Amphiphilic Random Copolymers Research Articles

Amphiphilic block and random copolymers: aggregation and hydrophobic modification on metal-free tanned collagen fibers

Hydrophobicity enhancement of metal-free leather, which is crucial for improving its comprehensive performance, can be achieved by using amphiphilic copolymer retanning agents. However, the relationship between the sequential structure and the hydrophobic modification effect of amphiphilic copolymers remains unclear. Herein, an amphiphilic block copolymer was synthesized using stearyl methacrylate and 2-(dimethylamino)ethyl methacrylate via atom transfer radical polymerization, and the corresponding random copolymer with similar monomer compositions and molecular weights was prepared for comparison. The aggregation behavior of block and random copolymers was investigated. DLS and TEM results indicate that the block copolymer exhibits a larger aggregate size than the corresponding random copolymer. Molecular dynamics simulations suggest that the block copolymer aggregate exhibit a thicker hydrophilic shell and more concentrated distribution of cationic DMA block than the random copolymer aggregate. Subsequently, the block and random copolymers were used for the hydrophobic modification of metal-free tanned collagen fibers (CFs). The block copolymer shows superior binding capacity to CFs than the random one because of its larger size and more concentrated charge distribution. Hence, the block copolymer can form a dense and uniform hydrophobic film on the surface of collagen fibrils and endow CFs with higher hydrophobicity than the random one. This work provides theoretical guidance for modulating the hydrophobicity of CFs by tailoring the sequential structure of amphiphilic copolymers, which is expected to inspire the manufacturing of high-performance metal-free leather.Graphical

Alternating vs. random amphiphilic polydisulfides: aggregation, enzyme activity inhibition and redox-responsive guest release.

Herein, we report the synthesis of an alternating copolymer (ACP) with a bio-reducible amphiphilic polydisulfide backbone and highlight the impact of the alternating monomer connectivity on the self-assembly, morphology, chain-exchange dynamics, drug-release kinetics, and enzyme activity inhibition. Condensation polymerization between hydrophobic 1,10-bis(pyridin-2-yldisulfaneyl)decane and hydrophilic 2,3-mercaptosuccinic acid (1.04 : 1.00 ratio) generated amphiphilic ACP P1 (Mw = 8450 g mol-1, Đ = 1.3), which exhibited self-assembly in water, leading to the formation of an ultra-thin (height <5.0 nm) entangled fibrillar network. In contrast, structurally similar amphiphilic random copolymer P2 exhibited a truncated irregular disc-like morphology under the same conditions. It is postulated that due to the perfect alternating sequence of the hydrophobic and hydrophilic segments in P1, its immiscibility-driven aggregation in water leads to a pleated structure, which further assembles and forms the observed long fibrillar structures, similar to crystallization-driven self-assembly. In fact, wide-angle X-ray diffraction (WXRD) analysis of a lyophilized P1 sample showed sharp peaks, indicating its crystalline nature (approximately 37% crystallinity), and these were completely missing for P2. The effect of such distinct self-assembly on the chain-exchange dynamics was probed by fluorescence resonance energy transfer (FRET) using 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) as the FRET-donor and -acceptor, respectively. For DiI- and DiO-entrapped solutions of P1, when mixed, no prominent FRET appeared even after 24 h. In sharp contrast, for P2, intense FRET emission occurred, and the FRET ratio (approximately 0.9) reached saturation in approximately 15 h, indicating the greatly enhanced kinetic stability of P1 aggregates. Glutathione-induced release of encapsulated Nile red showed much slower kinetics for P1 compared to that of P2, which was corroborated by the observed slow chain-exchange dynamics of the highly stable alternating copolymer assembly. Furthermore, the well-ordered assembly of P1 exhibited an excellent surface-functional group display (zeta potential of -32 mV compared to -14 mV for P2), which resulted in the effective recognition of the α-chymotrypsin (Cht) protein surface by electrostatic interaction. Consequently, P1 significantly (>70%) suppressed the enzymatic activity of Cht, while in the presence of P2, the enzyme was still active with >70% efficacy.

Poly(oxyethylene)/Poly(oxypropylene) butyl ether prolongs the repellent effect of N,N-diethyl-3-toluamide on the skin.

