Amphiphilic Nanogels Research Articles

Amphiphilic Nanogels as Versatile Stabilizers for Pickering Emulsions.

Pickering emulsions (PEs) are stabilized by particles at the water/oil interface and exhibit superior long-term stability compared to emulsions with molecular surfactants. Among colloidal stabilizers, nano/microgels facilitate emulsification and can introduce stimuli responsiveness. While increasing their hydrophobicity is connected to phase inversion from oil-in-water (O/W) to water-in-oil (W/O) emulsions, a predictive model to relate this phase inversion to the molecular structure of the nano/microgel network remains missing. Addressing this challenge, we developed a library of amphiphilic nanogels (ANGs) that enable adjusting their hydrophobicity while maintaining similar colloidal structures. This enabled us to systematically investigate the influence of network hydrophobicity on emulsion stabilization. We found that W/O emulsions are preferred with increasing ANG hydrophobicity, oil polarity, and oil/water ratio. For nonpolar oils, increasing emulsification temperature enabled the formation of W/O PEs that are metastable at room temperature. We connected this behavior to interfacial ANG adsorption kinetics and quantified ANG deformation and swelling in both phases via atomic force microscopy. Importantly, we developed a quantitative method to predict phase inversion by the difference in Flory-Huggins parameters between ANGs with water and oil (χwater - χoil). Overall, this study provides crucial structure-property relations to assist the design of nano/microgels for advanced PEs.

Optically monitoring the microenvironment of a hydrophobic cargo in amphiphilic nanogels: influence of network composition on loading and release.

Amphiphilic nanogels (ANGs) are promising carriers for hydrophobic cargos such as drugs, dyes, and catalysts. Loading content and release kinetics of these compounds are controlled by type and number of hydrophobic groups in the amphiphilic copolymer network. Thus, understanding the interactions between cargo and colloidal carrier is mandatory for a tailor-made and cargo-specific ANG design. To systematically explore the influence of the network composition on these interactions, we prepared a set of ANGs of different amphiphilicity and loaded these ANGs with varying concentrations of the solvatochromic dye Nile Red (NR). Here, NR acts as a hydrophobic model cargo to optically probe the polarity of its microenvironment. Analysis of the NR emission spectra as well as measurements of the fluorescence quantum yields and decay kinetics revealed a decrease in the polarity of the NR microenvironment with increasing hydrophobicity of the hydrophobic groups in the ANG network and dye-dye interactions at higher loading concentrations. At low NR concentrations, the hydrophobic cargo NR is encapsulated in the hydrophobic domains. Increasing NR concentrations resulted in probe molecules located in a more hydrophilic environment, i.e., at the nanodomain border, and favored dye-dye interactions and NR aggregation. These results correlate well with release experiments, indicating first NR release from more hydrophilic network locations. Overall, our findings demonstrate the importance to understand carrier-drug interactions for efficient loading and controlled release profiles in amphiphilic nanogels.

Influence of Nanogel Amphiphilicity on Dermal Delivery: Balancing Surface Hydrophobicity and Network Rigidity.

Polymeric nanogels are promising nonirritating nanocarriers for topical delivery applications. However, conventional hydrophilic networks limit encapsulation of hydrophobic therapeutics and hinder tailored interactions with the amphiphilic skin barrier. To address these limitations, we present amphiphilic nanogels containing hydrophilic networks with hydrophobic domains. Two competing factors determine favorable nanogel-skin interactions and need to be balanced through network composition: suitable surface hydrophobicity and low network rigidity (through physical hydrophobic cross-links). To ensure comparability in such investigations, we prepared a library of nanogels with increasing hydrophobic cholesteryl amounts but similar colloidal features. By combining mechanical and surface hydrophobicity tests (atomic force microscopy (AFM)) with dermal delivery experiments on excised human skin, we can correlate an increased delivery efficacy of Nile red to the viable epidermis with a specific network composition, i.e., 20-30 mol % cholesterol. Thus, our nanogel library identifies a specific balance between surface amphiphilicity and network rigidity to guide developments of advanced dermal delivery vehicles.

