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Network Deconstruction Reveals Network Structure in Responsive Microgels
Abstract
Detailed characterization of hydrogel particle erosion revealed critical physicochemical differences between spheres, where network decomposition was informative of network structure. Real-time, in situ monitoring of the triggered erosion of colloidal hydrogels (microgels) was performed via multiangle light scattering. The solution-average molar mass and root-mean-square radii of eroding particles were measured as a function of time for microgels prepared from N-isopropylacrylamide (NIPAm) or N-isopropylmethacrylamide (NIPMAm), copolymerized with a chemically labile cross-linker (1,2-dihydroxylethylene)bisacrylamide (DHEA). Precipitation polymerization was employed to yield particles of comparable dimensions but with distinct topological features. Heterogeneous cross-linker incorporation resulted in a heterogeneous network structure for pNIPAm microgels. During the erosion reaction, mass loss proceeded from the exterior toward the interior of the polymer. In contrast, pNIPMAm microgels had a more homogeneous network structure, which resulted in a more uniform mass loss throughout the particle during erosion. Although both particle types degraded into low molar mass products, pNIPAm microgels were incapable of complete dissolution due to the presence of nondegradable cross-links arising from chain transfer and branching during particle synthesis. The observations described herein provide insight into key design parameters associated with the synthesis of degradable hydrogel particles, which may be of use in various biotechnological applications.
... As a result, these aggregates are of interest in applications such as in situ forming systems, [11][12][13][14][15] colloidal catalysis, 16,17 and pore blocking. 18,19 A potential limitation to the use of PNIPAM nanogels for biomedical applications is their persistent nature; the polymer shows very limited degradability and thus could potentially accumulate within the body. It is hoped that degradable nanogels could be used in biomedical applications, such as in situ forming systems, and the depot formed would degrade and be cleared by the body. ...
... For example, (1,2-dihydroxylethylene)bisacrylamide cross-linked particles have previously been reported to give incomplete degradation. 18 It was hypothesised that the hydrogen atom of the tertiary carbon of the polymer backbone of PNIPAM and the tertiary carbon proton of the isopropyl group can be abstracted, in a chain transfer reaction, to form permanent cross-links. 36,[42][43][44] Further studies found that replacing the NIPAM monomer with Nisopropylmethacrylamide (NIPMAM) (identical in structure except that NIPMAM has a methyl group in place of the hydrogen atom present in NIPAM on the tertiary carbon of the polymer backbone 45 ) could produce fully degradable nanogels. ...
... 36,[42][43][44] Further studies found that replacing the NIPAM monomer with Nisopropylmethacrylamide (NIPMAM) (identical in structure except that NIPMAM has a methyl group in place of the hydrogen atom present in NIPAM on the tertiary carbon of the polymer backbone 45 ) could produce fully degradable nanogels. 18 In other work, Gaulding et al., synthesised PNIPMAM nanogels with the degradable cross-linking agent BAC. 28 They observed incomplete degradability, which was attributed to the elevated temperature of synthesis (80 C) allowing the disulde bond of the BAC cross-linking agent to form nondegradable thioether cross-links. ...
We report the synthesis of core-shell nanogels by sequential addition of thermoresponsive monomers; N-isopropylacrylamide (NIPAM) and N-isopropylmethacrylamide (NIPMAM). The aggregation behaviour of aqueous dispersions of these particles in the presence of salt can be tuned by varying the monomer ratio. The inclusion of degradable cross-linker bis(acryloyl)cystamine (BAC) allows the nanogels to degrade in the presence of reducing agent, with nanogels composed of a copolymer of the two monomers not showing the same high levels of degradation as the comparable core-shell particles. These levels of degradation were also seen with physiologically relevant reducing agent concentration at pH 7. Therefore, it is hoped that the aggregation of these nanogels will have applications in nanomedicine and beyond.
