good solvent for all blocks breaks up the MCMs into single Janus particles. They now consist of a core of cross-linked B blocks and two phase-separated hemispheres of A and C. The process gives access to unprecedented structural features such as tunable core diameter and control over the Janus balance ranging from dominant A side to equal hemispheres to dominant C side. We demonstrate that this simple one-pot approach can be extended to a range of triblock terpolymers with different block lengths and block chemistries to furnish a library of tailor-made Janus particles with widely tunable physical properties. Such a diversity and simplicity has remained unreachable with our previously developed approach using the controlled cross-linking of bulk morphologies. We show that this new synthetic route can be upscaled to a high volume yield of 10 wt %, thereby enabling large-scale applications. We further demonstrate the effect of the Janus balance on colloidal self-assembly. Janus particles with a dominant hydrophobic and a small hydrophilic patch aggregate into large clusters in water, but merely di- or trimerize in chloroform.     

Facile Synthesis of Multicompartment Micelles Based on Biocompatible Poly(3‐hydroxyalkanoate)

In this paper, a straightforward method to produce poly(3‐hydroxyalkanoate)‐based multicompartment micelles (MCMs) is presented. Thiol‐ene addition is used to graft sequentially perfluorooctyl chains and poly(ethylene glycol) oligomers onto poly(3‐hydroxyoctanoate‐co‐hydroxyundecenoate) oligomers backbone. Well‐defined copolymers are obtained as shown by ¹H NMR and size‐exclusion chromatography. After nanoprecipitation in water, novel PHA‐based MCMs are evidenced by cryo‐transmission electron microscopy. Moreover, the cytocompatibility of MCMs is demonstrated in vitro via cell viability assay.     

Local detection of pH-induced disaggregation of biocompatible micelles by fluorescence switch ON

Fluorogenic nanoparticles (NPs) able to sense different physiological environments and respond with disaggregation and fluorescence switching OFF/ON are powerful tools in nanomedicine as they can combine diagnostics with therapeutic action. pH-responsive NPs are particularly interesting as they can differentiate cancer tissues from healthy ones, they can drive selective intracellular drug release and they can act as pH biosensors. Controlled polymerization techniques are the basis of such materials as they provide solid routes towards the synthesis of pH-responsive block copolymers that are able to assemble/disassemble following protonation/deprotonation. Ring opening metathesis polymerization (ROMP), in particular, has been recently exploited for the development of experimental nanomedicines owing to the efficient direct polymerization of both natural and synthetic functionalities. Here, we capitalize on these features and provide synthetic routes for the design of pH-responsive fluorogenic micelles via the assembly of ROMP block-copolymers. While detailed photophysical characterization validates the pH response, a proof of concept experiment in a model cancer cell line confirmed the activity of the biocompatible micelles in relevant biological environments, therefore pointing out the potential of this approach in the development of novel nano-theranostic agents.

pH-responsive micelles disassembly, upon acidification during lysosomal uptake, leads to fluorescence switch ON. These nanoparticles are promising candidates for the design of novel stimuli-responsive drug delivery systems.     

Structural evolution of multicompartment micelles self-assembled from linear ABC triblock copolymer in selective solvents

Using dissipative particle dynamics simulation, structural evolution from concentric multicompartment micelles to raspberry-like multicompartment micelles self-assembled from linear ABC triblock copolymers in selective solvents was investigated. The structural transformation from concentric micelles to raspberry-like micelles can be controlled by changing either the length of B blocks or the solubility of B block. It was found that the structures with B bumps on C surface (B-bump-C) are formed at shorter B block length and the structures with C bumps on B surface (C-bump-B) are formed at relative lower solubility of B blocks. The formation of B-bump-C is entropy-driven, while the formation of C-bump-B is enthalpy-dominated. Furthermore, when the length of C blocks is much lower than that of B blocks, an inner-penetrating vesicle was discovered. The results gained through the simulations provide an insight into the mechanism behind the formation of raspberry-like micelles.     

