Self-assembly In Aqueous Solution Research Articles

Actively Targeting Redox-Responsive Multifunctional Micelles for Synergistic Chemotherapy of Cancer.

Stimuli-responsive polymeric micelles decorated with cancer biomarkers represent an optimal choice for drug delivery applications due to their ability to enhance therapeutic efficacy while mitigating adverse side effects. Accordingly, we synthesized a digoxin-modified novel multifunctional redox-responsive disulfide-linked poly(ethylene glycol-b-poly(lactic-co-glycolic acid) copolymer (Bi(Dig-PEG-PLGA)-S2) for the targeted and controlled release of doxorubicin (DOX) in cancer cells. Within the micellar aggregate, the disulfide bond confers redox responsiveness, while the presence of the digoxin moiety acts as a targeting agent and chemosensitizer for DOX. Upon self-assembly in aqueous solution, Bi(Dig-PEG-PLGA)-S2 formed uniformly distributed spherical micelles with a hydrodynamic diameter (D h ) of 58.36 ± 0.78 nm and a zeta potential of -24.71 ± 1.01 mV. The micelles exhibited desirable serum and colloidal stability with a substantial drug loading capacity (DLC) of 6.26% and an encapsulation efficiency (EE) of 83.23%. In addition, the release of DOX demonstrated the redox-responsive behavior of the micelles, with approximately 89.41 ± 6.09 and 79.64 ± 6.68% of DOX diffusing from DOX@Bi(Dig-PEG-PLGA)-S2 in the presence of 10 mM GSH and 0.1 mM H2O2, respectively, over 96 h. Therefore, in HeLa cell lines, DOX@Bi(Dig-PEG-PLGA)-S2 showed enhanced intracellular accumulation and subsequent apoptotic effects, attributed to the targeting ability and chemosensitization potential of digoxin. Hence, these findings underscore the promising characteristics of Bi(Dig-PEG-PLGA)-S2 as a multifunctional drug delivery vehicle for cancer treatment.

Manipulating the hydrophilic / hydrophobic balance in novel cationic surfactants by ethoxylation: The impact on adsorption and self-assembly

HypothesisCationic surfactants have a wide range of applications, often associated with their affinity for a range of solid surfaces and their anti-microbial properties. Manipulating their adsorption and self-assembly properties is key to most applications, and this is commonly achieved through surfactant mixtures or manipulating their headgroup or alkyl chain structure. Achieving this through adjustments to their headgroup structure is less common in cationic surfactants than in anionic surfactants. Ethoxylation provides the ability to adjust the hydrophilic / hydrophobic balance, as extensively demonstrated in a range of anionic surfactants. ExperimentsThis same approach has been applied here to a range of ethoxylated cationic surfactants in the form of the quaternary ammonium salts, and their tertiary nonionic equivalents before quaternisation. Their adsorption and self-assembly properties are investigated using predominantly the neutron scattering techniques of neutron reflectivity, NR, and small angle neutron scattering, SANS. FindingsThe trends in the adsorption at the air–water interface and the self-assembly in aqueous solution demonstrate how the hydrophilic / hydrophobic balance can be adjusted by varying the degree of ethoxylation and the alkyl chain length, and illustrate the degree of interdependence of the different structural changes. The variation in the adsorption and the micelle structure shows how the surfactant conformation / packing changes as the degree of ethoxylation and alkyl chain length increases and how the introduction of charge induces further changes.

Comparison of the self-assembly and cytocompatibility of conjugates of Fmoc (9-fluorenylmethoxycarbonyl) with hydrophobic, aromatic, or charged amino acids.

