Self-assembly Of Amphiphiles Research Articles

Macrocycle-based self-assembled amphiphiles for co-delivery of therapeutic combinations to tumor

For tumor treatment, the efficiency of single chemotherapeutic agent is generally limited and the traditional combination chemotherapies frequently result in the aggravation of side effects. Herein, an amphiphilic pillararene-based self-assembled nanoparticle (APSN) composed of hydrazide-pillar[5]arene (HP5A-6C) that achieve effective co-delivery of therapeutic combinations was reported. Through integrating multitudinous macrocyclic cavities into a single nanoparticle, the APSN could co-load two antitumor drugs, cisplatin (CP) and nitrogen mustard (NM) via host-guest interactions. A serious of safety tests preliminary demonstrated that blank carrier APSN had good biocompatibility. Cytotoxicity assay verified that co-delivery system CP+NM@APSN could exert a synergistic antitumor effect at the cellular level. In vivo studies demonstrated that CP+NM@APSN could not only improve chemotherapeutic outcomes in tumor-bearing model mouse but also alleviate two medications-related side effects. These favorable findings were attributed to the formation of ternary supramolecular assembly that benefited from an enhanced permeability and retention effect. © 2024 Elsevier Science. All rights reserved

A Supramolecular Self-Assembled Nanoprodrug for Enhanced Ferroptosis Therapy.

Ferroptosis can induce cell death that leverages Fe2+-triggered Fenton reactions within living organisms, leading to an excessive accumulation of lipid peroxides (LPOs) and inducing cell death. Ferroptosis can effectively circumvent the inevitable drug resistance encountered with traditional apoptotic therapies. However, several issues remain in the clinical application of ferroptosis anticancer therapy, primarily due to the poor efficiency of intracellular Fenton reaction. To address this issue, we developed a supramolecular self-assembled codelivery nanoprodrug (DOX@C18Fc-Q[7] NPs) composed of ferrocene (Fc)-based supramolecular amphiphiles (C18Fc-Q[7]) and a nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). The C18Fc-Q[7] is based on Fc linked to a hydrophobic long-chain alkane via a disulfide linkage, which interacts with hydrophilic Q[7] to form self-assembled amphiphiles. Importantly, the host-guest interaction between Q[7] and Fc effectively enhances the solubility of Fc while maintaining the stability of the Fe2+ source. Moreover, C18Fc-Q[7] also acts as a good carrier for loading DOX due to its good self-assembly. In cancer cells, elevated glutathione (GSH) triggers the disassembly of nanoprodrug, leading to the release of DOX, which upregulates NOX4 expression and increases H2O2 level, thereby promoting an efficient Fenton reaction for Fc-induced ferroptosis. Moreover, DOX induces cell death through apoptosis, providing a synergistic effect to further enhance the ferroptosis therapy. In vivo studies have demonstrated that this enhanced ferroptosis therapy effectively inhibits tumor growth and metastasis while maintaining good biosafety.

Hydrogen bond, protonation, and coordination-induced supramolecular chirality inversion in glutamide-based amphiphilic self-assembly

In this study, we have synthesized two types of Y-shaped chiral amphiphiles, namely L-BG and L-PG, with a benzene or pyridine ring at the terminal position, respectively. The optimized conformations of both amphiphiles indicate the presence of intramolecular interactions. In dimethylformamide (DMF) solution at the monomeric state, both amphiphiles exhibit positive cotton effects; however, in DMF/H2O mixed solution, the cotton effects are inverted. Molecular dynamics simulations reveal that both intermolecular and intramolecular hydrogen bonds facilitate the inversion of supramolecular chirality. Additionally, protonation and coordination of L-PG assembly results in chirality inversion and transformation of emission. This study emphasizes the significance of both inter- and intramolecular hydrogen bonds in the assembly process, providing insights into stimuli-responsive chiral supramolecular materials.

Self-Assembly of Metallo-Supramolecular Amphiphiles based on Azadipyrromethenes: Consecutive Pathways to Nanodiscs and Nanosheets.