Multicompartment micelles from star and linear triblock copolymer blends

Dissipative particle dynamics simulations were performed on multicompartment micelles formed by blending star and linear triblock copolymers, in which the influences of blending options and blending ratio as well as copolymer chain compositions were studied systematically. The results show that blending of copolymers with different architectures is a promising strategy to control the morphology and structure of multicompartment micelles. This work revealed several new morphologies of multicompartment micelles by blending star and linear triblock copolymers, and the dynamic processes were elucidated at the molecular level by tracing the motions of copolymer chains. The results of this work provide deep insight into micro/mesoscopic details of the underlying mechanisms, contributing to a more complete understanding of multicompartment micelle formation and structural control.     

A facile route to design pH-responsive viscoelastic wormlike micelles: Smart use of hydrotropes

A simple and effective route to design pH-responsive viscoelastic wormlike micelles based on commercial compounds is reported. According to this route, pH-sensitive viscoelastic fluids can be easily obtained by introducing a pH-responsive hydrotrope into a surfactant solution. In this paper, the mixed system of cetyltrimethylammonium bromide (CTAB) and potassium phthalic acid (PPA) was studied in detail. This pH-sensitive fluid can be switched between a gellike state and a waterlike state within a narrow pH change. Rheology and DLS results revealed that the pH-sensitive flowing behavior was attributed to the microstructure transition between wormlike micelles and short cylindrical micelles. Combined with fluorescence anisotropy, NMR, and UV–vis, it was demonstrated that the pH response of viscoelastic fluid originated from the different binding abilities of hydrotrope to surfactant as pH varies. Furthermore, different kinds of hydrotropes can be utilized to prepare pH-responsive viscoelastic fluids in the desired pH areas.     

pH-Responsive Reversible DNA Self-assembly Mediated by Zwitterion

pH-Responsive DNA assembles have drawn growing attentions owing to their great potential in diverse areas.However,pH-responsive motifs are limited to specific DNA sequences and annealing is usually needed for DNA assemblies;therefore,sequence-independent pH-responsive DNA assembly at room temperature is highly desired as a more general way.Here,we propose a reversible pH-responsive DNA assembly strategy at room-temperature using zwitterion,glycine betaine(GB),as charge-regulation molecules.The reversible assembly and disassembly of DNA nanostructures could be achieved by alternatively regulating the acidic and basic environments in the presence of GB,respectively.In an acidic environment,carboxylate group in GB was protonated and GB was positively charged,which facilitated to shield the inherent electrostatic repulsion of DNA strands.Molecular simulation showed that the newly formed carboxyl group in protonated GB could form hydrogen bonds with bases in DNA to promote the assembly of DNA strands.In a basic solution,carboxylate group in GB was deprotonated and GB was neutral,thus inducing the dissociation of DNA assembly.     

三嵌段共聚物和两嵌段共聚物在水溶液中共混自组装成多室胶束结构的耗散粒子动力学模拟(英文)

利用耗散粒子动力学模拟研究了在水溶液中混合不同的线形三嵌段共聚物AxByCz和线形两嵌段共聚物AmBn对多室胶束的形貌多样性的影响.通过改变线形的三嵌段共聚物和两嵌段共聚物的链长来寻找多室胶束的形成条件.由线形三嵌段共聚物和线形两嵌段共聚物的不同混合形成的多室胶束结构是多种多样的,例如"蠕虫状"胶束、"汉堡包"胶束、"球上球"胶束、"核-壳-壳"胶束等等.多室胶束的整体形貌和内部结构的控制都可以从线形三嵌段共聚物和两嵌段共聚物的二元共混得到.为了表征获得的多室胶束结构,我们计算了密度图和成对分布函数图.在此工作中,可以获得和观察到复杂的多室胶束.结果表明,简单地混合线形的三嵌段共聚物和线形的两嵌段共聚物是一个控制多室胶束形貌和结构的有效方法,在工程实验中可以更简单更经济地形成多室胶束结构.因此,在设计新的多室胶束方面,聚合物共混仍然是未来值得更加关注的一个话题.     