The self-assembly in aqueous solution of three Fmoc-amino acids with hydrophobic (aliphatic or aromatic, alanine or phenylalanine) or hydrophilic cationic residues (arginine) is compared. The critical aggregation concentrations were obtained using intrinsic fluorescence or fluorescence probe measurements, and conformation was probed using circular dichroism spectroscopy. Self-assembled nanostructures were imaged using cryo-transmission electron microscopy and small-angle X-ray scattering (SAXS). Fmoc-Ala is found to form remarkable structures comprising extended fibril-like objects nucleating from spherical cores. In contrast, Fmoc-Arg self-assembles into plate-like crystals. Fmoc-Phe forms extended structures, in a mixture of straight and twisted fibrils coexisting with nanotapes. Spontaneous flow alignment of solutions of Fmoc-Phe assemblies is observed by SAXS. The cytocompatibility of the three Fmoc-amino acids was also compared via MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] mitochondrial activity assays. All three Fmoc-amino acids are cytocompatible with L929 fibroblasts at low concentration, and Fmoc-Arg shows cell viability up to comparatively high concentration (0.63 mM).

Turn-on Near-Infrared Phosphorescent Recognition of Anion Based on Self-Assembly of Cyclometalated Platinum Complexes That Induce Oncosis and Monitor Living Cells.

The design of bio-responsive functional molecular materials that can undergo self-assembly to form nanostructures within cells in response to cellular endogenous stimuli and the clarification of their prospective reaction mechanisms are of paramount significance. This work aims to elucidate the spatiotemporal generation of subcellular nanostructures and their influence on cellular functionality. Three sets of cyclometalated platinum complexes have been designed and synthesized as near-infrared phosphorescent turn-on probes for specific anions based on dynamic self-assembly in aqueous solution. The augmentation of the quantity of aromatic rings in the NN bidentate ligand of the complex modifies both the intensity of the intermolecular Pt-Pt interaction and the capacity to generate self-assembled nanowires with near-infrared emission. Besides, we explored the impact of the CN ligand's substituent effect on anion recognition, which revealed that complexes with electron-absorbing F atom substitution exhibit superior selectivity for Br-. These complexes display vivid green turn-on luminescence upon interaction with cellular biomolecules, enabling dynamic monitoring of their subcellular distribution and their interaction on diverse conditions. Furthermore, our complexes were observed to induce oncosis in cancer cells, underscoring the potential of our work in facilitating in vitro diagnosis and developing effective theranostic agents for cancer therapy.

Synthesis of Poly(propylene oxide)-Poly(N,N'-dimethylacrylamide) Diblock Copolymer Nanoparticles via Reverse Sequence Polymerization-Induced Self-Assembly in Aqueous Solution.

Sterically-stabilized diblock copolymer nanoparticles comprising poly(propylene oxide) (PPO) cores are prepared via reverse sequence polymerization-induced self-assembly (PISA) in aqueous solution. N,N'-Dimethylacrylamide (DMAC) acts as a cosolvent for the weakly hydrophobic trithiocarbonate-capped PPO precursor. Reversible addition-fragmentation chain transfer (RAFT) polymerization of DMAC is initially conducted at 80% w/w solids with deoxygenated water. At 30-60% DMAC conversion, the reaction mixture is diluted to 5-25% w/w solids. The PPO chains become less solvated as the DMAC monomer is consumed, which drives in situ self-assembly to form aqueous dispersions of PPO-core nanoparticles of 120-190 nm diameter at 20 °C. Such RAFT polymerizations are well-controlled (Mw/Mn ≤ 1.31), and more than 99% DMAC conversion is achieved. The resulting nanoparticles exhibit thermoresponsive character: dynamic light scattering and transmission electron microscopy studies indicate the formation of more compact spherical nanoparticles of approximately 33 nm diameter on heating to 70 °C. Furthermore, 15-25% w/w aqueous dispersions of such nanoparticles formed micellar gels that undergo thermoreversible (de)gelation on cooling to 5 °C.

Tuning the Solution Self-Assembly of a Peptide-PEG (Polyethylene Glycol) Conjugate with alpha-Cyclodextrin.

