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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]

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]