N,N-diethyl-meta-toluamide (DEET) is a widely used insect repellent, with minimal skin permeation and sustained repellent activity in the superficial layers of the skin. In this study, we prepared a 10% DEET formulation consisting of 40% ethanol with or without 2% poly(oxyethylene)/poly(oxypropylene) butyl ether (POE-POP), an amphiphilic random copolymer. Further, we demonstrated the effects of POE-POP on tensile stress (stickiness), hydrophobicity, skin retention, permeation, and repellent activity of DEET. Stickiness was measured in male ICR mice (7-week old), and skin retention and permeation were evaluated in male Wistar rats (7-week old). In addition, female Aedes albopictus were used to measure the repellent action of DEET. The addition of POE-POP did not affect stickiness, volatility, and degradability but decreased logP and increased viscosity of DEET. Next, we demonstrated the behavior of DEET formulations in the rat skin. POE-POP prolonged the retention of DEET in the superficial layers of the rat skin (skin surface and stratum corneum) and decreased the penetration of DEET into rat skin tissues (epithelium and dermis). The repellent effect of DEET was also enhanced by the addition of POE-POP. However, severe skin damage was not observed after repetitive treatment with DEET formulations containing POE-POP for one month (twice a day). In conclusion, we demonstrated that a 10% DEET formulation consisting of 40% ethanol and 2% POE-POP attenuated the skin penetration and prolonged the repellent action of DEET without causing stickiness and skin damage. We conclude that the combination of ethanol and POE-POP is useful as a safe and effective delivery system for the development of insect repellent formulations containing DEET.

Enhanced permeability and antifouling properties of polyvinylidene fluoride ultrafiltration membrane with hydrophilic P(AMPS‐co‐MMA) copolymer

AbstractIn this research, a new amphiphilic random copolymer of 2‐acrylamido‐2‐methylpropane sulfonic acid (AMPS) and methyl methacrylate (MMA) (abbreviated as P(AMPS‐co‐MMA)) was synthesized by solution free radical copolymerization method, and was introduced into hydrophobic polyvinylidene fluoride (PVDF) membrane via nonsolvent induced phase separation (NIPS) process without adding pore‐forming agent to enhance the permeability and antifouling properties of PVDF ultrafiltration membrane. The FT‐NMR spectroscopy confirmed the chemical structure of P(AMPS‐co‐MMA) and copolymerization of AMPS and MMA, the effects of P(AMPS‐co‐MMA) on membrane surface chemical compositions, morphology, roughness, charge, hydrophilicity, permeability and antifouling properties were characterized in‐detail. The results indicate that the PVDF/P(AMPS‐co‐MMA) composite membranes demonstrated excellent permeability, improved antifouling property and long‐term stability due to the optimized membrane microstructure, stronger hydrophilicity and endowed negative charge. The PVDF composite membrane blended with 1.5 wt% P(AMPS‐co‐MMA) showed the best membrane performances, the pure water flux was 286.5 L·m−2·h−1 while the BSA rejection was as high as 98%, and the flux recovery ratio (FRR) and reversible fouling ratio to the total fouling ratio (Rr/Rt) reached 94.8% and 87% respectively, which outpaced ever reported and commercial PVDF membranes. Therefore, P(AMPS‐co‐MMA) copolymer was expected to be a potential excellent pore‐forming material in fabricating high‐performance membranes.

Dynamic Exchange of Amphiphilic Random Copolymers between Micelles in Water: Kinetics and Mechanism Analyzed by TR-SANS

Amphiphilic random copolymers bearing poly(ethylene glycol) (PEG) and alkyl groups as side chains are intermolecularly self-assembled into size-controlled multichain micelles in water. The random copolymer micelles are known to induce the exchange of their polymer chains, whereas the details of the kinetics and mechanism have not been elucidated yet. Herein, we investigated the exchange kinetics and mechanism of the random copolymer chains between their micelles by time-resolved small-angle neutron scattering (TR-SANS). For this purpose, random copolymers carrying PEG and deuterated butyl or dodecyl groups were designed for deuterated micelles. After mixing deuterated and non-deuterated micelle solutions, the resulting mixtures were monitored by TR-SANS at various concentrations and temperatures. The scattering intensity of the micelle mixtures decayed with time, indicating that deuterated copolymers were gradually mixed with non-deuterated copolymers via chain exchange between their micelles to form micelles consisting of both deuterated and non-deuterated copolymers. The kinetic analysis revealed that the exchange of their polymer chains involved two mechanisms: A unimer release and insertion pathway was dominant in diluted conditions, whereas the contribution of a micelle collision pathway increased with increasing total polymer concentration and temperature. The activation energy of the polymer exchange process was dependent on the hydrophobic alkyl groups and larger than that of a related surfactant micelle.

