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[Display omitted] • Coarse-grained models of oil-water systems with amphiphilic macromolecule (CHPEI) are developed by dissipative particle dynamics simulation. • CHPEI exhibits various adsorption configurations at phase interface, including lamellar, seaweed-like, and even jellyfish-like structures. • CHPEI maintains demulsification efficiency exceeding 96.7 % under high acid-alkali-salt environments or even after being recycled four times. • Integrating mesoscopic DPD simulations with macroscopic experiments validates the design and effectiveness of advanced demulsifiers. Hypothesis: An innovative strategy for designing high-performance demulsifiers is proposed. It hypothesizes that integrating mesoscopic molecular simulations with macroscopic physicochemical experiments can enhance the understanding and effectiveness of demulsifiers. Specifically, it is suggested that amphiphilic hyperbranched polyethyleneimine (CHPEI) could act as an efficient demulsifier in oil–water systems, with its performance influenced by its adsorption behaviors at the oil–water interface and its ability to disrupt asphaltene-resin aggregates. Experiments: Several coarse-grained models of oil–water systems, with CHPEI, are constructed using dissipative particle dynamics (DPD) simulation. Following the insights gained from the simulations, a series of CHPEI-based demulsifiers are designed and synthesized. Demulsification experiments are conducted on both simulated and crude oil emulsions, with the process monitored using laser scanning confocal microscopy. Additionally, adsorption kinetics and small angle X-ray scattering are employed to reveal the inherent structural characteristics of CHPEI demulsifiers. Findings: CHPEI demonstrates over 96.7 % demulsification efficiency in high acid-alkali-salt systems and maintains its performance even after multiple reuse cycles. The simulations and macroscopic experiments collectively elucidate that the effectiveness of a demulsifier is largely dependent on its molecular weight and the balance of hydrophilic and hydrophobic groups. These factors are crucial in providing sufficient interfacial active functional groups while avoiding adsorption sites for other surfactants. Collaborative efforts between DPD simulation and macroscopic measurements deepen the understanding of how demulsifiers can improve oil–water separation efficiency in emulsion treatment. [ABSTRACT FROM AUTHOR]

In bio‐medical field, one of the most challenging hurdles connected with development of therapeutics is the efficient transport and delivery of drugs to the infected cells of human body. Supramolecular chemistry provides innovative designs for effective biological applications such as drug and gene delivery. In various applications of supramolecular chemistry, macrocyclic molecules such as calixarenes, cyclodextrins, cucurbiturils, and pillar arenes serve as ideal hosts that can bind guest molecules based on the electron density and size of their cavities. This review focuses on the recent advancements in major supramolecular systems such as calixarenes (CA), curcurbiturils (CB), cyclodextrins (CD) and pillar[n] arenes (PAs). Owing to their non‐covalent interactions and adaptive capability, these supramolecular‐based nucleic acid delivery systems provide customized treatment options in cancer therapy. These supramolecular carriers are distinct due to their capacity to functionalize and alter their structure in accordance with the required application. The use of such amphiphilic macromolecules as a carrier for gene transfection have been thoroughly investigated leading to advancements in therapeutic research. The aim of this review is to highlight and showcase the endeavours of utilising supramolecular systems in drug/nucleic acid delivery. [ABSTRACT FROM AUTHOR]

Atherosclerosis, an inflammatory lipid-rich plaque disease is perpetuated by the unregulated scavenger-receptor-mediated uptake of oxidized lipoproteins (oxLDL) in macrophages. Current treatments lack the ability to directly inhibit oxLDL accumulation and foam cell conversion within diseased arteries. In this work, we harness nanotechnology to design and fabricate a new class of nanoparticles (NPs) based on hydrophobic mucic acid cores and amphiphilic shells with the ability to inhibit the uncontrolled uptake of modified lipids in human macrophages. Our results indicate that tailored NP core and shell formulations repress oxLDL internalization via dual complementary mechanisms. Specifically, the most atheroprotective molecules in the NP cores competitively reduced NP-mediated uptake to scavenger receptor A (SRA) and also down-regulated the surface expression of SRA and CD36. Thus, nanoparticles can be designed to switch activated, lipid-scavenging macrophages to antiatherogenic phenotypes, which could be the basis for future antiatherosclerotic therapeutics.

Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties.

Stimuli-responsive nano-assemblies from amphiphilic macromolecules could undergo controlled structural transformations and generate diverse macroscopic phenomenon under stimuli. Due to the controllable responsiveness, they have been applied for broad material and biomedical applications, such as biologics delivery, sensing, imaging, and catalysis. Understanding the mechanisms of the assembly-disassembly processes and structural determinants behind the responsive properties is fundamentally important for designing the next generation of nano-assemblies with programmable responsiveness. In this review, we focus on structural determinants of assemblies from amphiphilic macromolecules and their macromolecular level alterations under stimuli, such as the disruption of hydrophilic-lipophilic balance (HLB), depolymerization, decrosslinking, and changes of molecular packing in assemblies, which eventually lead to a series of macroscopic phenomenon for practical purposes. Applications of stimuli-responsive nano-assemblies in delivery, sensing and imaging were also summarized based on their structural features. We expect this review could provide readers an overview of the structural considerations in the design and applications of nano-assemblies and incentivize more explorations in stimuli-responsive soft matters. [Display omitted] [ABSTRACT FROM AUTHOR]

A series of novel amphiphilic macromolecules composed of alkyl chains as the hydrophobic block and poly(ethylene glycol) as the hydrophilic block were designed to inhibit highly oxidized low density lipoprotein (hoxLDL) uptake by synthesizing macromolecules with negatively charged moieties (ie, carboxylic acids) located in the two different blocks. The macromolecules have molecular weights around 5,500 g/mol, form micelles in aqueous solution with an average size of 20-35 nm, and display critical micelle concentration values as low as 10(-7) M. Their charge densities and hydrodynamic size in physiological buffer solutions correlated with the hydrophobic/ hydrophilic block location and quantity of the carboxylate groups. Generally, carboxylate groups located in the hydrophobic block destabilize micelle formation more than carboxylate groups in the hydrophilic block. Although all amphiphilic macromolecules inhibited unregulated uptake of hoxLDL by macrophages, inhibition efficiency was influenced by the quantity and location of the negatively charged-carboxylate on the macromolecules. Notably, negative charge is not the sole factor in reducing hoxLDL uptake. The combination of smaller size, micellar stability and charge density is critical for inhibiting hoxLDL uptake by macrophages.

The domain structuring in concentrated mixtures of amphiphilic macromolecules with a different stiffness of backbone has been discovered and studied by means of molecular dynamics simulation. The macromolecules were composed of identical amphiphilic H -graft- P monomer units. In flexible macromolecules, the H -graft- P units are connected freely, whereas the stiff macromolecules have limitations imposed on torsion and bending angles and carry local helical structure. In solvent which is poor for the backbone, stiff macromolecules form filament clusters from few intertwined helical chains. The filaments can be aligned along each other sharing a common director or form a few liquid-crystalline domains oriented randomly with respect to each other. It was shown that increase of fraction of helical macromolecules leads to decrease of order parameter and its high variation over different samples due to the increase of length and polydispersity of persistent filaments. [ABSTRACT FROM AUTHOR]