... Interestingly, comparing the size of nanogels initiated with KPS (or APS) we found smaller diameters of the PNIPMAM-dPG nanogels than for PNIPAM based ones even though NIPMAM is reacting slower than NIPAM. These findings are in contrast to reported nano-and microgels of PNIPAM and PNIPMAM crosslinked with di-acrylates like BIS and/or (1,2,-dihydroxylethylene)bisacrylamide (DHEA) [42,46]. Nevertheless, different reaction kinetics of NIPAM and NIPMAM in comparison with the crosslinker is reported to play a crucial role for particle architecture [42,46]. ...
... These findings are in contrast to reported nano-and microgels of PNIPAM and PNIPMAM crosslinked with di-acrylates like BIS and/or (1,2,-dihydroxylethylene)bisacrylamide (DHEA) [42,46]. Nevertheless, different reaction kinetics of NIPAM and NIPMAM in comparison with the crosslinker is reported to play a crucial role for particle architecture [42,46]. In addition, Lyon et al. demonstrated that hydrophilicity of the crosslinker is an important factor for the gel structure as the nucleation process is driven by hydrophobic polymer-to-polymer interactions [46]. ...
... Nevertheless, different reaction kinetics of NIPAM and NIPMAM in comparison with the crosslinker is reported to play a crucial role for particle architecture [42,46]. In addition, Lyon et al. demonstrated that hydrophilicity of the crosslinker is an important factor for the gel structure as the nucleation process is driven by hydrophobic polymer-to-polymer interactions [46]. The hydrophilic character of dPG in combination with the differences in polymerization rate could provide an explanation for the smaller particle diameter of PNIPMAM nanogels (Fig. 3C). ...
Macromolecular bioactives, like proteins and peptides, emerged as highly efficient therapeutics. The main limitation for their clinical application is their instability and potential immunogenicity. Thus, controlled delivery systems able protect the proteins prior release are highly on demand. In the present study, we developed hydrophilic thermo-responsive nanogels with tunable volume phase transition temperatures (VPTTs) and suitable features for controlled protein delivery by the use of multifunctional, dendritic polyglycerol (dPG) as macromolecular cross-linker and temperature-sensitive polymers poly(N-isopropylacrylamide) (NIPAM) and poly(N-isopropylacrylmethacrylate) as linear counterpart. We comprehensively studied the impact of the initiator, monomers and cross-linker on the nanogel structure during the synthesis. Careful analysis of the polymerization process revealed importance of balanced reactions kinetics to form particles with diameters in the range 100–200 nm and low polydispersity. We can control the cross-linking density of the nanogels mainly by the dPG feed and its degree of acrylation. In addition, our screenings revealed that the hydrophilic character of dPG enables it to stabilize the growing particles during the polymerization and thereby reduces final particle size. Co-polymerization of NIPAM and NIPMAM allows precise tuning of the VPTT of the nanogels in the desired range of 34–47 °C. Our nanogels showed outstanding high protein encapsulation efficiency and triggered cargo release upon a temperature change. The delivery efficiency of these nanogels was investigated on excised human skin demonstrating efficient dermal penetration of encapsulated proteins dependent on a temperature triggered release mechanism.
... 2,3 Yet, heterogeneities in the microgel structures, caused by the mismatched reactivity ratios for the monomer and crosslinker during precipitation polymerization, where the reactivity ratio is a measure of the propensity of a monomer to propagate by reacting with itself or a different monomer in the synthetic mixture, are oen observed. 54,55 Typically, poly(N-isopropylacrylamide) microgels crosslinked with MBAAm show a radial distribution of cross-links within the particle, with the highest crosslinker concentrations residing at the microgel interior; this uneven incorporation of MBAAm has been attributed to a high reactivity ratio for the crosslinker relative to the monomer (e.g., N-isopropylacrylamide: the resonance parameter Q ¼ 0.21, the electronic parameter e ¼ 0.43; MBAAm: Q ¼ 0.46, e ¼ 0.54). 54,56 In synthesis of poly(N-isopropylacrylamide) microgels by precipitation polymerization, as the consumption of the crosslinker is much faster than that of the monomer, the active vinyl groups from the unreacted parts of the crosslinker would decrease rapidly with increasing the microgel size at a long reaction time (when $1 hour, no vinyl groups can be found in the microgels). ...