Surface encapsulating UV filters based on self-assembly of an amphiphilic random copolymer by miniemulsion polymerization

A nanoparticles encapsulating UV filters were prepared by miniemulsion polymerization, in which methyl methacrylate (MMA) as the monomer, and ethylene glycol dimethacrylate (EGDMA) as the cross-linker. Scanning electron microscopy (SEM) and X-ray photoelectron spectrometry (XPS) confirmed that the amphiphilic random copolymers poly (styrene-co-methacrylic acid) P(St-co-MAA) not only acted as the stabilizer but also self-assembled on the surface of the P(MMA-EGDMA) polymers. During the miniemulsion polymerization, most UV filters were encapsulated in the P(St-co-MAA) self-assembly aggregates on the surface of nanoparticles, giving the nanoparticles a raspberry-like structure. As the mass ratio of P(St-co-MAA) to MMA and EGDMA at 1.0, the encapsulation efficiency of UV filters was 69.85%, whereas 70.7% of UV filters were located in the P(St-co-MAA) self-assembly layer. The leakage of UV filters from the raspberry-like nanoparticles was negligible after continuous stirring in isopropyl myristate (IPM) for 24 h. The sun protection factor (SPF) and UVA Protection Factor (UVAPF) value of sunscreen formulation incorporated with the raspberry-like nanoparticles could reach 58.8 and 6.82, respectively. It enhanced UV protection more efficiently than the nanoparticles with a smooth surface.

Self-Aggregation in Aqueous Media of Amphiphilic Diblock and Random Block Copolymers Composed of Monomers with Long Side Chains.

Amphiphilic diblock copolymers and hydrophobically modified random block copolymers can self-assemble into different structures in a selective solvent. The formed structures depend on the copolymer properties, such as the ratio between the hydrophilic and the hydrophobic segments and their nature. In this work, we characterize by cryogenic transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS) the amphiphilic copolymers poly(2-dimethylamino ethyl methacrylate)-b-poly(lauryl methacrylate) (PDMAEMA-b-PLMA) and their quaternized derivatives QPDMAEMA-b-PLMA at different ratios between the hydrophilic and the hydrophobic segments. We present the various structures formed by these copolymers, including spherical and cylindrical micelles, as well as unilamellar and multilamellar vesicles. We also examined by these methods the random diblock copolymers poly(2-(dimethylamino) ethyl methacrylate)-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (P(DMAEMA-co-Q6/12DMAEMA)-b-POEGMA), which are partially hydrophobically modified by iodohexane (Q6) or iodododecane (Q12). The polymers with a small POEGMA block did not form any specific nanostructure, while a polymer with a larger POEGMA block formed spherical and cylindrical micelles. This nanostructural characterization could lead to the efficient design and use of these polymers as carriers of hydrophobic or hydrophilic compounds for biomedical applications.

Micelle‐crosslinked hydrogels with stretchable, self‐healing, and selectively adhesive properties: Random copolymers work as dynamic yet self‐sorting domains

AbstractThe design of crosslinking domains is a vital factor to create functional hydrogels with controlled physical, mechanical, and adhesive properties. This paper demonstrates versatile synthetic systems of micelle‐crosslinked hydrogels with highly stretchable, self‐healing, and selectively adhesive properties. For this, methacrylate‐bearing random copolymer micelles are designed as physical and covalent crosslink domains via the self‐assembly of amphiphilic random copolymers carrying hydrophilic poly(ethylene glycol) (PEG), hydrophobic butyl or dodecyl groups, and methacrylate‐terminal PEG in water. The size, aggregation number, and pendant methacrylate number of the micelles are controlled by the composition and degree of polymerization. Hydrogels are efficiently obtained from the free radical polymerization of hydrophilic monomers such as PEG acrylate and acrylamide in the presence of the micelle crosslinkers in water. Owing to the dynamic yet selective chain exchange properties of the micelle domains, the hydrogels are highly stretchable up to over 1000% and show self‐healing and selectively adhesive properties. The self‐healing of hydrogels is promoted upon heating due to the fast chain exchange of the micelle domains, whereas hydrogels consisting of micelles with different alkyl groups are never adhesive because of their self‐sorting properties.