Cyclodextrins are saccharide ring molecules which act as host cavities that can encapsulate small guest molecules or thread polymer chains. We investigate the influence of alpha-cyclodextrin (αCD) on the aqueous solution self-assembly of a peptide-polymer conjugate YYKLVFF-PEG3K previously studied by our group [Castelletto et al., Polym. Chem., 2010, 1, 453-459]. This conjugate comprises a designed amyloid-forming peptide YYKLVFF that contains the KLVFF sequence from Amyloid β peptide, Aβ16-20, along with two aromatic tyrosine residues to enhance hydrophobicity as well as polyethylene glycol PEG with molar mass 3000 g mol-1. The conjugate self-assembles into β-sheet fibrils in aqueous solution. Here we show that complexation with αCD leads instead can produce free-floating nanosheets in aqueous solution (with a β-sheet structure). The transition from fibrils to nanosheets is driven by an increase in the number of αCD molecules threaded on the PEG chains, as determined by 1H NMR spectroscopy.These findings point to the use of cyclodextrin additives as a powerful means to tune the solution self-assembly in peptide-polymer conjugates and potentially other polymer/biomolecular hybrids.

Substituent alkyl-chain-dependent supramolecular chirality, tunable chiroptical property, and dye adsorption in azobenzene-glutamide-amphiphile based hydrogel

Controlling the supramolecular chirality of a self-assembly system by molecular structure design and external stimuli in aqueous solution is significant but challenging. Here, we design and synthesize several glutamide-azobenzene-based amphiphiles with different length alkyl chains. The amphiphiles can form self-assemblies in aqueous solution and show CD signals. As the number of the alkyl chain of amphiphiles increases, the CD signals of the assemblies can be enhanced. However, the long alkyl chains conversely restrict the isomerization of the azobenzene and the corresponding chiroptical property. Moreover, the alkyl length can determine the nanostructure of the assemblies and exert critical influence on the dye adsorption efficiency. This work exhibits some insights into the tunable chiroptical property of the self-assembly by delicate molecular design and external stimuli, and emphasizes the molecular structure can determine the corresponding application.

Pyridine-containing block copolymeric nano-assemblies obtained through complementary hydrogen-bonding directed polymerization-induced self-assembly in water

A diversity of pyridine-containing polymeric nanomaterials with controllable structures and multiple responses were developed through complementary hydrogen-bonding directed polymerization-induced self-assembly in aqueous solution.

Molecular simulation studies of self-assembly for a chromonic perylene dye: All-atom studies and new approaches to coarse-graining

Perylene tetracarboxylic acid bisimides are compounds that show intense visible light absorption and exhibit excellent chemical, photochemical and thermal stability. As such, they have been widely used as dyes and have a range of industrial applications. These dyes have also been investigated for various applications in aqueous media as chromonic liquid crystals: lyotropic systems characterised by the association of aromatic mesogenic cores into stacked structures. In this study, we focus on one perylene dye bis-(N,N-diethylaminoethyl) perylene-3,4,9,10-tetracarboxylic diimide dihydrochloride, PER, and study its self-assembly in aqueous solution through both atomistic and coarse-grained molecular models. All-atom molecular dynamics simulations demonstrate spontaneous self-assembly into chromonic H-aggregate stacks with an interparticle twist between molecules. The coarse-graining of complex chromonic mesogens introduces a wealth of subtle complexities that presents a significant challenge to overcome. Consequently, we developed coarse-grained (CG) models using both bottom-up and top-down approaches: the multiscale coarse-graining method (MS-CG) in the form of hybrid force matching (FM) and the MARTINI 3 force field, respectively. We discuss the successes/deficiencies of these approaches and introduce changes to improve upon their performance and representability. For the MARTINI 3 model, careful optimisation of parameters allows it to exactly reproduce the atomistic self-assembly behaviour including the relevant thermodynamic properties in solution. The bottom-up CG model, produced using a conventional MS-CG treatment, fails to reproduce most of the target properties, but the implementation of the potentials into a combined FM-MARTINI 3 framework allows the recovery of the correct self-assembly behaviour in solution.

Sequentially Self-Assembled Nanoreactor Comprising Tannic Acid and Phenylboronic Acid-Conjugated Polymers Inducing Tumor-Selective Enzymatic Activity.