Reversible pH-triggered encapsulation and release of pyrene by adsorbed block copolymer micelles

The well-established ability of copolymer micelles to encapsulate and release hydrophobic molecules has been investigated following their adsorption onto silica particles. Here, a pH-responsive copolymer, poly(2-(dimethylamino)ethyl methacrylate)- b-poly(2-(diethylamino)ethyl methacrylate) (PDMA(106)- b-PDEA(25)), has been used to study the formation and dissociation of adsorbed micelles through pH variation. This copolymer behaves as free unimers in aqueous solutions below pH 8 and forms micelles 29 nm in hydrodynamic diameter above this pH. Encapsulation and release of a model hydrophobic compound (pyrene) by in situ adjustment of the solution pH has been compared for both free and adsorbed micelles using fluorescence spectrophotometry, epifluorescence microscopy, and zeta potential measurements. At basic pH values, pyrene is solubilized within the cores of micelles adsorbed on silica particles: addition of acid leads to micelle dissociation and release of the pyrene into the bulk aqueous solution. Micelle adsorption does not appear to hinder the extent of pyrene uptake/release. Moreover, this pH-responsive behavior is both reversible and reproducible over multiple pH cycles.     

A pH-Responsive Zwitterionic Polyurethane Prodrug as Drug Delivery System for Enhanced Cancer Therapy

Numerous nanocarriers with excellent biocompatibilities have been used to improve cancer therapy. However, nonspecific protein adsorption of nanocarriers may block the modified nanoparticles in tumor cells, which would lead to inefficient cellular internalization. To address this issue, pH-responsive polyurethane prodrug micelles with a zwitterionic segment were designed and prepared. The micelle consisted of a zwitterionic segment as the hydrophilic shell and the drug Adriamycin (DOX) as the hydrophobic inner core. As a pH-responsive antitumor drug delivery system, the prodrug micelles showed high stability in a physiological environment and continuously released the drug under acidic conditions. In addition, the pure polyurethane carrier was demonstrated to be virtually non-cytotoxic by cytotoxicity studies, while the prodrug micelles were more efficient in killing tumor cells compared to PEG-PLGA@DOX. Furthermore, the DOX cellular uptake efficiency of prodrug micelles was proved to be obviously higher than the control group by both flow cytometry and fluorescence microscopy. This is mainly due to the modification of a zwitterionic segment with PU. The simple design of zwitterionic prodrug micelles provides a new strategy for designing novel antitumor drug delivery systems with enhanced cellular uptake rates.     

Structural dynamics,phase behavior,and applications of polyelectrolyte complex micelles

Self-assembly between oppositely charged polyelectrolytes conjugated to neutral polymeric blocks form polyelectrolyte complex (PEC) micelles. These nanostructures have gained significant interest in the field of nucleic acid and protein delivery, along with emerging applications in biosensing and catalysis. These carriers are highly modular systems, with the ability to engineer stimuli-responsive and targeting properties, making them smart platforms for biomedical applications. In this review, we discuss the current understanding of mechanisms involved in the assembly and disassembly of these nanoparticles, and the structural and functional changes as a response to solution conditions. We also discuss the latest and most impactful applications of PEC micellar systems in the biomedical field, with far-reaching influence on the treatment of various human diseases.     

ABC三嵌段共聚物胶束从多间隔结构到多核结构转变的Monte Carlo模拟

采用Monte Carlo模拟方法研究了疏水-亲水-疏水(H-P-H)型ABC三嵌段共聚物在B嵌段的选择性溶剂中的自组装行为. 模拟结果表明, 通过调节A嵌段和C嵌段的疏水性和二者之间的不相容性, 体系中可以形成多种形貌各异的胶束. 根据胶束中疏水核结构的特点, 这些胶束大体上可以被分为多核型胶束和多间隔型胶束两种类型. 通过增强疏水嵌段的疏水性或降低A嵌段和C嵌段间的不相容性, H-P-H型ABC三嵌段共聚物胶束能够发生从多核型胶束向多间隔型胶束的转变. 进一步分析胶束中聚合物的链构象等微观结构信息发现, A嵌段和C嵌段间的排斥作用和疏水作用之间存在竞争关系, 而这种竞争关系是影响体系中形成多核型胶束还是多间隔型胶束的决定性因素.     

