Thermoresponsive Polymeric Nanoparticles Research Articles

Correction to “Thermoresponsive Polymeric Nanoparticles as Efficient Pickering Interfacial Catalysts for Selective Oxidation of Sulfides”

Correction to “Thermoresponsive Polymeric Nanoparticles as Efficient Pickering Interfacial Catalysts for Selective Oxidation of Sulfides”

Thermoresponsive Polymeric Nanoparticles as Efficient Pickering Interfacial Catalysts for Selective Oxidation of Sulfides

Thermoresponsive Polymeric Nanoparticles as Efficient Pickering Interfacial Catalysts for Selective Oxidation of Sulfides

Controlled reversible aggregation of thermoresponsive polymeric nanoparticles by interfacial Diels-Alder reaction

HypothesisStimuli-responsive polymers, with properties changing upon different environmental factor variations such as pH, light, mechanical stress or temperature, and polymeric nanoparticles have found many important applications in fields such as drug delivery, biosensing and environmental research. ExperimentsIn this work, thermoresponsive nanoparticles that are able to react by Diels-Alder reaction (a diene-dienophile cycloaddition) were studied. Thermoresponsive polymers were synthesized from a biocompatible polymer (poly(lactic-co-glycolic) acid, PLGA) and diene (furan) or dienophile (maleimide) derivatives. Emulsification-evaporation method was then used as a fast and reproducible method to obtain highly monodispersed polymeric nanosuspensions able to react by Diels-Alder (DA) reaction. FindingsThe nanoparticles’ size decreased down to 25 nm by increasing the emulsification’s time. The possible direct and retro-Diels-Alder (rDA) reactions between furan- and maleimide-functionalized nanoparticles were studied by dynamic light scattering and electron microscopy. For the first time, the reactivity of the interfacial DA and rDA reactions between functionalized-nanoparticles was studied, leading to the determination of the activation energy, the enthalpy of activation and the entropy of activation.

Probing Thermoresponsive Polymerization-Induced Self-Assembly with Variable-Temperature Liquid-Cell Transmission Electron Microscopy

Summary We directly initiate and visualize the formation of polymeric nanomaterials via variable-temperature liquid-cell transmission electron microscopy (VT-LCTEM). With temperature control in the liquid cell, reversible addition-fragmentation chain transfer polymerization was thermally initiated, leading to the formation of amphiphilic block copolymers that assemble upon dispersion polymerization-induced self-assembly (PISA). In combination with traditional ex situ analyses, VT-LCTEM enabled not only the characterization of the nanoparticles in situ but also the observation of a thermal phase transition. Critically, because these assemblies form from thermoresponsive components, any temperature changes during sample preparation and analysis can alter morphologies, necessitating direct in situ characterization of reaction progression. We believe that the findings and the technique described herein will lead to unprecedented possibilities for the development and characterization of self-organizing soft matter.

Biodegradable zwitterionic nanoparticles with tunable UCST-type phase separation under physiological conditions.

Thermo-responsive polymeric nanoparticles (NPs) are emerging as a powerful tool in nanomedicine for the fabrication of advanced drug delivery systems. In addition to their size and biodegradation rate, phase separation of NPs upon application of a thermal stimulus provides an additional switch to control the rate of release of active components. Among the materials currently developed for biomedical applications, NPs stabilized by zwitterionic polymers are gaining increasing interest due to their high stability and ability to escape the body immune response. Yet, biodegradable zwitterionic NPs with temperature response under physiological conditions are currently not available. Here, we develop a new class of biodegradable zwitterionic NPs that exhibit UCST phase transition in the biological temperature range (T = 30-45 °C) and in physiological solution (i.e. 0.9% w/w NaCl). We design a strategy that relies on the self-assembly of block copolymers produced via reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization. These copolymers comprise a zwitterionic portion exhibiting an upper critical solution temperature (UCST) and a biodegradable hydrophobic block consisting of oligoesters functionalized with a vinyl group. This modular macromolecular architecture allows us to independently control a variety of NP properties by modifying the individual components of the copolymer. In particular, the zwitterionic block of the copolymers controls the UCST-type phase separation behavior, while the number of the oligoester repeating units governs the size of the NPs and the length of the oligoester dictates the degradation rate. After demonstrating the synthesis of highly controlled degradable NPs, we show the potential of this new class of materials in the context of drug delivery by controlling the release of a drug-mimic molecule upon temperature variations in a broad time range from few minutes to 20 hours.