A new class of metallo-supramolecular amphiphilic dyes 1 a, b was constructed by using two azadipyrromethene units which were respectively modified with two hydrophobic alkyl and two hydrophilic oligo(ethylene glycol) chains. The spectroscopic and morphological studies revealed the consecutive self-assembly pathways of 1 a in EtOH/H2O mixed solvent. The monomers of 1 a firstly aggregated into the kinetic-controlled, nanodisc-shaped Agg. I upon cooling and the latter spontaneously transformed into the thermodynamically more stable Agg. II with a nanosheet morphology. While the non-fluorescent Agg. I displayed a broad absorption band (λmax=615 nm), the Agg. II displayed a more intensive and narrowed J-band (λmax=693 nm) and a fluorescence band with a maximum at 760 nm (Φfl=0.1), which could be ascribed to the J-aggregation induced emission enhancement. The kinetics of Agg. I to Agg. II transformation was further modulated by seed-initiated supramolecular polymerization with various ratios of Seedagg.II, in which the transformation rate was significantly increased by ca. 2 orders of magnitude compared to the spontaneous process. The supramolecular amphiphile 1 b bearing longer hydrophilic chains formed only one type aggregate, which exhibited spectroscopic and morphological properties that were highly comparable with that of Agg. I.

Specific ion effects on the self-assembly and interfacial properties of double- and single-chain cationic amphiphiles

Understanding the specific ion effects (SIE) on the self-assembly of ionic amphiphiles is a key unresolved issue in colloid and interface chemistry. We investigated the SIE on interfacial properties, aggregation behaviours, and interfacial molarities of dioctyldimethylammonium (DiC8X) and tetradecyltrimethylammonium (TTAX) (X = Br, Cl, and Ac) surfactants. Our results demonstrate strong SIE on the aggregation behaviours in both single-chain and double-chain surfactants. The aggregation behaviour depends on the net effect of nonspecific interactions and SIE. Vesicle-micelle transitions are observed exclusively in the double-chained surfactants studied in this work, regardless of their tail symmetry, and are absent in the single-chained surfactants examined. These transitions are counterion-dependent, occurring only with bromide, while the surfactants bearing acetate consistently form vesicles. The chemical trapping (CT) results reveal several key insights on interfacial molarities: 1) double-chain surfactants exhibit higher interfacial water molarity compared to single-chain surfactants, with counterion molarity showing an inverse trend; 2) within both TTAX and DiC8X classes, the interfacial water molarity is highest for surfactants with bromide, followed by chloride, and lowest for acetate; 3) for surfactants undergoing vesicle-micelle transitions, both interfacial water and bromide molarity increase with rising surfactant concentration at low concentration ranges, indicating looser interfacial packing with increasing concentration; and 4) the combined CT and molecular dynamic simulations indicate that acetate penetration into interfacial regions significantly increases with surfactant concentration in TTAAc and DiC8Ac aggregates, explaining the consistent vesicle formation of amphiphiles with acetate. Overall, this study provides critical insights into the delicate balance-of-forces controlling the morphologies of aggregates composed of ionic amphiphiles.

Hybrid Protocells Based on Coacervate-Templated Fatty Acid Vesicles Combine Improved Membrane Stability with Functional Interior Protocytoplasm.

Prebiotically-plausible compartmentalization mechanisms include membrane vesicles formed by amphiphile self-assembly and coacervate droplets formed by liquid-liquid phase separation. Both types of structures form spontaneously and can be related to cellular compartmentalization motifs in today's living cells. As prebiotic compartments, they have complementary capabilities, with coacervates offering excellent solute accumulation and membranes providing superior boundaries. Herein, protocell models constructed by spontaneous encapsulation of coacervate droplets by mixed fatty acid/phospholipid and by purely fatty acid membranes are described. Coacervate-supported membranes form over a range of coacervate and lipid compositions, with membrane properties impacted by charge-charge interactions between coacervates and membranes. Vesicles formed by coacervate-templated membrane assembly exhibit profoundly different permeability than traditional fatty acid or blended fatty acid/phospholipid membranes without a coacervate interior, particularly in the presence of magnesium ions (Mg2+). While fatty acid and blended membrane vesicles are disrupted by the addition of Mg2+, the corresponding coacervate-supported membranes remain intact and impermeable to externally-added solutes. With the more robust membrane, fluorescein diacetate (FDA) hydrolysis, which is commonly used for cell viability assays, can be performed inside the protocell model due to the simple diffusion of FDA and then following with the coacervate-mediated abiotic hydrolysis to fluorescein.