Theranostic hyaluronic acid prodrug micelles with aggregation-induced emission characteristics for targeted drug delivery

Theranostic hyaluronic acid (HA) prodrug micelles with pH-responsive drug release and aggregation-induced emission (AIE) properties were prepared by chemical graft of biomimetic phosphorylcholine (PC), anticancer drug doxorubicin (DOX) and AIE fluorogen tetraphenylene (TPE) to the HA backbone. DOX was conjugated to the HA backbone by a hydrazone bond which can be hydrolyzed under acidic environment and result in pH-triggered smart release of DOX. The TPE units with typical AIE characteristics were applied for real time drug tracking in cancer cells. The HA-based prodrugs could self-assemble into micelles in aqueous solution as confirmed by the dynamic light scattering (DLS) and transmission electron microscopy (TEM). The intracellular distribution of HA prodrug micelles could be clearly observed by fluorescence microscopy based on the strong fluorescence of TPE. Moreover, after treated with the micelles, stronger fluorescence of TPE in CD44 overexpressed MDA-MB-231 cancer cells was observed, compared to the CD44 negative cell line, NIH3T3 cells, suggesting efficient cell uptake of HA prodrug micelles by receptor-mediated endocytosis. The cell viability results indicated that the prodrug micelles could inhibit the proliferation of the cancer cells effectively. Such pH-triggered theranostic drug delivery system with AIE features can provide a new platform for targeted and image-guided cancer therapy.     

RAFT聚合法制备聚合物胶束及其应用前景

聚合物胶束由于具有优良的组织渗透性、增容效果好、结构多样性和热稳定性等特点,成为国内外研究的热点之一。本文综述了近几年发展起来的一些具有特殊结构和特殊性能的双亲性嵌段聚合物胶束的研究进展,详细阐述了RAFT聚合法合成聚合物胶束的机理和优势,表明了RAFT聚合法可直接在水溶液中方便快捷地制备出温度和pH双响应性聚合物胶束。然而,当聚合物胶束的浓度低于其临界胶束浓度时,胶束的稀释效应大大影响了其实际应用,为提高聚合物胶束的稳定性,文章归纳总结了一系列有关壳交联聚合物胶束的制备方法及研究进展。最后,文章展望了聚合物胶束在药物可控释放、靶向、生物成像、催化剂负载及其他领域的应用前景。     

Controlled chemical stabilization of self-assembled PS-P4VP nanostructures

Supramolecular self-assemblies in selective solvents give rise to many patterning possibilities. The diblock copolymer polystyrene-b-poly(4-vinylpyridine) (PS-P4VP) is one such polymer that self-assembles into neat nanostructures in toluene. These nanostructures once formed are highly susceptible to solvent influence. Unfortunately, for use as nanotemplates and in the synthesis of nanoparticles, the susceptibility of the films to solvents can be a problem. In this study, we present a method to stabilize the structures through chemical means in solution. We used 1,4-dibromobutane in solution to chemically crosslink the pyridine residues of each of PS-P4VP to yield a series of stable spherical aggregates. In this way, the cross-linking ratio can be precisely controlled. The solution properties were studied using dynamic light scattering and small angle X-ray scattering and the morphology of the resulting micellar film was studied using transmission electron microscopy (TEM). The size of the micelles formed was found to be dependent on the amount of cross-linking and the shape of the PS-P4VP micelles remains stable when exposed to a selective solvent for PS.     

Morphologies of multicompartment micelles formed by ABC miktoarm star terpolymers

Several new multicompartment micellar structures have been identified by cryogenic transmission electron microscopy (cryoTEM) from the aqueous self-assembly of mu-[poly(ethylethylene)][poly(ethylene oxide)][poly(perfluoropropylene oxide)] (mu-EOF) miktoarm star terpolymers. This work extends our previous studies, in which it was found that, upon decreasing the length of the hydrophilic block (O), the resulting micelles evolved from "hamburger" micelles to segmented worms and ultimately to nanostructured bilayers and vesicles. In the terpolymers examined here segmented ribbons and bilayers were found at an intermediate composition between segmented worms and nanostructured bilayers, provided that the fluoropolymer (F) was the minority component in the micelle core. On the other hand, when the F block exceeded the chain length of the hydrocarbon block (E), the superhydrophobic F block imposed a "double frustration" on the self-assembly of the mu-EOF(2-9-5) terpolymer; while F prefers to minimize its interfacial contact with the O corona, it must occupy the majority of the micellar core. Therefore, a richer variety of multicompartment micelles, including well-defined segmented worms, raspberry-like micelles, and multicompartmentalized worms, were formed from one terpolymer, as revealed by cryoTEM. Despite the complexity and variety of the observed aggregate morphologies, a small number of common structural elements can be invoked to interpret the observed micelles and to relate a given structure to the terpolymer composition.     