... 54,55 Typically, poly(N-isopropylacrylamide) microgels crosslinked with MBAAm show a radial distribution of cross-links within the particle, with the highest crosslinker concentrations residing at the microgel interior; this uneven incorporation of MBAAm has been attributed to a high reactivity ratio for the crosslinker relative to the monomer (e.g., N-isopropylacrylamide: the resonance parameter Q ¼ 0.21, the electronic parameter e ¼ 0.43; MBAAm: Q ¼ 0.46, e ¼ 0.54). 54,56 In synthesis of poly(N-isopropylacrylamide) microgels by precipitation polymerization, as the consumption of the crosslinker is much faster than that of the monomer, the active vinyl groups from the unreacted parts of the crosslinker would decrease rapidly with increasing the microgel size at a long reaction time (when $1 hour, no vinyl groups can be found in the microgels). [54][55][56] In this respect, following the main objective to introduce surface active vinyl groups to microgels for the subsequent synthesis of macrogels, our pPBA microgels were synthesized from the copolymerization of St, 4-VPBA, DMAEA, and the crosslinker MBAAm in water (Scheme 1), rather than the usually used N-isopropylacrylamide. ...
... 54,56 In synthesis of poly(N-isopropylacrylamide) microgels by precipitation polymerization, as the consumption of the crosslinker is much faster than that of the monomer, the active vinyl groups from the unreacted parts of the crosslinker would decrease rapidly with increasing the microgel size at a long reaction time (when $1 hour, no vinyl groups can be found in the microgels). [54][55][56] In this respect, following the main objective to introduce surface active vinyl groups to microgels for the subsequent synthesis of macrogels, our pPBA microgels were synthesized from the copolymerization of St, 4-VPBA, DMAEA, and the crosslinker MBAAm in water (Scheme 1), rather than the usually used N-isopropylacrylamide. 42 With the large difference in Q value of St (Q ¼ 1.00, e ¼ À0.80) and MBAAm, and VPBA (Q ¼ 0.38, e ¼ À0.52) 56,57 and DMAEA (Q ¼ 0.54, e ¼ 0.61) 58 as well, the microgels should possess a relatively high crosslinker concentration residing at the microgel exterior, rendering the existing of the active vinyl groups on the surface of the microgels at the light penetration depth. ...
Polymer macrogels that can undergo rapid and significant volume changes in response to an external stimulus, such as a fluctuation in blood glucose concentration, are critical for their versatility. We report here such a polymer macrogel, which is made of a highly-ordered array of poly(phenylboronic acid) microgels tethered chemically to bridging polymers (a thin hydrogel matrix). This unique microstructure makes the newly developed macrogels exhibit a rapid response rate and extraordinarily large responsive swelling ratio upon adding glucose into the bathing medium over a glucose concentration range of 0–30 mM at a physiological pH of 7.4. While the macrogels can swell (e.g., the weight of the macrogels increases by ca. 310-fold if the glucose concentration in the bathing medium increases from 0 to 30.0 mM) and reach stability shortly (reach ∼99% of the maximum change within 90 s) after increasing glucose concentration from 0 to a concentration in the 150.0 μM to 30.0 mM range, the volume changes of the macrogels can be fully reversible within the experimental error even after twenty cycles of adding/removing glucose. The macrogels in this extremely expanded state were somewhat flowable, allowing their use as injectable glucose-sensing materials. With the macrogels as carriers, in vitro insulin release can be modulated in a pulsatile profile in response to glucose concentrations, and in vivo studies revealed that these formulations may improve glucose control in streptozotocin-induced diabetic mice subcutaneously administered with the insulin-loaded macrogels.
... The degradation of cross-linking network could regulate the release of loaded drugs from the microgels in a controllable manner. Various degradable cross-linkers like N,N′-(1,2-dihydroxyethylene)bisacrylamide (DHEA), N,N′bis(acryloyl)cystamine (BAC), and 1,4-phenylene bis (4bromobutanoate) have been introduced into the cross-linking network of the resultant microgels to give degradable microgels [28][29][30][31][32][33]. It has also been pointed out that the morphology and network structures of the hydrogels would strongly affect the corresponding degradable property and drug release behavior. ...