Thermoresponsive polymeric nanoparticles based on poly(2‐oxazoline)s and tannic acid

ABSTRACTHydrogen bonding is widely present and plays a significant role in material science and supramolecular chemistry. This work reports a straightforward strategy for the preparation of polymeric nanoparticles from neutral poly(2‐oxazoline)s (POx) and tannic acid (TA) driven by their intermolecular hydrogen bonding. Dynamic light scattering (DLS) and scanning electron microscope (SEM) measurements showed that POx bearing different substituents, that is, methyl, ethyl and n‐propyl in the 2‐position all could assemble with TA into stable nanoparticles in water or ethanol. The diameter of the assembled nanoparticles could be manipulated by varying parameters such as molecular weight of POx, concentration and ratio of POx, and TA. Interestingly, POx/TA nanoparticles exhibited upper critical solution temperature (UCST)‐type thermoresponsive properties in ethanol or water depending on the molecular weight and substituent in the 2‐position of POx. Increasing or decreasing the temperature at the transition point resulted in the reversible transformation between assembled nanoparticles and disassembled poly(2‐n‐propyl‐2‐oxazoline) (PnPrOx) and TA. In view of the tailored size of the stable nanoparticles and the biocompatibilities of POx and TA, the prepared thermoresponsive nanoparticles are promising candidates as carriers for medicine toward related biomedical applications. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1520–1527

Smart polymeric nanoparticles for boron scavenging

Boron is biologically beneficial but only in trace quantities. It is hard to detect and remove from water, as sometimes required in the treatment of residual waters. We have designed an approach based on thermo-responsive polymer nanoparticles containing vicinal diol groups for boron scavenging. The particles have a core of poly(methyl methacrylate) (PMMA) and a thermosensitive shell with a brush composed of a copolymer of N-isopropylacrylamide (NIPAM), 2-aminoethyl methacrylate (AEMH), and either d-gluconoamidoethyl methacrylate (GAEM) or monodiol methacrylate (MDM) boron chelating monomers. The nanoparticles show boron removal efficiencies of up to 96%, with removal of phenylboronic acid being more efficient than that of boric acid. The best boron scavenging efficiency was obtained for the higher specific surface area particles containing d-gluconoamidoethyl groups. At temperatures above ca. 35°C the particle shell collapses, inducing particle aggregation which allows simple separation and recovery of the nanoparticles. These can be subsequently used for boron scavenging, without loss of efficiency.

Thermoresponsive Polymer Nanoparticles Co-deliver RSV F Trimers with a TLR-7/8 Adjuvant.

Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV), and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here, we show that nanoparticle-forming thermoresponsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity. Although primary amine conjugation of TLR-7/8a to F trimers severely disrupted the recognition of critical neutralizing epitopes, F trimers site-selectively coupled to TRP nanoparticles retained appropriate antigenicity and elicited high titers of prefusion-specific, TH1 isotype anti-RSV F antibodies following vaccination. Moreover, coupling F trimers to TRP delivering TLR-7/8a resulted in ∼3-fold higher binding and neutralizing antibody titers than soluble F trimers admixed with TLR-7/8a and conferred protection from intranasal RSV challenge. Overall, these data show that TRP nanoparticles may provide a broadly applicable platform for eliciting neutralizing antibodies to structure-dependent epitopes on RSV, influenza, HIV-1, or other pathogens.