Assembled Morphology of Copper-Thiourea Coordination-Mediated Metallo-Supramolecular Polymers.

Metallo-supramolecular polymers represent a powerful platform to construct self-assembled morphologies. Copper-thiourea (Cu-TU) coordination interactions, though have been extensively studied in small molecular system, the role of TU motifs in synthetic polymers using metal-ligand coordination to afford supramolecular aggregation and their morphology are often overlooked. Herein, an amphiphilic random copolymer, poly(oligo(ethylene glycol) ethyl acrylate-r-acylthiourea) (P(OEGEA-r-ATU)), bearing pendant TU motifs behaving as the ligand to coordinate Cu, a design characterized by core-coordinated metallo-supramolecular polymer is rationally synthesized. Indeed, rod-like nano-objects are successfully generated via the self-assembly and coordination interaction between P(OEGEA-r-ATU) and Cu.The spatial distribution of TU moieties in polymer chain, along with their Cu chelating capability, featuring the interchain coordination interaction, is tightly related to metallo-supramolecular polymer organization. The specific Cu-TU coordination interactions enable the prompted robustness and stability of soft P(OEGEA-r-ATU), induce the polymer chain configuration, which eventually furnish efficient fabrication of rod-like nano-objects via straightforward nanoprecipitation procedure. These structural motifs of copper-coordinated, rod-like nano-objects from such metallo-supramolecular polymers endow the potential therapeutic properties, such as anti-inflammatory and antitumor effects.

Toughening of epoxy thermosets by self-assembled nanostructures of amphiphilic comb-like random copolymers.

Amphiphilic comb-like random copolymers synthesized from poly(ethylene glycol) methyl ether methacrylate (PEGMMA) and stearyl methacrylate (SMA) with PEGMMA contents ranging between 30 wt% and 25 wt% were demonstrated to self-assemble into various well-defined nanostructures, including spherical micelles, wormlike micelles, and vesicle-like nanodomains, in anhydride-cured epoxy thermosets. In addition, the polymer blends of the comb-like random copolymer and poly(stearyl methacrylate) were prepared and incorporated into epoxy thermosets to form irregularly shaped nanodomains. Our research findings indicate that both the comb-like random copolymers and polymer blends are suitable as toughening modifiers for epoxy. When added at a concentration of 5 wt%, both types of modifiers lead to substantial improvements in the tensile toughness (>289%) and fracture toughness of epoxy thermosets, with minor reductions in their elastic modulus (<16%) and glass transition temperature (<6.1 °C). The fracture toughness evaluated in terms of the critical stress intensity factor (KIC) and the strain energy release rate (GIC) increased by more than 67% and 131% for the modified epoxy thermosets containing comb-like random copolymers.

Amphiphilic random copolymers bearing linear poly(oxyethylene) side chains and lateral dendritic wedges: Synthesis and their emulsifying performances

In this study, we demonstrated nonaqueous macroemulsions stabilized by amphiphilic random copolymers exhibiting linear poly(oxyethylene) side chains and two-generation dendritic wedges along their backbones, which were synthesized by traditional radical random copolymerization of oligo (ethylene glycol) methyl ether methacrylate (POEGMA) with 2-methyl-2-((2-(4-methyl-1H-1,2,3-triazol-1-yl) ethoxy) carbonyl) propane-1,3-diylbis(2,2,5-trimethyl-1,3-dioxane-5-carboxylate)) methacrylate (MPDMA) in THF using AIBN as initiators. PPOEGMA-ran-PMPDMA copolymers containing different molar fractions of MPDMA monomer unit ranging from 0.28 to 0.65 were achieved through the adjustment of the feed ratio of monomer pairs during the copolymerization. Interfacial tension experiments revealed the critical micelle concentrations of PPOEGMA-ran-PMPDMA copolymers decreased with the increase of the contents of MPDMA monomer unit in copolymer chains. [Bmim][PF6]-in-toluene emulsions were subsequently prepared using amphiphilic PPOEGMA-ran-PMPDMA copolymers as macromolecular emulsifiers. The average size of the emulsion droplets showed an increasing tendency with the increase of the contents of MPDMA monomer unit in random copolymer chains. Under the otherwise identical conditions, the emulsifying performances of PPOEGMA-ran-PMPDMA copolymers were better than those of PPOEGMA-b-PMPDMA diblock copolymer counterparts judging from the size of the emulsion droplets and the stability of the emulsions.