In this work, pH-sensitive amphiphilic macromolecules are designed to possess good biocompatibility and drug loading while employing an acid-sensitive linkage to trigger drug release at tumor tissues. Specifically, two pH-sensitive amphiphilic macromolecules were synthesized with a hydrazone linkage between the hydrophobic and hydrophilic segments. The chemical structure, molecular weight, critical micelle concentration, micelle size, and pH-triggered cleavage of the amphiphilic macromolecules were characterized via matrix-assisted laser desorption/ionization time-of-flight, nuclear magnetic resonance, and dynamic light scattering techniques. Drug loading and release as well as cytotoxicity studies were performed using doxorubicin. Hydrodynamic diameters of the micelles formed with pH-sensitive amphiphilic macromolecules were within an optimal range for cellular uptake. The critical micelle concentration values were 10–8–10–6 M, indicating micellar stability upon dilution. The degradation products of the amphiphilic macromolecules after acidic incubation were identified using mass spectrometry, nuclear magnetic resonance, and dynamic light scattering methods. A pH-dependent release profile of the doxorubicin-encapsulated amphiphilic macromolecules was observed. Cytotoxicity studies against two cancer cell lines, MDA-MB-231 human breast cancer cells and A549 lung cancer cells, showed that doxorubicin encapsulated in pH-sensitive amphiphilic macromolecules decreased cell viability more efficiently than free doxorubicin, possibly due to the toxicity of the amphiphilic macromolecule degradation products. Resulting from enhanced release at acidic pH due to hydrolysis of the hydrazone linkage, pH-sensitive amphiphilic macromolecules also had improved efficacy toward cancer cells compared to other carriers (e.g. Pluronics®). These findings indicate that pH-sensitive amphiphilic macromolecules can potentially be applied as anticancer drug delivery vehicles to achieve controlled release and improved therapeutic effects. [ABSTRACT FROM AUTHOR]

Amphiphilic macromolecules, possessing sugar-based hydrophobic and poly(ethylene glycol) hydrophilic domains, provide tunable structures that form effective polymeric micellar drug delivery systems. In this work, we compare traditional dynamic micelles and covalently bound unimolecular amphiphilic macromolecule micelles to study the effects of amphiphilic macromolecule hydrophobic domain branching, micelle architecture, and hydrodynamic volume of two drugs (triclosan and suloctidil) to elucidate the micellar structure–property relationships that govern drug loading and release kinetics. Overall, more hydrophobic micelles with either longer amphiphilic macromolecule alkyl side chains or a higher degree of hydrophobic domain branching exhibited increased triclosan loading compared to less hydrophobic micelles with smaller amphiphilic macromolecule hydrophobic domains. However, varying levels of micelle hydrophobicity did not significantly change suloctidil loading, where only minimal loading differences were seen between micelles with highly hydrophobic and less hydrophobic domains. In both dynamic and unimolecular micelles, the loading extent was primarily drug volume-dependent, where the smaller triclosan molecules demonstrated increased loading and sustained release compared to the larger suloctidil molecules. Unimolecular micelles followed a similar trend with generally higher loading capacities compared to dynamic micelles. Release characteristics for both amphiphilic macromolecule micelle types demonstrated little correlation to the amphiphilic macromolecule chemistry or micelle architecture and were instead primarily drug-dependent, with suloctidil- and triclosan-loaded micelles following the Korsmeyer–Peppas and Weibull models, respectively. The micelle structure–property relationships identified herein allow for improved drug–micelle compatibility to optimize drug delivery systems for poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • The pore channel was successfully reconstructed by the confined-region swelling. • The high-flux membrane with excellent hydrophilicity and mechanical strength was achieved. • The high-flux membrane has small pore size and narrow pore size distribution. Herein, a novel strategy to reconstruct the pore channels of crystalline polymer porous membrane is reported. The method is based on the property that molecular chains in amorphous regions of the crystalline polymer are in the high elasticity form, and the swelling of amphiphilic macromolecules used to reconstruct the pore channel in the amorphous region of membrane. The hydrophilic polyvinylidene fluoride (PVDF)/PVDF-graft-poly (ethylene glycol) methyl ether methacrylate (PVDF-g-PEGMA) blended membrane was prepared. Then the reconstruction of membrane pore channel is based on that the PVDF chains in the amorphous regions are in the high elasticity form and the swelling property of PEGMA chains. After the reconstruction of membrane pore channel, the pore size decreased from 164.2 to 73.5 nm and the membrane flux increased from 670 to 1298 L·m−2·h−1. This strategy of membrane pore channel reconstruction can not only improve the membrane hydrophilicity and flux, but also avoid the adverse influence accompanied by conventional methods on the pore size and mechanical strength, which is an innovative and effective method to prepare the antifouling and high-flux porous membrane. [ABSTRACT FROM AUTHOR]