Thermo-responsive polymeric nanoparticles for enhancing neuronal differentiation of human induced pluripotent stem cells

We report thermo-responsive retinoic acid (RA)-loaded poly(N-isopropylacrylamide)-co-acrylamide (PNIPAM-co-Am) nanoparticles for directing human induced pluripotent stem cell (hiPSC) fate. Fourier transform infrared spectroscopy and 1H nuclear magnetic resonance analysis confirmed that RA was efficiently incorporated into PNIAPM-co-Am nanoparticles (PCANs). The size of PCANs dropped with increasing temperatures (300-400nm at room temperature, 80-90nm at 37°C) due to its phase transition from hydrophilic to hydrophobic. Due to particle shrinkage caused by this thermo-responsive property of PCANs, RA could be released from nanoparticles in the cells upon cellular uptake. Immunocytochemistry and quantitative real-time polymerase chain reaction analysis demonstrated that neuronal differentiation of hiPSC-derived neuronal precursors was enhanced after treatment with 1-2μg/ml RA-loaded PCANs. Therefore, we propose that this PCAN could be a potentially powerful carrier for effective RA delivery to direct hiPSC fate to neuronal lineage. From the Clinical EditorThe use of induced pluripotent stem cells (iPSCs) has been at the forefront of research in the field of regenerative medicine, as these cells have the potential to differentiate into various terminal cell types. In this article, the authors utilized a thermo-responsive polymer, Poly(N-isopropylacrylamide) (PNIPAM), as a delivery platform for retinoic acid. It was shown that neuronal differentiation could be enhanced in hiPSC-derived neuronal precursor cells. This method may pave a way for future treatment of neuronal diseases.

Cytotoxicity of thermo-responsive polymeric nanoparticles based on N-isopropylacrylamide for potential application as a bioscaffold

Polymeric nanoparticles based on poly-N-isopropylacrylamide (pNiPAM NPs) and their bio-medical applications have been widely investigated in recent years. These tunable nanoparticles are considered to be great candidates for drug delivery systems, biosensors and bioanalytical devices. Thus, the biocompatibility and toxicity of these nanoparticles is clearly a crucial issue. In this work, the cytotoxicity of thermo-responsive pNiPAM nanoparticles was studied, followed by a detailed analysis of the NPs morphology in growing cell cultures and their 3D structure. Cytotoxic examination was conducted for two cell cultures - HeLa (cervical cancer cell line) and HeK293 (human embryonic kidney cell line), employing MTT (3-4, 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide) assay and viability tests. We used Cryo-SEM (scanning electron microscopy) and fluorescence microscopy (IN Cell Analyzer) in order to investigate the morphological structure of the polymer network. We show that pNiPAM nanoparticles do not exhibit any cytotoxicity effects on the investigated cell lines. Additionally, we report that the pNiPAM nanoparticle based scaffold promotes cell growth.

Thermoresponsive Polymeric Nanoparticles: Nucleation from Cooperative Polymerization Driven by Dative Bonds

Cooperative polymerization, aided by the nucleation–elongation mechanism, has the promise of providing polymers and nanostructures that are otherwise inaccessible. The molecular origin of the cooperative growth of polymers is driven by a secondary interaction, often based on polarization, electrostatics, or sterics-driven secondary structure. Here, we demonstrate that covalent dative interactions can be used to achieve cooperative polymerization. Our results suggest that the initial polymer formation serves as the nucleus for monodisperse nanoparticle assembly. The dynamic nature of the dative interaction in this equilibrium self-assembly has been shown to endow these nanoparticles with thermal responsive characteristics.