Thermo- and UV-responsive amphiphilic nanogels via reversible [4+4] photocycloaddition of PEG/PCL-based polyurethane dispersions

Amphiphilic nanogels are emerging as promising materials for several applications due to their high loading capacity of hydrophobic substances. In this context, a thermoresponsive anthracene end-capped hyperbranched polyurethane (HPU-AM) based on poly(ethylene glycol), polycaprolactone-triol, and isophorone diisocyanate, was used as a platform for nanogel preparation. Both polymer synthesis and functionalization with anthracene were one-pot and controlled. HPU-AM self-assembled in aqueous solutions to form micelles, while heating above the solution cloud point (Tcp) led to phase separation and globule formation, as verified by 1H nuclear magnetic resonance and dynamic light scattering experiments. Nanogel dispersions were prepared by UV-irradiation of the globule dispersions. The UV-light (λ = 365 nm) triggers the [4+4] cycloaddition of the anthracene chain-ends, yielding chemically cross-linked nanogels. Their hydrodynamic radius was tuned from 28 to 50 nm by varying the quench temperature (T > Tcp) and HPU-AM concentration. Evidence of nanogel softness, spherical morphology, narrow size distributions, and phase-segregated inner structure was provided by microscopy, light scattering, and Nile-red loading experiments. The hydrodynamic volume of the nanogels was reversibly reduced up to 85% by heating from 15 to 45 °C. Finally, irradiation of the nanogel dispersions at λ = 280 nm cleaved the anthracene dimer, partially reverting the crosslinking, and promoting nanogel disaggregation into micelles of hydrodynamic radius of 7 nm.

Luminescent amphiphilic nanogels by terpyridine-Zn(II) complexation of polymeric micelles

In this work, we investigated terpyridine (tpy)/Zn(II) complexation for the crosslinking of polymeric micelles of the branched poly(ethylene oxide)–poly(propylene oxide) block copolymer Tetronic® 1107 (T1107) in water and produce physically stable amphiphilic luminescent nanogels. Nanoparticles displayed a size of 235 ± 25 and 318 ± 57 nm before and after Zn(II) crosslinking, respectively, as measured by dynamic light scattering. High-resolution scanning electron microscopy analysis revealed the multimicellar nature of the crosslinked nanoparticles. In addition, Zn(II) complexation prevented nanoparticle disassembly after extreme dilution below the critical micellar concentration and reduced the minimum concentration required for the reverse thermal gelation of concentrated aqueous T1107 systems. The cell compatibility and uptake were initially assessed in the murine macrophage cell line RAW 264.7. Results showed that complexation increases the cell compatibility of the nanoparticles with respect to the non-complexed counterparts. In addition, non-crosslinked nanoparticles accumulated in the cell membrane, while the complexed ones were internalized, as observed by confocal laser scanning fluorescence microscopy. Then, the antiproliferative activity of the crosslinked nanoparticles was confirmed in the rhabdomyosarcoma cell line Rh30; their inhibitory concentration 50 (IC50) being 101 μg/mL (6.7 μM). Finally, the encapsulation and release of the hydrophobic antiretroviral efavirenz was characterized in vitro. Complexation slightly reduced the release kinetics with respect to the pristine nanoparticles. Overall results demonstrate the promise of this simple modification strategy to produce amphiphilic nanogels with a set of advantageous physicochemical, optical, and biological properties.

Amphiphilic Nanogels: Fuzzy Spheres with a Pseudo-Periodic Internal Structure.