The construction of enzyme delivery systems, which can control enzymatic activity at a target site, is important for efficient enzyme-prodrug therapy/diagnosis. Herein we report a facile technique to construct a systemically applicable β-galactosidase (β-Gal)-loaded ternary complex comprising tannic acid (TA) and phenylboronic acid-conjugated polymers through sequential self-assembly in aqueous solution. At physiological conditions, the ternary complex exhibited a hydrodynamic diameter of ∼40 nm and protected the loaded β-Gal from unfavorable degradation by proteinase. Upon cellular internalization, the ternary complex recovered β-Gal activity by releasing the loaded β-Gal. The intravenously injected ternary complex thereby delivered β-Gal to the target tumor in a subcutaneous tumor model and exerted enhanced and selective enzymatic activity at the tumor site. Sequential self-assembly with TA and phenylboronic acid-conjugated polymers may offer a novel approach for enzyme-prodrug theragnosis.

Insights into the composition, structure-function relationship, and molecular organization of surfactants from spent coffee grounds

Macromolecular/polymeric constituents of surfactants and their self-assembly in aqueous solutions play a key role in their technologically relevant application such as stabilization of foams and emulsions. However, such information on coffee-based surfactants is scarce. The present study is first-of-its-kind in elucidating the chemical and molecular fingerprints of surfactants derived from spent coffee grounds (SCG). Initial part of the study involved estimation of the total proteins and sugars, and monosaccharide composition of high (HMW) and low molecular weight (LMW) surfactants derived from dry and defatted SCG, which in turn is the residue obtained after hot water brewing of roasted Robusta and Arabica coffee granules. The HMW surfactants had higher protein and sugar contents that were directly related to their foamability and foam stability, respectively. Mannose and arabinose were the major sugars identified in HMW surfactants. LMW surfactants showed lower protein and sugar contents and absence of arabinose. Thus, only the HMW surfactants were subjected to MALDI-TOF mass spectrometry, LC-MS-MS based protein profiling, circular dichroism spectroscopy, and small-angle X-ray scattering. The presence of quercetin-sugar complexes, protease, transferase, and acylated proteins and a β-turn type protein secondary structure were detected in the SCG-surfactants. The transition from lamellar to rod-shaped micellar structures was observed when the surfactant concentration in aqueous solution was increased from a lower concentration to its critical micelle concentration (0.2%–0.8%, w/v).

Tetraphenylethylene based amphiphilic derivatives: The self-assembly, photo-responsiveness and their application for erasable fluorescent ink

Since the discovery of aggregation induced emission (AIE) phenomenon, various stimuli-responsive materials have been rapidly developed. However, the development of self-assembled amphiphilic light-responsive materials in aqueous solution needs to be solved urgently. In this work, three new amphiphilic tetraphenylethylene (TPE) derivatives (TPE-1, TPE-2 and TPE-3) with AIE properties and photochromism were synthesized and investigated. Owing to the different electron-donating abilities of the three groups attached to TPE units, the TPE-1, TPE-2 and TPE-3 displayed blue-green, yellow-green, and orange fluorescence emission in the aggregation state respectively. Furthermore, ordered nanoparticles formed via self-assembly in aqueous solution showed interesting photocyclization behaviors, which lead to fluorescence quenching under ultraviolet light irradiation (λ = 365 nm). Therefore, the compounds can be used as anti-counterfeiting ink in the information encryption due to their amphiphilicity and photo-responsiveness. This work contributes new members to the amphiphilic light-responsive materials family and demonstrates the potential for applications in the fields of optical information storage, information security protection, and erase/rewrite systems.

Heteroternary cucurbit[8]uril complexes as supramolecular scaffolds for self-assembled bifunctional photoredoxcatalysts.

The self-assembly of bifunctional photoredoxcatalysts is reported. A series of photosensitizers and water-reducing catalysts were functionalized with viologen- and naphthol-units, respectively. Subsequent formation of the heteroternary cucurbit[8]uril-viologen-naphthol complexes was used for the constitution of bifunctional photoredoxcatalysts for hydrogen generation.

Construction of a pH-sensitive self-assembly in aqueous solutions based on a dansyl-modified β-cyclodextrin.