Nanostructural diversity: self-assembly of isomeric pyrene-cholane amphiphiles into sheets, tubes, and worm-like morphologies.

Phosphodiester-linked cholane-pyrene-cholane trimers self-assemble into sheet-, tube- and worm-like nanostructures in aqueous conditions. The nanotubes and worm-like assemblies exist as single- or multi-walled objects.

Self-Assembly of Chemically Programmed Amphiphiles into Aqueous Nanotubes with a Lipophilic Lumen.

The creation of complex hollow nanostructures with precise control over size and shape represents a great challenge in supramolecular soft materials. Here, we have further developed a bioinspired methodology for the formation of aqueous nanotubes of well-defined dimensions and pore coating through the self-assembly of amphiphiles that are chemically programmed with complementary nucleobases. These nanotubes are endowed with a hydrophobic lumen, whose diameter can be expanded as a function of the monomer length, in which apolar dyes can be efficiently encapsulated.

Monomer Composition as a Mechanism to Control the Self-Assembly of Diblock Oligomeric Peptide-Polymer Amphiphiles.

Diblock oligomeric peptide-polymer amphiphiles (PPAs) are biohybrid materials that offer versatile functionality by integrating the sequence-dependent properties of peptides with the synthetic versatility of polymers. Despite their potential as biocompatible materials, the rational design of PPAs for assembly into multichain nanoparticles remains challenging due to the complex intra- and intermolecular interactions emanating from the polymer and peptide segments. To systematically explore the impact of monomer composition on nanoparticle assembly, PPAs were synthesized with a random coil peptide (XTEN2) and oligomeric alkyl acrylates with different side chains: ethyl, tert-butyl, n-butyl, and cyclohexyl. Experimental characterization using electron and atomic force microscopies demonstrated that the tail hydrophobicity impacted accessible morphologies. Moreover, the characterization of different assembly protocols (i.e., bath sonication and thermal annealing) revealed that certain tail compositions provide access to kinetically trapped assemblies. All-atom molecular dynamics simulations of micelle formation unveiled key interactions and differences in core hydration, dictating the PPA assembly behavior. These findings highlight the complexity of PPA assembly dynamics and serve as valuable benchmarks to guide the design of PPAs for a variety of applications, including catalysis, mineralization, targeted sequestration, antimicrobial activity, and cargo transportation.

Complex Phase Transitions of Fully Rigid Sphere-Rod Amphiphiles Induced by Solvent Polarity in Dilute Solutions.

We report complex macrophase and microphase transitions of rigid amphiphiles with spherical Keggin molecular clusters as the solvophilic block and rod-like rigid oligofluorene (OF) as the solvophobic block in mixed solvents of water and polar organic solvent. By properly adjusting the solvent polarity, the amphiphiles are found to respond accordingly by self-assembling into multilayered incomplete onion-like structures (10-25 vol % THF), single-layered vesicular structures (60 vol % THF), and an unexpected macrophase separation in the middle (40-50 vol % THF), which is due to the anomalous trends in Keggin solubility as a result of the nature of TBA+ counterions. The rigidity of the OF block prevents the amphiphile from assembling by following the rule of packing parameters; instead, interdigitation among different rods leads to the formation of the solvophobic domain to achieve self-assembly. The incomplete onion structures are controlled by the interdigitation of rigid rods for the number of layers and the electrostatic interaction among Keggin head groups for the interlayer distance. When the degree of interdigitation becomes lower, the self-assembly process shows a trend that can be explained by the traditional rule of packing parameter. This study demonstrates the formation of different self-assembled structures by rigid amphiphiles and their transitions induced by solvent composition. The self-assembly (microphase separation) of rigid amphiphiles in a dilute solution could indeed represent a broad area containing complicated, uncharted rules.

Ohta–Kawasaki energy for amphiphiles: Asymptotics and phase-field simulations

We study the minimizers of a degenerate case of the Ohta–Kawasaki energy, defined as the sum of the perimeter and a Coulombic nonlocal term. We start by investigating radially symmetric candidates which give us insights into the asymptotic behaviors of energy minimizers in the large mass limit. In order to numerically study the problems that are analytically challenging, we propose a phase-field reformulation which is shown to Gamma-converge to the original sharp interface model. Our phase-field simulations and asymptotic results suggest that the energy minimizers exhibit behaviors similar to the self-assembly of amphiphiles, including the formation of lipid bilayer membranes.