Amphiphilic polymer nanogels (NGs) are promising drug delivery vehicles that extend the application of conventional hydrophilic NGs to hydrophobic cargoes. By randomly introducing hydrophobic groups into a hydrophilic polymer network, loading and release profiles as well as surface characteristics of these colloids can be tuned. However, very little is known about the underlying internal structure of such complex colloidal architectures. Of special interest is the question how the amphiphilic network composition influences the internal morphology and the "fuzzy" surface structure. To shine light into the influence of varying network amphiphilicity on these structural features, we investigated a small library of water-swollen amphiphilic NGs using small-angle X-ray scattering (SAXS). It was found that overall hydrophilic NGs, consisting of pure poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA), display a disordered internal structure as indicated by the absence of a SAXS peak. In contrast, a SAXS peak is present for amphiphilic NGs with various amounts of incorporated hydrophobic groups such as cholesteryl (CHOLA) or dodecyl (DODA). The internal composition of the NGs is considered structurally homologous to microgels. Application of the Teubner-Strey model reveals that hydrophilic PHPMA NGs have a disordered internal structure (positive amphiphilicity factor) while CHOLA and DODA samples have an ordered internal structure (negative amphiphilicity factor). From the SAXS data it can be derived that the internal structure of the amphiphilic NGs consists of regularly alternating hydrophilic and hydrophobic domains with repeat distances of 3.45-5.83 nm.

Amphiphilic biodegradable co-networks of Poly(butylene succinate)-Poly(ethylene glycol) chains for nano-gelation via Click chemistry and its potential dispersant for multi-walled carbon nanotubes

Amphiphilic nanogel (APNG) is a class of material miscible with water and oil which is practical for active molecules incorporation, water-oil dispersion, etc. In general, preparation of APNGs requires multi-steps involving the copolymer with different hydrophilic units and the micelles formation to confine the nano-level for the crosslink. The present work proposes a simple way to prepare APNGs by applying the co-networks of biodegradable hydrophilic and hydrophobic chains. The co-networks between alkyno-poly(acrylic acid) (alkyno-PAA) and diazido-poly(ethylene glycol) (N3-PEG-N3) as well as diazido-poly(butylene succinate) (N3-PBS-N3) via copper-catalyzed azide-alkyne cycloaddition (CuAAC) Click lead to APNG. The variation of hydrophilic N3-PEG-N3 and hydrophobic N3-PBS-N3 controls the amphiphilicity as evidenced from the swelling performances in various solvents with different polarity. The APNG obtained favors multi-walled carbon nanotubes (MWCNTs) to be dispersed in water for weeks without precipitation suggesting a potential dispersant of MWCNTs in hydrophilic media, especially aqueous solution.

Amphiphilic nanogels: influence of surface hydrophobicity on protein corona, biocompatibility and cellular uptake.

Background and purposeNanogels (NGs) are promising drug delivery tools but are typically limited to hydrophilic drugs. Many potential new drugs are hydrophobic. Our study systematically investigates amphiphilic NGs with varying hydrophobicity, but similar colloidal features to ensure comparability. The amphiphilic NGs used in this experiment consist of a hydrophilic polymer network with randomly distributed hydrophobic groups. For the synthesis we used a new synthetic platform approach. Their amphiphilic character allows the encapsulation of hydrophobic drugs. Importantly, the hydrophilic/hydrophobic balance determines drug loading and biological interactions. In particular, protein adsorption to NG surfaces is dependent on hydrophobicity and critically determines circulation time. Our study investigates how network hydrophobicity influences protein binding, biocompatibility and cellular uptake.MethodsBiocompatibility of the NGs was examined by WST-1 assay in monocytic-like THP-1 cells. Serum protein corona formation was investigated using dynamic light scattering and two-dimensional gel electrophoresis. Proteins were identified by liquid chromatography-tandem mass spectrometry. In addition, cellular uptake was analyzed via flow cytometry.ResultsAll NGs were highly biocompatible. The protein binding patterns for the two most hydrophobic NGs were very similar to each other but clearly different from the hydrophilic ones. Overall, protein binding was increased with increasing hydrophobicity, resulting in increased cellular uptake.ConclusionOur study supports the establishment of structure–property relationships and contributes to the accurate balance between maximum loading capacity with low protein binding, optimal biological half-life and good biocompatibility. This is an important step to derive design principles of amphiphilic NGs to be applied as drug delivery vehicles.