Amphiphilic Copolymer-Lipid Chimeric Nanosystems as DNA Vectors.

Lipid-polymer chimeric (hybrid) nanosystems are promising platforms for the design of effective gene delivery vectors. In this regard, we developed DNA nanocarriers comprised of a novel poly[(stearyl methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate] [P(SMA-co-OEGMA)] amphiphilic random copolymer, the cationic 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP), and the zwitterionic L-α-phosphatidylcholine, hydrogenated soybean (soy) (HSPC) lipids. Chimeric HSPC:DOTAP:P[(SMA-co-OEGMA)] nanosystems, and pure lipid nanosystems as reference, were prepared in several molar ratios of the components. The colloidal dispersions obtained presented well-defined physicochemical characteristics and were further utilized for the formation of lipoplexes with a model DNA of linear topology containing 113 base pairs. Nanosized complexes were formed through the electrostatic interaction of the cationic lipid and phosphate groups of DNA, as observed by dynamic, static, and electrophoretic light scattering techniques. Ultraviolet-visible (UV-Vis) and fluorescence spectroscopy disclosed the strong binding affinity of the chimeric and also the pure lipid nanosystems to DNA. Colloidally stable chimeric/lipid complexes were formed, whose physicochemical characteristics depend on the N/P ratio and on the molar ratio of the building components. Cryogenic transmission electron microscopy (Cryo-TEM) revealed the formation of nanosystems with vesicular morphology. The results suggest the successful fabrication of these novel chimeric nanosystems with well-defined physicochemical characteristics, which can form stable lipoplexes.

Core-Coordinated Elliptic Polymer Nanoparticles Loading Copper(II) and Chlorambucil for Cooperative Chemodynamic/Chemotherapy.

Chemodynamic therapy (CDT) reflects an innovative cancer treatment modality; however, to enhance its relatively low therapeutic efficiency, rational combination with extra therapeutic modes is highly appreciated. Here, core-coordinated amphiphilic, elliptic polymer nanoparticles (Cu/CBL-POEGEA NPs) are constructed via the self-assembly of a glutathione (GSH)-responsive polymer-drug conjugate, bearing side-chain acylthiourea (ATU) motifs which behave as ligands capable of coordinating Cu(II), such a design is featured by combined chemo (CT)/CDT with dual GSH depletion collectively triggered by the Cu(II) reduction reaction and disulfide bond breakage. To do so, an amphiphilic random copolymer poly[oligo(ethylene glycol)ethyl acrylate-co-thiourea] [P(OEGEA-co-ATU)] is synthesized, followed by conjugation of chlorambucil (CBL) to ATU motifs linked via a disulfide bond, thus yielding the targeted P[OEGEA-co-(ATU-g-CBL)]. In such a system, hydrophilic POEGEA serves as the biocompatible section and ATU motifs coordinate Cu(II), resulting in core-coordinated elliptic Cu/CBL-POEGEA NPs. Benefitting from the GSH-induced reduction reaction, Cu(II) is converted into Cu(I) and subsequently react with endogenous H2O2 to create •OH, realizing GSH-depletion-promoted CDT. Additionally, the disulfide bond endows GSH-responsive CBL release and provokes further GSH decline, finally realizing combined CDT/CT toward enhancing antitumor outcomes, and in vitro as well as in vivo studies indeed reveal remarkable efficacy. Such a system can provide valuable advantages to create novel nanomedicines toward cascade antitumor therapy.

Amphiphilic Polymers for Color Dispersion: Toward Stable and Low-Viscosity Inkjet Ink.