Synthesis and characterization of thermoresponsive polymeric nanoparticles

We synthesized drug-loaded thermoresponsive poly(N-isopropylacrylamide) with acrylic acid (poly(NIPAM-co-AA)) nanoparticles. Dynamic light scattering analysis showed that the size of poly (NIPAM-co-AA) nanoparticles was significantly affected by temperatures, indicating that the sizes were changed from 400 nm at 25°C to 100 nm at 37°C. 1H nuclear magnetic resonance (NMR) and fourier transform infrared spectroscopy (FT-IR) analysis demonstrated the synthesis of poly(NIPAM-co-AA) nanoparticles, showing that drugs (e.g., doxorubicin, retinoic acid) were conjugated with poly(NIPAM-co-AA) nanoparticles. We also analyzed the cumulative release of drugs in a temporal manner, indicating that doxorubicin was highly released from poly(NIPAM-co-AA) nanoparticles at 48 hours compared to retinoic acid. Therefore, this thermoresponsive drug-loaded poly (NIPAM-co-AA) nanoparticle could be a powerful tool for drug delivery and release applications.

Fine Tuning the Disassembly Time of Thermoresponsive Polymer Nanoparticles.

Timed-released disassembly of nanoparticles without a remote trigger or environmental cues is demonstrated in this work. The reversible addition-fragmentation chain transfer (RAFT) polymerization allowed the fine-tuning of the chemical composition in the diblock copolymers, in which the first block consisted of a hydrophilic monomer (DMA) and the second random block consisted of three different monomers: (a) the thermoresponsive NIPAM, (b) the self-catalyzed hydrolyzable DMAEA, and (c) the hydrophobic BA. These diblock copolymers were solubilized in water below the lower critical solution temperature (LCST) of the thermoresponsive second block, and heated to 37 °C (i.e., >LCST) to form small micelle nanoparticles with a narrow particle size distribution. As DMAEA hydrolyzed to acrylic acid groups, the LCST of the diblock increased, and the time at the start of micelle disassembly (t(start)) corresponded to the point where the LCST was equal to the solution temperature (i.e., 37 °C). The high water content in the PNIPAM core allowed an even degradation of the core over time. The copolymer composition allowed fine control over t(start), as this time was linearly dependent upon the BA units in the second block. These nanoparticles could also be designed to be stable (i.e., not disassemble) over a wide pH range or disassemble below a pH of 7.3. Additionally, the time from the start of disassembly to full unimer formation (t(degrade)) could be controlled by the amount of DMAEA units in the second block. A longer t(degrade) (~5.5 h) was found when the number of DMAEA units was 42 compared to t(degrade) of 1.1 h for 25 units. The nanoparticles designed in this work, through fine control of the polymer chemical composition, have the potential for drug delivery purposes for timed-release of drugs and prodrugs and other wide-ranging applications where timed-release would be beneficial.

Synthesis of single chain thermoresponsive polymernanoparticles

Poly(N-isopropylacrylamide) (pNIPAM) is a thermoresponsive polymer of great interest in biomedical applications. In this work we combine RAFT polymerization and “click chemistry” for the synthesis of well defined single chain pNIPAM nanoparticles below 10 nm size with increasing degree of cross-linking. The method consists of the synthesis of NIPAM based terpolymers containing alkyne and azide functional groups by RAFT polymerization. Using this procedure terpolymers with polydispersity values below 1.2 were obtained. The terpolymers were collapsed by intramolecular “click” cycloaddition for the synthesis of the corresponding nanoparticles. Thermal phase transition behaviour has been studied for single-chain polymer nanoparticles (PNPs) and linear polymers. Temperature-dependent turbidimetry experiments showed a gradual decrease of transmittance for NPs compared to linear precursors, which presented a sharp decrease of transmittance. In the case of collapsed polymers, this effect was highly affected by the pH, exhibiting significant pH dependency in comparison to their linear precursors.

Curcumin-loaded biocompatible thermoresponsive polymeric nanoparticles for cancer drug delivery

This study aims at the formulation of curcumin with biodegradable thermoresponsive chitosan-g-poly (N-vinylcaprolactam) nanoparticles (TRC-NPs) for cancer drug delivery. The spherical curcumin-loaded nanoparticles of size 220nm were characterized, and the biological properties were studied using flow cytometry and cytotoxicity by MTT assay. The in vitro drug release was higher at above LCST compared to that at below LCST. TRC-NPs in the concentration range of 100–1000μg/mL were non-toxic to an array of cell lines. The cellular localization of the curcumin-loaded TRC-NPs was confirmed from green fluorescence inside the cells. The time-dependent curcumin uptake by the cells was quantified by UV spectrophotometer. Curcumin-loaded TRC-NPs showed specific toxicity to cancer cells at above their LCST. Flow cytometric analysis showed increased apoptosis on PC3 compared to L929 by curcumin-loaded TRC-NPs. These results indicate that novel curcumin-loaded TRC-NPs could be a promising candidate for cancer drug delivery.