Synthesis and physicochemical properties of dual-responsive acrylic acid/butyl acrylate cross-linked nanogel systems

HypothesisA cross-linked amphiphilic nanogel containing a high mole% of hydrophilic pH-responsive moiety can provide enhanced functionality regarding stimuli-responsiveness, water-dispersibility, hydrophobic substance loading, and structural stability under harsh environmental conditions. These nanogels could be synthesized using a one-pot procedure for large-scale applications. Moreover, the interplay of various interaction forces in these colloidal systems is being investigated. ExperimentsModel nanogels consisting of acrylic acid-butyl acrylate-ethylene glycoldimethacrylate were synthesized using an emulsion copolymerization via a seeded semi-batch process under an acidic condition. The structures were assessed by Fourier transform infrared spectroscopy and potentiometric-conductometric titrations. Zeta potential, field-emission scanning electron microscopy, and transmission electron microscopy were used to evaluate the dispersion stability, size distribution, and structural distribution, respectively. Their stimuli-responsive behavior was studied by combining static and dynamic light scattering and titration analyses. FindingsMonodisperse nanospheres of approximately 150 nm were successfully prepared by implementing a one-pot practical pathway. These nanogels displayed a dual thermo- and pH-responsive behavior, reflecting the high efficiency of physical cross-linking make it ideal for drug delivery and oil industry applications. Moreover, a novel symmetric pH-activated morphology transformation behavior was revealed. Accordingly, a compositional distribution was proposed and assessed by exploring the polymerization process.

Synthesis of amphiphilic V-type silica nanogels and study of their self-assembling at the air–water interface

The methods for the synthesis of silica nanogels and a modifying agent, as well as related amphiphilic V-type silica nanogels are presented. Self-assembly of the synthesized amphi philic nanogels during the formation of Langmuir monolayers at the air–water interface is considered. Aggregate structures were revealed to form during ordering of the silica V-type nanogels at the air–water interface after collapse of the Langmuir monolayer. For the low-molecular-weight fraction of the silica nanogels, the aggregates do not completely decompose upon the expansion of the Langmuir layer since are formed by mutually penetrating macromolecules. For the highmolecular- weight fraction, they are reversibly formed and decompose in consecutive compression– expansion cycles, which is characteristic of Langmuir layers of nanoparticles.

A New Strategy for Intestinal Drug Delivery via pH-Responsive and Membrane-Active Nanogels.

Oral administration of hydrophobic and poorly intestinal epithelium-permeable drugs is a significant challenge. Herein, we report a new strategy to overcome this problem by using novel, pH-responsive, and membrane-active nanogels as drug carriers. Prepared by simple physical cross-linking of amphiphilic pseudopeptidic polymers with pH-controlled membrane-activity, the size and hydrophobicity-hydrophilicity balance of the nanogels could be well-tuned. Furthermore, the amphiphilic nanogels could release hydrophobic payloads and destabilize cell membranes at duodenum and jejunum pH 5.0-6.0, which suggests their great potential for intestinal drug delivery.

A versatile synthetic platform for amphiphilic nanogels with tunable hydrophobicity

Functionalization of reactive precursor particles allows the preparation of amphiphilic nanogel libraries with tunable network hydrophobicity and comparable colloidal features.

Novel poly(vinyl alcohol)-based amphiphilic nanogels by non-covalent boric acid crosslinking of polymeric micelles.