Amphiphilic random and block copolymers were synthesized as potential inkjet inks. This study evaluated the potential of these polymers for color dispersion by examining the following factors: surface tension, zeta potential, viscosity, and particle size. Acrylic acid and (ethoxyethoxy)ethyl acrylate were used as the hydrophilic molecular units. Styrene, butyl acrylate, and phenoxyethyl acrylate were used as hydrophobic units. Color dispersions were prepared by using organic dye and these amphiphilic polymers. The color dispersions containing random copolymers exhibited low viscosity, which is preferable for jetting, but the dye particles tended to sediment after the thermal aging test. In contrast, those containing block copolymers showed high viscosity, which was unsuitable for jetting. However, they retained their initial dispersion state after the aging test. The advantages and disadvantages of each monomer arrangement (random or block) were demonstrated, providing a future outlook on the molecular design of polymer dispersants for color dispersions.

Synthesis and Phase Behavior of a Linear Amphiphilic Multiblock Copolymer.

Linear amphiphilic multiblock copolymer PPMPEs, obtained through a stepwise method, and linear amphiphilic random copolymer PPMPEs-1, obtained through a one-pot method, were synthesized using poly(propylene glycol) diglycidyl ether (PPGDGE), poly(ethylene glycol) diglycidyl ether (PEGDGE), and monoethanolamine (MEA) as the main raw materials. The structures of PPMPEs and PPMPEs-1 were characterized by FT-IR, 1H NMR, and gel permeation chromatography, which proved that the copolymers were synthesized with different components. Transmittance of the copolymer was tested by UV–vis. By changing the ratio of PEGDGE content and the concentration of the copolymer aqueous solution, the phase behaviors of PPMPEs and PPMPEs-1 were compared and studied in depth. It mainly highlighted the advantages of the stepwise method compared to the one-pot method. The transmittance of the polymer solutions could be improved by lowering the pH value in the acidic solution or increasing the pH value in the alkaline solution. Moreover, as the reaction degree of the PPMPEs hydrophobic chain segment increased, the transmittance decreased.

Photonic crystal sensor for melamine based on magnetic molecularly imprinted nanoparticles self-assembled with an amphiphilic random copolymer.

Magnetic molecularly imprinted nanoparticles (MMINPs) were obtained with a one-step process through miniemulsion self-assembly using an amphiphilic random copolymer as both an emulsifier and MMINP coating, oleic acid-modified magnetite nanoparticles as magnetic cores, and melamine (MEL) as the template molecule. MMINPs were assembled under an external magnetic field to construct photonic crystal (PC) sensor for naked-eye detection of MEL. The MMINPs were characterized by FT-IR, TEM, TGA, and VSM. The analytical performances of themagnetic molecularly imprinted PC sensor for MEL (MEL-MMIPCs) were investigated with respect to sensitivity, response time, selectivity, and stability. As the MEL concentration increases from 1.0 to 1.0 × 106μg/l, the reflection wavelength of MEL-MMIPCs shifted from 497 to 709nm, and was linear with the logarithm of MEL concentration in this range. The detection limit was 0.21μg/l (S/N = 3) and response time was within 30s. The MEL-MMIPC sensor had an imprinting factor of 5.09, and selectivity factors for theanalogs cyanuric acid and atrazine were 8.76 and 5.75, respectively, indicating the high sensitivity and selectivity. After 10 cycles of elution/response, MEL-MMIPCs still had a good ability to recognize MEL.

Properties of Solutions of Amphiphilic Diblock and Random Copolymers of 2-Perfluorohexylethyl Methacrylate and 2-Hydroxyethyl Methacrylate and Coatings Based on Them

Properties of Solutions of Amphiphilic Diblock and Random Copolymers of 2-Perfluorohexylethyl Methacrylate and 2-Hydroxyethyl Methacrylate and Coatings Based on Them

Micellar aggregation and thermogelation of amphiphilic random copolymers in water hierarchically dependent on chain length