Here we present a pH-responsive self-assembly based on a β-cyclodextrin (β-CD) derivative bearing a dansyl terminus (βCD-C6-Dns). Vesicular structures were formed over the entire studied pH range (8.5-0.7); however, the molecular configuration and packing within the vesicles were different at different pH values. Intramolecular host-guest complexation occurred mainly between the dansyl group and β-CD at pH values where the dansyl group was not protonated. The alkyl chain also acted as a competitive guest to form host-guest inclusions as confirmed by 2D 1H NMR measurements. The pH-responsive βCD-C6-Dns vesicles have potential application prospects in pH-controlled drug release based on the low cytotoxicity of βCD-C6-Dns.

Benzene tricarboxamide derivatives with lipid and ethylene glycol chains self-assemble into distinct nanostructures driven by molecular packing

The self-assembly in aqueous solution of benzene-1,3,5-tricarboxamide (BTA) bearing one alkyl chain and two PEG (polyethylene glycol) chains or two alkyl chains and one PEG chain yields molecular-packing driven nanostructures.

Contrasting effect of 1-butanol and 1,4-butanediol on the triggered micellar self-assemblies of C16-type cationic surfactants.

The self-assembly in aqueous solutions of three quaternary salt-based C16-type cationic surfactants with different polar head groups and identical carbon alkyl chain viz., cetylpyridinium bromide (CPB), cetyltrimethylammonium tosylate (CTAT), and cetyltriphenylphosphonium bromide (CTPPB) in the presence of 1-butanol (BuOH) and 1,4-butanediol (BTD) was investigated using tensiometry, 2D-nuclear Overhauser enhancement spectroscopy (2D-NOESY) and small angle neutron scattering (SANS) techniques. The adsorption parameters and micellar characteristics evaluated at 303.15 K distinctly showed that BuOH promotes the mixed micelle formation while BTD interfered with the micellization phenomenon. The SANS data fitted using an ellipsoid (as derived by Hayter and Penfold using the Ornstein-Zernike equation and the mean spherical approximation) and wormlike micellar models offered an insight into the micelle size/shape and aggregation number (Nagg) in the examined systems. The evaluated descriptors presented a clear indication of the morphology transition in cationic micelles as induced by the addition of the two alcohols. We also offer an investigation into the acceptable molecular interactions governing the differences in micelle morphologies, using the non-invasive 2D-NOESY technique and molecular modeling. The experimental observations elucidated from computational simulation add novelty to this work. Giving an account to the structural complexity in the three cationic surfactants, the molecular dynamics (MD) simulation was performed for CPB micelles in an aqueous solution of alcohols that highlighted the micelle solvation and structural transition, which is further complemented in terms of critical packing parameter (PP) for the examined systems.

Synthesis of cyclodextrin-derived star poly(N-vinylpyrrolidone)/poly(lactic-co-glycolide) supramolecular micelles via host-guest interaction for delivery of doxorubicin

Supramolecular micelles are of particular interest in cancer therapy, owing to their capability to enable the on-demand drug release in tumor microenvironments. Nano platforms of supramolecular micelles can be facilely achieved from β-cyclodextrin (β-CD) based polymers. Herein, we developed novel supramolecular micelles of β-CD-(PNVP)4-AD-PLGA produced from β-CD-grafted star poly(N-vinylpyrrolidone) (β-CD-(PNVP)4) and adamantine-terminated linear-poly(lactic-co-glycolide) (AD-PLGA) by host-guest interaction between β-cyclodextrin and adamantine groups. A model anticancer drug, doxorubicin (DOX) was loaded into the supramolecular micelles during self-assembly in aqueous solution. The dissociation of the supramolecular micelles was triggered by acidic environments, which led to the release of DOX more in pH 6.4 compared to pH 7.4. The in vitro toxicity of the drug loaded micelles revealed 87% of cytotoxicity after 72 h against glioblastoma (C6 cells) while β-CD-(PNVP)4-AD-PLGA was biocompatible to HEK 293 cells (non-cancerous). Furthermore, β-CD-(PNVP)4-AD-PLGA and β-CD-(PNVP)4-AD-PLGA/DOX were found to be hemocompatible and more suitable for Intravenous administration. Our results suggest that the developed micelle system can provide a promising robust and sustained anticancer drug delivery system for the future cancer treatment.