In this work, we report a new type of poly(vinyl alcohol)-g-poly(N-isopropylacrylamide) (PVA-g-PNiPAAm) amphiphilic nanogel produced by the non-covalent crosslinking of PVA polyol domains in preformed polymeric micelles with boric acid. The nanomaterials showed sizes in the 100-250 nm range (DLS) and a spherical morphology (HR-SEM). We demonstrated that the size of the polymeric micelles could be fine-tuned by changing the concentration (and the aggregation pattern) of the polymeric amphiphile in water. Upon crosslinking, the polymeric micelles turned into physically stable amphiphilic nanogels that displayed both size and size distribution similar to the micellar precursor for up to two weeks, even under disfavored conditions of concentration and temperature that, in the case of non-crosslinked counterparts, resulted in quick disassembly. In addition, we show for the first time the feasibility of spray-drying technology to consolidate the 3D network formed between PVA and boric acid and to produce stable powders that can be reconstituted upon use at any desired concentration. Moreover, the formation of a borated surface conferred the nanogels with good mucoadhesiveness in vitro. Finally, these novel nanomaterials showed optimal cell compatibility in a model of the intestinal epithelium, the Caco2 cell line. Overall results demonstrate the unprecedented versatility of the proposed modular approach and opens completely new horizons in the application of polymeric micelles and other self-assembled polymeric nanomaterials in diagnostics and therapeutics.

Influence of nanogel additive hydrophilicity on dental adhesive mechanical performance and dentin bonding

ObjectiveTo assess the influence of hydrophilicity of reactive nanogels on the mechanical performance of dental adhesives and microtensile bond strength (μTBS) to dentin after 24h or 3 months of aging. MethodsA series of three nanogels were synthesized: NG1—IBMA/UDMA; NG2—HEMA/BisGMA; NG3—HEMA/TE-EGDMA. The nanogels were dispersed in solvent, HEMA or BisGMA/HEMA. The degree of conversion (DC) of the materials was measured and the flexural modulus of these polymers was evaluated in dry or wet conditions. For μTBS analysis, a model adhesive was used without nanogel (control) or with the incorporation of nanogels. μTBS was evaluated after storage in distilled water for 24h or 3 months. The analysis of the fracture was performed after μTBS testing. Data were analyzed using ANOVA and Tukey’s test (α=0.05). ResultsWater significantly increased the modulus of NG1 and NG2 dispersed in solvent, while significantly decreased the stiffness of NG3. All polymers dispersed in HEMA and BisGMA/HEMA had significantly lower modulus when stored in water. NG2 showed the highest DC in solvent and BisGMA/HEMA. In HEMA, NG1 and NG3 produced the highest DC. After three months, NG2 showed the best μTBS. The μTBS of NG2-containing adhesive resin significantly increased after 3 months, while storage had no effect in the control group, NG1 and NG3. SignificanceThe more hydrophobic IBMA/UDMA nanogel showed higher bulk material mechanical property results, but the best dentin bond strength values, and notably strength values that improved upon storage, were obtained with the amphiphilic nanogel based on BisGMA/HEMA.

Core phosphine-functionalized amphiphilic nanogels as catalytic nanoreactors for aqueous biphasic hydroformylation

Amphiphilic phosphine-functionalized nanogel particles were synthesized by aqueous polymerization-induced self-assembly insuring a well-defined architecture as well as a narrow size distribution (average diameter of ca. 90nm in water). They were successfully applied as ligands for the biphasic hydroformylation of 1-octene catalyzed by rhodium, yielding TOFs in the 350–650h−1 range and a linear to branched aldehyde ratio of 3.5. Embedding the phosphine ligands within a cross-linked structure did not strongly impede mass transfer toward the active centers, as proved by fast metal coordination and a catalytic activity tantamount to that of higher chain mobility micelles or core-cross-linked micelles that have phosphine moieties located on flexible linear arms. However, this extended cross-linking reduced particle swelling and transfer to the organic phase, affording a significantly lowered Rh loss. For all the architectures, a low functionalization degree was preferable to achieve high activity, the selectivity remaining essentially unchanged.

Advanced Artificial Extracellular Matrices Using Amphiphilic Nanogel-Cross-Linked Thin Films To Anchor Adhesion Proteins and Cytokines.