Micellar aggregates and thermoresponsive gelation of amphiphilic random copolymers in water were examined in detail, focused on effects of the degree of polymerization (DP) on the behavior. For this purpose, we designed random copolymers carrying hydrophilic poly(ethylene glycol) and hydrophobic dodecyl groups, where the DP was varied from 63 to 358. The content of the hydrophobic monomer was set to 60 mol% to facilitate thermogelation. All the copolymers formed multichain aggregates in water, while the size distribution depended on DP. Since copolymers with larger DP had less composition distribution, the copolymers with 145 or more of DP formed size-controlled aggregates in water. Their concentrated solutions, above the overlap concentration of the aggregates, gelled entirely upon heating, followed by syneresis. In contrast, the short copolymer with 63 of DP formed aggregates with multimodal size distribution, and the concentrated solution underwent macroscopic phase separation upon heating, followed by gelation of the polymer-rich lower layer. As confirmed by small-angle neutron scattering, the copolymer suitable for thermogelation originally formed aggregates consisting of multiple micelle subunits in the aqueous dilute solution, and the thermogelation of the concentrated solution was driven by the physical packing of the micelle subunits upon heating. Thus, we revealed that the DP hierarchically affected not only the self-assembly of the copolymers into size-controlled micellar aggregates in water but also the thermogelation of the concentrated solutions via intermicellar association.

An Antimicrobial Peptide-Mimetic Methacrylate Random Copolymer Induces Domain Formation in a Model Bacterial Membrane.

To address the emerging issue of drug-resistant bacteria, membrane-active synthetic polymers have been designed and developed to mimic host-defense antimicrobial peptides (AMPs) as antibiotic alternatives. In this study, we investigated the domain formation induced by synthetic polymer mimics of AMPs using model membranes to elucidate the biophysical principles that govern their membrane-active mechanisms. To that end, lipid vesicles mimicking Escherichia coli(E. coli) membrane were prepared using an 8:2 (molar ratio) mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol), sodium salt (POPG). Our studies using differential scanning calorimetry (DSC) and fluorescence microscopy indicated that cationic amphiphilic methacrylate random copolymers induced the phase separation to form POPE- or POPG-rich domains. A rhodamine-labeled polymer also showed the binding to separated domains in the membrane. Based on these results, we propose the mechanism that the copolymers induce domain formation by clustering of anionic POPG lipids similar to natural AMPs. In addition, the time-course of polymer binding to the GUV membrane was sigmoidal, suggesting the positive feedback loop in the membrane binding. We also hypothesize that this cooperative binding of the polymer is driven by the domain formation. This study demonstrates the potential of the amphiphilic copolymers to modulate the lipid organization of cell membranes, which may provide a new strategy to design membrane-active antimicrobial agents.

Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug.

Water-soluble amphiphilic random copolymers composed of tri(ethylene glycol) methacrylate (TEGMA) or poly(ethylene glycol) methyl ether methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) were synthesized by ARGET-ATRP, and their self-assembling and thermoresponsive behavior in water was studied by dynamic light scattering (DLS) and UV-vis spectroscopy. The copolymer ability to self-fold in single-chain nano-sized structures (unimer micelles) in aqueous solutions was exploited to encapsulate Combretastatin A-4 (CA-4), which is a very hydrophobic anticancer drug. The cloud point temperature (Tcp) was found to linearly decrease with increasing drug concentration in the drug/copolymer system. Moreover, while CA-4 was preferentially incorporated into the unimer micelles of TEGMA-ran-FA, the drug was found to induce multi-chain, submicro-sized aggregation of PEGMA-ran-FA. Anyway, the encapsulation efficiency was very high (≥81%) for both copolymers. The drug release was evaluated in PBS aqueous solutions both below and above Tcp for TEGMA-ran-FA copolymer and below Tcp, but at two different drug loadings, for PEGMA-ran-FA copolymer. In any case, the release kinetics presented similar profiles, characterized by linear trends up to ≈10–13 h and ≈7 h for TEGMA-ran-FA and PEGMA-ran-FA, respectively. Then, the release rate decreased, reaching a plateau. The release from TEGMA-ran-FA was moderately faster above Tcp than below Tcp, suggesting that copolymer thermoresponsiveness increased the release rate, which occurred anyway by diffusion below Tcp. Cytotoxicity tests were carried out on copolymer solutions in a wide concentration range (5–60 mg/mL) at 37 °C by using Balb/3T3 clone A31 cells. Interestingly, it was found that the concentration-dependent micro-sized aggregation of the amphiphilic random copolymers above Tcp caused a sort of “cellular asphyxiation” with a loss of cell viability clearly visible for TEGMA-ran-FA solutions (Tcp below 37 °C) with higher copolymer concentrations. On the other hand, cells in contact with the analogous PEGMA-ran-FA (Tcp above 37 °C) presented a very good viability (≥75%) with respect to the control at any given concentration.