Rational design of fluorescent nanoparticles: From wavelength redshift to increased water solubility for stable and high-resolution imaging of latent fingerprints

Efficient and accurate visual identification of latent fingerprints is crucial in areas such as criminal investigation and information security. Aggregation-induced luminescence (AIE) fluorescent materials are widely used in this field because of their strong fluorescence and easy functionalization. They have attracted significant interest and emerged as a promising area since the introduction of the AIE concept. Here a new water-soluble fluorescent nanoparticle, flu-p-DITPA, through amphiphilic self-assembly with amphiphilic polymers macro-CTA-mPEG2000 (P1) and exhibits typical AIE properties. The core molecule, indo-DITPA, derived from the triphenylamine backbone, was obtained through rational molecular design and theoretical calculations, and the calculated results were confirmed with experimental results. The photophysical properties of indo-DITPA and flu-p-DITPA have been meticulously studied, revealing their remarkable characteristics. Taking advantage of their favorable photophysical properties, good water solubility, and biocompatibility, the researchers have devised a simple yet effective method for visualizing latent fingerprints (LFPs) with high resolution under UV light. This method enables the easy decoding of latent fingerprint information at primary, secondary, and tertiary levels. Importantly, this technique is simple, rapid, and user-friendly, marking a significant step forward in the field of forensic science and fingerprint analysis.

Hierarchical Nanostructures Constructed by Soft Epitaxial Self-Assembly of Organic-Inorganic Hybrid Giant Amphiphiles.

2D nanomaterials with ångström-scale thicknesses offer a unique platform for confining molecules at an unprecedentedly small scale, presenting novel opportunities for modulating material properties and probing microscopic phenomena. In this study, mesogen-tethered polyhedral oligomeric silsesquioxane (POSS) amphiphiles with varying numbers of mesogenic tails to systematically influence molecular self-assembly and the architecture of the ensuing supramolecular structures, are synthesized. These organic-inorganic hybrid amphiphiles facilitate precise spatial arrangement and directional alignment of the primary molecular units within highly ordered supramolecular structures. The correlation between molecular design and the formation of superlattices through comprehensive structural analyses, incorporating molecular thermodynamics and kinetics, is explored. The distinct intermolecular interactions of the POSS core and the mesogenic tails drive the preferential formation of a 2D inorganic sublattice while simultaneously guiding the hierarchical assembly of organic lamellae via soft epitaxy. The findings reveal the intricate balance between shape, size, and interaction strengths of the inorganic and organic components, and how these factors collectively influence the structural hierarchy of the superstructures, which consist of multiple sublattices. By controlling this unique molecular behavior, it is possible to modulate or maximize the anisotropy of optical, mechanical, and electrical properties at the sub-nanometer scale for nanotechnology applications.

Reversing the Trend: Deciphering Self-Assembly of Unconventional Amphiphiles Having Both Alkyl-Chain and PEG.

In the field of molecular self-assembly, the core of an assembly is always made up of hydrophobic moiety like a long alkyl chain, whereas the outer part has always been a hydrophilic moiety such as poly(ethylene glycol) (PEG), or charged species. Hence, reversing the trend to manifest self-assembled structures with a PEG core and a surface consisting of alkyl chains in aqueous system is incredibly challenging. Herein, we architected a unique class of cationic bolaamphiphiles containing low molecular weight PEG and alkyl chains of different lengths. The bolaamphiphiles spontaneously form vesicles without external stimuli. These vesicles are unprecedented because PEG makes up the vesicle core, while the alkyl chains appear on the vesicles' exterior. Hence, this particular design reverses the usual trend of self-assembly formation. The vesicle size increases with the increase in alkyl chain-length. To our great surprise, we obtained large micelles for longest alkyl-chain amphiphile, which in turn act as a gemini amphiphile. The shift from a particular bolaamphiphile to gemini amphiphile with the variation of alkyl chain is also unexplored. Therefore, this specific class of self-assembled structure would compound a new paradigm in molecular self-assembly and supramolecular chemistry.