A novel type of nanogel-cross-linked (NanoClik) film composed of acryloyl-modified cholesterol-bearing pullulan nanogels with pentaerythritol tetra(mercaptoethyl)polyoxyethylene as a cross-linker is created through the Michael addition coupled with solvent evaporation. Tensile testing and atomic force microscopy show that the elastic property of the NanoClik films can be controlled by changing the cross-linker concentration. The NanoClik films strongly absorb proteins after simple immersion in solutions of functional proteins, including the hormone insulin, cytokine bone morphogenetic protein-2 (BMP-2), and vitronectin. The amphiphilic nanogels in the films induce this absorption by acting as anchoring and loading proteins. Mouse embryo fibroblast cells adhere to and proliferate on the NanoClik films anchoring vitronectin, while NanoClik films loaded with BMP-2 strongly increase the differentiation of human mesenchymal stem cells into osteoblasts. These results suggest that the NanoClik films act as a novel artificial extracellular matrix that enables the reservation of various biological proteins to the nanogels.

Nanogel tectonic porous gel loading biologics, nanocarriers, and cells for advanced scaffold

We developed a new self-assembled amphiphilic nanogel-crosslinked porous (NanoCliP) gel that can trap proteins, liposomes, and cells. The NanoCliP gel was prepared by Michael addition of a self-assembled nanogel of acryloyl group-modified cholesterol-bearing pullulan to pentaerythritol tetra (mercaptoethyl) polyoxyethylene, followed by freezing-induced phase separation. Dynamic rheological analysis revealed that the storage modulus (G′) of the NanoCliP gel was approximately 10 times greater than that of a nonporous nanogel-crosslinked gel. Two-photon excitation deep imaging revealed that the NanoCliP gel comprises interconnected pores of several hundred micrometers in diameter. The NanoCliP gel trapped proteins and liposomes via hydrophobic interactions because its amphiphilic nanogels exhibit chaperone-like activity. Mouse embryonic fibroblasts penetrated the interconnected pores and adhered to the porous surface of fibronectin-complexed NanoCliP gel. In vivo, the NanoCliP gel enhanced cell infiltration, tissue ingrowth, and neovascularization without requiring exogenous growth factors, suggesting that the NanoCliP gel is a promising scaffold for tissue engineering.

One-pot synthesis of amphiphilic nanogels from vinylated SPIONs/HEMA/PEG via a combination of click chemistry and surfactant-free emulsion photopolymerization: Unveiling of the protein-nanoparticle interactions

In this study, freshly prepared Fe3O4 nanoparticles (MNP1) were coated with 3-aminopropyltriethoxysilane (APTES) to produce core–shell Fe3O4@SiO2 nanoparticles (MNP2), amine terminated nanoparticles was converted into the triazide in the presence of as-prepared triflic azide (MNP3). Propargyl acrylate (PgA) was synthesized from propargyl alcohol and acryloyl chloride and their structures were characterized by FT-IR and 1H NMR spectroscopy. MNP3 were modified by PgA via click reaction to produce fully decorated triazole product (MNP4). Photopolymerization of MNP4 in the presence of hydroxyethyl methacrylate (HEMA) and acrylated methyl ether poly (ethylene glycol) (ACMPEG) were carried out by emulsion method without any surfactant (MNP5). The in-vitro release behavior of quercetin from MNP5s was investigated at two pHs (7.4 and 5.8). The effect of fetal bovine serum (FBS) on MNPs and its ability to cover magnetite nanoparticles was investigated.

Amphiphilic nanogel of enzymatically synthesized glycogen as an artificial molecular chaperone for effective protein refolding

Enzymatically synthesized glycogen (ESG) bearing hydrophobic groups were prepared to construct a new artificial molecular chaperone system. The radius of the amphiphilic ESG nanogel was approximately 15 nm. The nanogels prevented irreversible aggregation of carbonic anhydrase. Cyclodextrin induced the release of carbonic anhydrase in its active form via a one-step mechanism without dissociation of the nanogels.