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Abstract: This study reports on the preparation and evaluation of amphiphilic macromolecules based on branched polyethylene glycol covalently linked with alkyl hydrocarbon chains. These macromolecules easily dissolved in an aqueous environment, with formation of micellar nanoaggregates endowed with hydrophobic inner cores capable of hosting fenretinide by complexation. The complexes increased fenretinide aqueous solubility, while hindering its release as a free drug in an aqueous environment. Particle size analysis indicated dimensional suitability of the complexes for intravenous administration. Neuroblastoma cell lines (SH-SY5Y and NGP) exhibited increased sensitivity to fenretinide in complex as compared to free drug, associated with higher intracellular concentrations of fenretinide observed after treatment with the complex. Transmission electronic microscopy images revealed endocytosis of the micellar complex. Moreover, fenretinide conversion to its metabolite 4-oxo-fenretinide was delayed in cells treated with the complex, further supporting the hypothesis that fenretinide may be absorbed by micellar transport and exposed to the cytoplasm for conversion to its metabolite only after micelle destabilization. From the Clinical Editor: Glioblastoma remains one of the most notoriously treatment-unresponsive brain cancer, and is clearly the most common such primary malignancy. This team of authors describe novel micelles based on amphiphilic branched PEG as carriers for fenretinide, and demonstrate their enhanced anti-tumor cell efficacy in cell cultures. [Copyright &y& Elsevier]

Abstract: Amphiphilic macromolecules (AM) were electrostatically complexed with a 1:1 ratio of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) to form AM–lipid complexes with drug delivery applications. The complexes exist as AM-coated liposomes and their drug delivery properties can be tuned by altering the AM–lipid weight ratio. The complexation and tuning are achieved in a simple, efficient, and scalable manner. The gradual increase in lipid ratios concurrently increased the zeta potential of the complexes, which directly correlates to increased cell uptake of the complexes in vitro with preferential uptake noted in BT-20 carcinoma cells versus normal fibroblasts. Increasing AM content increased complex steric stability in the presence of serum proteins and reduced the inherent cytotoxicity towards fibroblasts in vitro. AM–lipid complexes solubilized paclitaxel and showed drug-mediated, dose-dependent cytotoxicity towards target BT-20 cells in vitro. AM–lipid complexes make good candidates as drug delivery systems due to their tunable zeta potential, steric stability, inherently low cytotoxicity, and ability to load and deliver insoluble chemotherapeutic agents. Significantly, their preferential uptake in a carcinoma cell line over normal cells in vitro demonstrates a unique, passive targeting approach to delivery anti-cancer therapeutics. [Copyright &y& Elsevier]

Amphiphilic star-like macromolecules and amphiphilic scorpionlike macromolecules are polymeric micelles capable of water-solubilizing hydrophobic molecules for intravenous injection. In this work, four different amphiphilic macromolecules (M12P5, M6P5, NC12P5, NC6P5) were evaluated using human primary cell lines of the vasculature: human umbilical endothelial cells (HUVEC), umbilical arterial smooth muscle cells (UASM), and normal dermal human fibroblasts (NDHF). The three primary cell types were incubated with culture media containing amphiphilic macromolecules at five concentrations ranging from 10-3M to 10-7M at 24, 48, and 72 h. All cell types treated with both amphiphilic macromolecules showed similar cell viability compared to the vehicle control at all concentrations, except at 10-3 M, which showed a substantially lower cell viability. Cells treated with amphiphilic macromolecules also exhibited similar characteristic cell morphologies at all concentrations, except for 10-3 M, which showed distressed cells. The initial screening of amphiphilic macromolecules against primary human cells associated with the vasculature exhibited good biocompatibility. [ABSTRACT FROM AUTHOR]