Fabricating supramolecular lyotropic crystals at subzero temperatures: The pivotal role of antifreeze and nanostructures

The classical lyotropic liquid crystals (LLCs) prepared in pure water are not adapted to subzero temperatures. However, the fabrication of cryogenic LLCs is highly significant for gaining profound insights into self-assembly at extremely low temperatures. A proficient solution strategy, namely introducing alcohol antifreeze to water, faces a challenge in balancing frozen resistance and efficient self-assembly. Herein, we address this unmet challenge by selecting four alcohols with comparable structure to fabricate cryogenic LLCs system through the supramolecular self-assembly of a long-chain non-ionic surfactant. The freezing point, surfactant solubility, and self-assembly behavior at subzero temperatures were investigated. The alcohol antifreeze plays a significant role in depressing water freezing point and governing assembled microstructures. Both experimental and computational results revealed that alcohols bearing more hydroxyl groups are efficient to lower water freezing point while remain the capability to induce surfactant self-assembly. They can realize solvophobic balance and strong hydrogen-bond interactions. A simple approach based on Gordon parameter was established to evaluate the suitability as an anti-freezing medium for amphiphile self-assembly. Strikingly, a new LLCs system capable of withstanding the extremely low temperature of −80 °C was developed, which shows interestingly continuous phase transitions as temperature lowers to subzero. Overall, this study provides valuable insights into cryogenic supramolecular self-assembly, and offers a significant foundation and evaluation method for the selection of appropriate alcohol antifreeze for cryogenic self-assembly.

Engineering a nanoantibiotic system displaying dual mechanism of action

In recent decades, peptide amphiphiles (PAs) have established themselves as promising self-assembling bioinspired materials in a wide range of medical fields. Herein, we report a dual-therapeutic system constituted by an antimicrobial PA and a cylindrical protease inhibitor (LJC) to achieve broad antimicrobial spectrum and to enhance therapeutic efficacy. We studied two strategies: PA-LJC nanostructures (Encapsulation) and PA nanostructures + free LJC (Combination). Computational modeling using a molecular theory for amphiphile self-assembly captures and explains the morphology of PA-LJC nanostructures and the location of encapsulated LJC in agreement with transmission electron microscopy and two-dimensional (2D) NMR observations. The morphology and release profile of PA-LJC assemblies are strongly correlated to the PA:LJC ratio: high LJC loading induces an initial burst release. We then evaluated the antimicrobial activity of our nanosystems toward gram-positive and gram-negative bacteria. We found that the Combination broadens the spectrum of LJC, reduces the therapeutic concentrations of both agents, and is not impacted by the inoculum effect. Further, the Encapsulation provides additional benefits including bypassing water solubility limitations of LJC and modulating the release of this molecule. The different properties of PA-LJC nanostructures results in different killing profiles, and reduced cytotoxicity and hemolytic activity. Meanwhile, details in membrane alterations caused by each strategy were revealed by various microscopy and fluorescent techniques. Last, in vivo studies in larvae treated by the Encapsulation strategy showed better antimicrobial efficacy than polymyxin B. Collectively, this study established a multifunctional platform using a versatile PA to act as an antibiotic, membrane-penetrating assistant, and slow-release delivery vehicle.

An anti-GD2 aptamer-based bifunctional spherical nucleic acid nanoplatform for synergistic therapy targeting MDM2 for retinoblastoma

Retinoblastoma (RB) is a type of pediatric solid tumor in the fundus. The lack of precision therapies combined with the difficulty of delivering small interfering RNA (siRNA) into the eyes means that there is currently no nucleic acid-based therapy for RB in clinical practice. Here, we reported on anti-GD2 and glutathione-responsive spherical nucleic acids (SNAs), loaded with siRNA and the inhibitor NVP-CGM097, which jointly blocked the oncogenic factor n in RB cells (Y79 and WERI-RB-1). The SNAs were formed through the self-assembly of bifunctional cholesterol amphiphiles containing aptamers that specifically targeted GD2-positive RB cells, allowing for the formation of an SNA with a dense DNA shell. The aptamer/siRNA component functioned both as a carrier and a payload, enhancing the specific recognition and delivery of both components and constituting an active agent for MDM2 regulation. Following SNA endocytosis by RB cells, siRNA and NVP-CGM097 were released from the SNA particles by glutathione, which synergistically blocked the MDM2-p53 pathway, increasing p53 protein content and inducing cell apoptosis. This study showed a potent antitumor effect following intravitreal injection of SNAs in Y79 tumor-bearing mice through clinical manifestation and tumor pathological analysis. In hematological analysis and hepatotoxicity assays, SNAs were safer for mice than melphalan, the favored drug for treating RB in clinical practice. Our results illustrated the potential of intravitreally injected SNAs as a precision medicine for treating RB.