DNA Hybridization in Thermoresponsive Polymer Nanoparticles

We achieve very high hybridization efficiencies by using a new method to immobilize DNA strands on the surface of thermoresponsive polymer nanoparticles. Hybridization efficiencies of about 70 % are obtained between the DNA immobilized in the particles and a complementary strand in solution, even at very low ionic strengths (1 mM). The polymer nanoparticles have a glassy poly(methylmethacrylate) (PMMA) core and a thermoresponsive shell of poly(N-isopropylacrylamide) (PNIPAM) containing positive charges. After a DNA strand labeled with a fluorescence probe is loaded onto the particles at room temperature, the temperature is increased above the volume phase transition temperature of the PNIPAM shell, TVPT approximately 28 degrees C. The collapse of the particle shell immobilizes the DNA while maintaining its availability for hybridization with a complementary strand. Förster resonance energy transfer (FRET) is used to detect the hybridization with a complementary DNA strand labeled with a FRET acceptor probe.

Control of Oligonucleotide Distribution on the Shell of Thermo-responsive Polymer Nanoparticles

We used Forster resonance energy transfer (FRET) to characterized the adsorption of single strand oligonucleotides (ODN) onto the thermo-responsive shell of polymer nanoparticles with a glassy poly...

Thermoresponsive polymeric nanoparticles stabilized by surfactants

Solutions of poly(N-isopropylacrylamide) (PNIPA) with ionic and nonionic surfactants were investigated by light scattering methods at temperatures 15–45 °C. In contrast to previous studies, where surfactants were used in excess, lower concentrations of surfactants were used. The formation of well-defined nanoparticles of PNIPA was observed on heating above the lower critical solution temperature. The effect of PNIPA and surfactant concentrations, and molecular weight of PNIPA on nanoparticle parameters and on the phase transition temperature of PNIPA solutions were investigated. An interpretation based on stabilization of PNIPA nuclei by surfactants was suggested.

Thermo-responsive polymer nanoparticles with a core-shell micelle structure as site-specific drug carriers

The success of most advanced drug delivery strategies requires development of sophisticated new site-specific carriers. Several new targeting methods use physical and chemical signals such as magnetic fields or changes in pH or temperature as targeting and triggering tools. In addition to site-specificity, the carrier should achieve passive targeting to evade the body's reticulo-endothelial system (RES) and exhibit long blood circulation times in order to efficiently distribute active drug to the site of action (active targeting). To fulfil these requirements, thermo-responsive polymeric micelles have been prepared from amphiphilic block copolymers composed of N-isopropylacrylamide (IPAAm) (a thermo-responsive outer shell) and styrene (St) (hydrophobic inner core). The polymeric micelle which is very stable in aqueous media was formed by the dialyzed method from DMF solution against water. The micelles have a unimodal size distribution (24±4 nm) and CMC was around 10 mg/l (ml→l). These micelles have a small diameter with a low critical micelle concentration, providing a carrier that may have long blood circulation times and a low RES uptake. When the temperature is increased above the transition temperature of the thermo-responsive block chains (32°C), the outer shell chains dehydrate and collapse, allowing aggregation between micelles and favoring binding interactions with cell membrane surfaces. Moreover, these changes are reversible. Hydrophobic molecules are shown to be incorporated into the inner hydrophobic core of the thermo-responsive micelles. Consequently, these micelles are valuable for site-specific delivery of drugs using changes in temperature as a trigger.