Understanding Multicompartment Micelles Using Dissipative Particle Dynamics Simulation

Multicompartment micelles are a new class of nanomaterials that may find wide applications in the fields of drug delivery, nanotechnology and catalysis. Due to their structural complexity, as well as the wide parameter space to explore, experimental investigations are a difficult task, to which molecular simulation may contribute greatly. In this paper, the application of the dissipative particle dynamics simulation technique to the understanding of multicompartment micelles is introduced, illustrating that DPD is a powerful tool for identifying new morphologies by varying block length, block ratio and solvent quality in a systematic way. The formation process of multicompartment micelles, as well as shear effects and the self-assembly of nanoparticle mixtures in multicompartment micelles, can also be studied well by DPD simulation. The present work shows that DPD, as well as other simulation techniques and theories, can complement experiments greatly, not only in exploring properties in a wider parameter space, but also by giving a preview of phenomena prior to experiments. DPD, as a mesoscopic dynamic simulation technique, is particularly useful for understanding the dynamic processes of multicompartment micelles at a microscopic level.

     

核交联的含磺酸甜菜碱pH敏感胶束的制备与表征

制备了一种在疏水段带有侧基叠氮官能团的两亲性pH敏感的聚合物——聚己内酯-聚(甲基丙烯酸二乙氨基乙酯-磺酸甜菜碱)((PCL-ACL)-PDEAS);同时合成了两端带有炔基中间带有二硫键的交联剂,用红外、核磁表征了目标分子.通过两亲性高分子自组装形成胶束,并通过点击化学反应获得了核交联的胶束.通过动态光散射测定粒径,胶束酸碱滴定表征胶束的pH敏感性,还原条件下释放药物的速度,对比了非交联胶束和交联胶束的性质.结果表明,交联胶束在正常生理条件下的释放速度比未交联胶束更慢;而在有DTT的存在条件下,交联胶束由于二硫键断裂,释放速率明显加快.因此,核交联载药胶束有可能响应肿瘤的微环境实现靶向释放.     

Multicompartment micelles from hyperbranched star-block copolymers containing polycations and fluoropolymer segment

In this Article, we have investigated the self-assembly of a series of amphiphilic hyperbranched star-block copolymers to form multicompartment micelles in acidic aqueous solution (pH 3.0) or in a dimethylformamide/water (pH 3.0) mixture. These hyperbranched star-block copolymers were prepared via oxyanion-initiated polymerization process, using hydroxyl-terminated hyperbranched poly[3-ethyl-3-(hydroxymethyl)oxetane] (HP) as a macroinitiator precursor with multi-reactive sites. It was turned into oxyanion end-capped macroinitiator through the reaction with potassium hydride, and followed by a sequential addition of 2-(N,N-dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate (OFPMA). The resultant HP-star-PDMAEMA-b-POFPMA copolymers were characterized via 1H NMR, 19F NMR, and gel permeation chromatography (GPC). The analyses of transmission electron microscopy (TEM), dynamic light scattering (DLS), and microelectrophoresis confirmed that these copolymers could directly self-organize into supramolecular multicompartment micelles with different diameters, depending on the length of the PDMAEMA segment, which can be protonated in acidic aqueous medium. The measurement of the zeta potential gave further evidence of the aggregating structures for the multicompartment micelles.     

Self‐Assembly of Two Agents in a Core‐Shell‐Corona Multicompartment Micelle Studied by Dissipative Particle Dynamics Simulations

Summary: Dissipative particle dynamics simulations are performed on the distributions of two agents in a core‐shell‐corona multicompartment micelle. The simulated results show that when the agents are weakly hydrophobic, their distributions in the multicompartment micelle are largely affected by the interactions between the agents and the blocks; while for strongly hydrophobic agents, the self‐assembly of solubilized species in the micelle is also affected largely by the interactions between the species. This work confirms that a multicompartment micelle can store two agents within separate nanoscopic compartments simultaneously, and shows that the distributions of the agents can be tailored easily by changing the interactions presented. This provides molecular‐level information that is useful for the future rational design of new micellar systems with tailored properties.

Simulated cross sections of the multicompartment micelles with strongly hydrophobic solubilized agents (the solvent and block A are omitted for clarity, block B is dark gray, block C is light gray, agent P is white, and agent Q is black).