Transient Metallo-Lipidoid Assemblies Amplify Covalent Catalysis of Aqueous and Non-Aqueous Reactions.

Dissipative supramolecular assemblies are hallmarks of living systems, contributing to their complex, dynamic structures and emerging functions. Living cells can spatiotemporally control diverse biochemical reactions in membrane compartments and condensates, regulating metabolite levels, signal transduction or remodeling of the cytoskeleton. Herein, we constructed membranous compartments using self-assembly of lipid-like amphiphiles (lipidoid) in aqueous medium. The new double-tailed lipidoid features Cu(II) coordinated with a tetravalent chelator that dictates the binding of two amphiphilic ligands in cis-orientation. Hydrophobic interactions between the lipidoids coupled with intermolecular hydrogen bonding led to a well-defined bilayer vesicle structure. Oil-soluble SNAr reaction is efficiently upregulated in the hydrophobic cavity, acting as a catalytic crucible. The modular system allows easy incorporation of exposed primary amine groups, which augments the catalysis of retro aldol and C-N bond formation reactions. Moreover, a higher-affinity chelator enables consumption of the Cu(II) template leveraging the differential thermodynamic stability, which allows a controllable lifetime of the vesicular assemblies. Concomitant temporal upregulation of the catalytic reactions could be tuned by the metal ion concentration. This work offers new possibilities for metal ion-mediated dynamic supramolecular systems, opening up a massive repertoire of functionally active dynamic "life-like" materials.

Self-Assembling Anti-Freezing Lamellar Nanostructures in Subzero Temperatures.

The requirement for cryogenic supramolecular self-assembly of amphiphiles in subzero environments is a challenging topic. Here, the self-assembly of lamellar lyotropic liquid crystals (LLCs) are presented to a subzero temperature of -70 °C. These lamellar nanostructures are assembled from specifically tailored ultra-long-chain surfactant stearyl diethanolamine (SDA) in water/glycerol binary solvent. As the temperature falls below zero, LLCs with a liquid-crystalline Lα phase, a tilted Lβ phase, and a new folded configuration are obtained consecutively. A comprehensive experimental and computational study is performed to uncover the precise microstructure and formation mechanism. Both the ultra-long alkyl chain and head group of SDA play a crucial role in the formation of lamellar nanostructures. SDA head group is prone to forming hydrogen bonds with water, rather than glycerol. Glycerol cannot penetrate the lipid layer, which mixes with water arranging outside of the lipid bilayer, providing an ideal anti-freezing environment for SDA self-assembly. Based on these nanostructures and the ultra-low freezing point of the system, a series of novel cryogenic materials are created with potential applications in extremely cold environments. These findings would contribute to enriching the theory and research methodology of supramolecular self-assembly in extreme conditions and to developing novel anti-freezing materials.

Polydiacetylene Micelles in Nanomedicine and Beyond

AbstractIn this account article, we give an overview of our contribution to the development of stable micellar carriers obtained by self-assembly and photo-polymerization of diacetylenic amphiphiles. The stabilized micelles can be loaded with active substances and used for diagnostic and therapeutic applications, or loaded with a metal catalyst to promote some synthetic transformations in fully aqueous medium.Table of content1 Introduction2 Polydiacetylene Micelles Applied to Nanomedicine2.1 From Amphiphilic Units to Micelles2.2 In vivo Behavior of Micelles2.3 Passive Targeting of Tumors with Micelles2.4 Drug Delivery with Micelles2.5 Towards Improved Delivery of Micelles to Tumors Using Sonoporation2.6 Active Targeting with Micelles2.7 Behavior of Micelles at the Cellular Level and Potential Cytotoxicity2.8 Micelles for siRNA Transfection3 Polydiacetylene Micelles Applied to Catalysis3.1 Copper Nanoparticles in Micelles3.2 Copper Salts in Micelles4 Conclusion