Abstract: Two classes of amphiphilic macromolecules were evaluated for drug delivery applications: those that exist as unimolecular micelles and those that self-assemble in aqueous solution to form micelles. This study compares the poly(ethylene glycol) (PEG) chain length and density that constitute the corona of both classes. In particular, the effect of PEG branching on micellar size, water-solubility, resolubilization rate, drug loading efficiency and drug release rate were analyzed. Pluronic P85 and Cremophor EL, commonly used in pharmaceutical applications, were used as controls. Indomethacin (IMC) was used as the drug for encapsulation, release and resolubilization experiments. Results indicated that smaller micellar sizes, higher water solubilities and faster resolubilization rates were achieved from higher PEG densities compared to linear PEG analog of similar mass. Further, micellar sizes of both higher density PEG and linear PEG macromolecules were constant over a wide temperature range (2–70°C). In contrast, Cremophor EL formed aggregates at 15°C and Pluronic P85 underwent a size transition at 45°C. IMC loading efficiencies for all amphiphilic macromolecules were comparable to controls. However, faster resolubilization and slower drug release were observed for higher density PEG macromolecules compared to linear PEG analogs and controls. [Copyright &y& Elsevier]

Amphiphilic scorpion-like macromolecules (AScMs), that self-assemble as nanocarriers, were evaluated for intracellular delivery. To qualitatively examine the intracellular fate of AScMs in human umbilical vein endothelial cells (HUVECs), representative polymers (M12P5) were labeled with a fluorescent dye, fluorescein isothiocyanate (FITC). The FITC-labeled M12P5 micelles were prepared by mixing a low concentration of FITC-labeled M12P5 polymer (10 wt%) with unlabeled M12P5 polymer (90 wt%). Optical sectioning by confocal laser scanning microscopy of HUVECs incubated with FITC-labeled polymer micelles revealed that the polymers were localized in subcellular components within 60 min. Transmission electron microscopy was used to highlight the rapid accumulation of a polymer-encapsulated agent in the nucleus by 60 min. This study demonstrated that the M12P5 polymers were internalized into HUVECs. Based on these data, the polymeric nanocarriers are potential candidates for intracytoplasmic and nuclear delivery of drugs, proteins and/or genes. [ABSTRACT FROM AUTHOR]

Abstract: Amphiphilic macromolecules, known as amphipols, have emerged as promising candidates to replace conventional detergents for handling integral membrane proteins in water due to the enhanced stability of protein/amphipol complexes as compared to protein/detergent complexes. The limited portfolio of amphipols currently available prompted us to develop amphipols bearing phosphorylcholine-based units (PC). Unlike carboxylated polymers, PC-amphipols remain soluble in aqueous media under conditions of low pH, high salt concentration, or in the presence of divalent ions. The solubilizing properties of four PC-amphipols were assessed in the case of two membrane proteins, cytochrome b 6 f and bacteriorhodopsin. The protein/PC-amphipol complexes had a low dispersity in size, as determined by rate zonal ultracentrifugation. Short PC-amphipols (≈22 kDa) of low dispersity in length, containing ∼30 mol% octyl side groups, ∼35 mol% PC-groups, and ∼35 mol% isopropyl side groups, appeared best suited to form stable complexes, preserving the native state of BR over periods of several days. BR/PC-amphipol complexes remained soluble in aqueous media at pH≥5, as well as in the presence of 1 M NaCl or 12 mM calcium ions. Results from isothermal titration calorimetry indicated that the energetics of the conversion of BR/detergent complexes into BR/amphipol complexes are similar for PC-amphipols and carboxylated amphiphols. [Copyright &y& Elsevier]