Transition of Ultrathick Polyamide Tubes into Vesicles with Great Stability.

This work reports on the transition of a polyamide ultrathick wall microtubes to microvesicles through self-assembly. An amphiphilic polyamide is synthesized first by the solution polycondensation of sodium isophthalate-5-sulfonate (SIPA) and poly(propylene glycol) bis(2-aminopropyl ether) 2000. Then, its self-assembly in aqueous solution is investigated through direct hydration. The size and morphology of the self-assemblies is investigated by transmission electron microscope (TEM), scanning electron microscope (SEM), atomic force microscope (AFM), and optical microscope (OM) measurements. The result shows that the as-prepared polyamide first self-assembles to thick walled tubes, then these tubes can gradually evolve to ultrathick wall microvesicles with an unusually thick membrane above 330 nm.Both the transition pathway and the mechanism are investigated in micromicroscopy. Most importantly, the microvesicles show great thermal and chemical stability. The novel superstable self-assembly structures as well as the transition mechanism presented here offer a promising perspective for the application in the scope of the biological membrane movements and nanoelectromechanics in medical devices.

Cell Membrane-Inspired Polymeric Vesicles for Combined Photothermal and Photodynamic Prostate Cancer Therapy.

Photothermal therapy (PTT) and photodynamic therapy (PDT) have emerged as highly prospective therapeutic modalities in cancer therapy. Notwithstanding, a critical challenge still remains in the exploration of an effective strategy to maximize the synergistic efficacy of PTT and PDT due to low photoconversion efficiency. Herein, inspired by the phospholipid bimolecular structure of the cell membrane, bionic cell membrane polymeric vesicles with photothermal/photodynamic synergy for prostate cancer therapy at one wavelength's excitation are constructed in one step by the coordination of hexadecyl trimethyl ammonium bromide (CTAB) from the surface of hydrophobic gold nanorods (AuNRs) with indocyanine green (ICG) and polycaprolactone (PCL), achieving their self-assembly in aqueous solutions. Importantly, the aggregation of the assembly improves the stability of the vesicles, realizing the synergistic effect of PTT and PDT for prostate cancer therapy. After being assembled within polymeric vesicles, bifunctional photosensitizer ICG can generate reactive oxygen species (ROS) and photothermal effect under light treatment. Their ROS not only induce PDT efficacy but also destroy the integrity of the lysosomal membrane, promoting the translocation of ICG and another photosensitizer called gold nanorods (AuNRs) into the cytosol. Moreover, their photothermal effects produced by both photosensitizers are able to engender greater damage to the tumor cells because of the close distance with organelles. This structure manifests good cellular uptake, highly effective tumor accumulation, high photothermal conversion efficiency, and excellent properties of enhanced photobleaching resistance, which are beneficial to ICG-based fluorescence tumor imaging. Using the same near-infrared (NIR) wavelength for excitation, the AuNR/ICG vesicles can reduce the side effect rate of photodamage on the skin. In addition, by generating reactive oxygen species (ROS) and double photothermal effect, the vesicles under NIR excitation can promote the apoptosis of PC3 tumor cells. Taken together, the spontaneous self-assembled AuNR/ICG vesicles exhibit huge potential in advanced-stage prostate cancer therapy, especially for the prostate-specific membrane antigen (PSMA)-negative castration-resistant subtype.

Functional Peptide Nanocapsules Self-Assembled from β-Annulus Peptides.

Spherical viruses are unique nanocapsules formed by self-assembly of coat proteins (capsids). By mimicking natural spherical capsids, various artificial viral capsids are developed by using self-assembled proteins and peptides as building blocks. We developed an artificial viral capsid consisting of a β-annulus peptide designed from natural viruses. The "β-annulus capsid" can be functionalized by encapsulating guest molecules to the inside and decoration of exogenous molecules on the outside. Here, we describe the encapsulation and decoration on the β-annulus capsids by connecting additional sequences to the β-annulus peptide, conjugation with objective molecules, and subsequent self-assembly in aqueous solutions.