Amphiphilic star-like macromolecules (ASMs) with chain ends terminating as ethoxy-, carboxy- and amine groups were synthesized for use as drug solubilization and delivery systems. Hydrophobic mucic acid derivatives were conjugated to the pentaerythritol tetraacrylate as the core molecule, then poly(ethylene glycol) chains with specific functionalized chain ends were attached. With respect to size in solution, the ASMs with longer alkyl chains (C12) in the core were slightly larger than polymers with shorter alkyl chains (C6), and the carboxy-terminated ASMs displayed slightly larger sizes than the methoxy- and amine-terminated polymers. In aqueous solution, the ASMs maintained their nanosize, ranging from 20 to 40nm in diameter in solutions with pH values of 2, 7.4 and 9. The shorter C6 chain polymers displayed sizes that were independent of pH, whereas the longer chain polymers displayed a more pronounced response to pH changes. With respect to thermal properties, ASMs with larger hydrophobic cores had slightly lowered melting and crystallization temperatures. The methoxy-terminated ASMs have higher melting and crystallization temperatures (by ∼8°C) than the ASMs terminated with carboxy and amine functionalities. [ABSTRACT FROM AUTHOR]

Abstract: A series of amphiphilic macromolecules, amphiphilic scorpion-like macromolecules (AScMs) and amphiphilic star-like macromolecules (ASMs), were evaluated as potential drug delivery systems for intravenous administration. AScMs aggregate to form polymeric micelles; whereas the ASMs have a covalently bound core structure and behave as unimolecular micelles. Four structurally different AScMs and two ASMs were selected for further evaluation focusing on micellar stability and biocompatibility. AScMs were determined to have extremely low cmc values, indicating excellent thermodynamic stability compared to other polymeric micelle systems. Particle sizes of the AScM polymeric micelles and ASM unimolecular micelles were between 10 and 20 nm, and remained constant for up to 3 weeks storages as aqueous solutions at room temperature (∼23 °C) and 37 °C. The dissociation kinetics of the AScM polymeric micelles were slowed relative to small molecule surfactant micelles, again indicating enhanced kinetic stability. With respect to hemolytic activity, AScMs with longer acyl chains were hemolytic; whereas the ASMs had minimal hemolytic activity due to the covalently bound structure. Both ASM unimolecular micelles and AScM polymeric micelles have excellent micellar stability, but the ASMs are more suitable as injectable drug delivery systems due to their low hemolytic activity. [Copyright &y& Elsevier]

Abstract: Synthetically designed anionic nanocarriers that mimic the charge properties of glycosaminoglycans can potentially sequester low-density lipoproteins (LDL) during the treatment of atherosclerosis. In this study, we explore the LDL retentivity of 15–20nm anionic micelles formed from amphiphilic scorpion-like macromolecules (AScMs) as building blocks. The macromolecules comprise four aliphatic chains attached to mucic acid and a linear polyethylene glycol (PEG) segment to form micellar nanocarriers with a hydrophobic core and hydrophilic corona. Dynamic light scattering and transmission electron microscopy studies indicate that the carboxylate-terminated nanocarriers (20nm) sequester LDL (22nm), resulting in complexes with a diameter of 60–90nm, but neutral ethoxy-terminated nanocarriers do not retain LDL. Further, carboxylate-terminated nanocarriers consistently bound to unoxidized LDL (Relative Electrophoretic Mobility, REM=1.0) and mildly oxidized LDL (REM=1.5), but not highly oxidized LDL (REM=3.6), whereas the neutral nanocarriers displayed no preference/affinity at all, indicating that the nanocarrier-LDL binding is charge-dependent. The binding affinity of unoxidized LDL for differentially charged nanocarriers, formed from varying ratios of carboxylate- and ethoxy-terminated macromolecules, was quantified. The 100% carboxylated nanocarriers elicited the highest binding affinity (Kd=567nm), whereas mixed micelles elicited significantly lower levels of binding affinity. Our results highlight the promise of synthetically designed nanomaterials in lipoprotein retention, a key step in managing the escalation of atherosclerosis. [Copyright &y& Elsevier]