... Lyon groups found that the type of initiator system and the preparation temperature significantly affected the network structure and degradation of the thermo-sensitive microgels [28][29][30]. By using the redox initiator system of APS and N,N,N′,N′-tetramethylethylenediamine (TEMED) at preparation temperature ranging from 37 to 45°C, the selfcross-linking of PNIPAm, which might usually occur with traditional thermally initiated method at 70°C, could be avoided, permitting the synthesis of completely degradable PNIPAm microgels when using DHEA as a cleavable crosslinker [28]. ...
... The apparent degradation rate of the microgels could be characterized by the normalized lifetime of τ/(1 − N ∞ ). The exponential decay is characteristic for bulk eroding polymers [29]. The solid lines in Fig. 7 were the best fits of Eq. (3). ...
Thermo-sensitive degradable poly(N-isopropylacrylamide) (PNIPAm)-based microgels were prepared by surfactant-free emulsion polymerization with a redox initiator pair of potassium persulfate (KPS) and N,N,N′,N′-tetramethylethylenediamine at 50 °C. NIPAm, sodium 2-acrylamido-2-methyl-1-propanesulfonate (AMPS-Na), and N,N′-bis(acryloyl)cystamine (BAC) were used as main monomer, anionic comonomer, and degradable cross-linker, respectively. It was found that the morphology and network structure of the resultant microgels could be tuned via the controlled addition of BAC and AMPS-Na, which, in turn, strongly affected the corresponding thermo-sensitivity, stability, and degradation behavior of the microgels. The inhomogeneous network structures of the microgels could be improved by increasing the time period tBAC between KPS initiation and the addition of BAC. The morphology of microgels changed from spherical into hollow interior spherical morphology. The stability of the microgels in physiological condition could be enhanced by the controlled addition of comonomer AMPS-Na. The extent of microgel degradation increased with increasing tBAC.
... 1 The VPTT of microgels can be controlled by varying the constituent chemical species, such as (meth)acrylamide analogues, 1,25,26 N-vinylcaprolactam (VCL), 27,28 and oligo(ethylene glycol) methylester (meth)acrylates. 9,10,29 This is especially notable in the case of N-isopropyl methacrylamide (NIPMAm), which differs from NIPAm only by a single methyl group at the a-position, where the obtained pNIPMAm microgels have a VPTT of $43 C. [30][31][32][33][34][35][36][37][38] The VPTT of microgels can also be tuned via the copolymerization of NIPMAm with other chemical species, such as NIPAm or VCL. [39][40][41][42] Thermoresponsive microgels are mainly synthesized via aqueous free radical precipitation polymerization in water. ...
... 25 The larger EPM of the pNIPMAm microgels in the swollen state at 25 C suggests that the cross-linking density of the surface of pNIPMAm microgels is lower than that of pNIPAm microgels, which is probably due to self-crosslinking in the latter. 33 ...
Thermoresponsive hydrogel microspheres (microgels) are smart materials that quickly respond to external stimuli, and their thermoresponsiveness can be tuned by varying the constituent chemical species. Although uniformly sized microgels can be prepared via aqueous free radical precipitation polymerization, the nanostructure of the obtained microgels is complex and remains unclear so far. In the present study, the nanostructure and thermoresponsiveness of poly(N-isopropyl methacrylamide) (pNIPMAm)-based microgels, which have a volume-transition temperature of ∼43 °C, were evaluated mainly using temperature-controllable high-speed atomic force microscopy. These observations, which are characterized by high spatio-temporal resolution, revealed that the pNIPMAm microgels have a peculiar heterogeneous structure, for example a core-shell and non-thermoresponsive nanostructure in the core region, that originates from the precipitation polymerization process. Furthermore, it was found that the adsorption concentration of the microgels on the substrate is one of the keys for controlling their thermoresponsiveness. These findings can be expected to advance the design of new materials such as thermoresponsive nanosheets and stimuli-responsive coatings.
... The erosion of pNIPMAm-BAC nanogels was monitored in situ, using a previously reported light scattering method. 29 Using Multiangle Light Scattering (MALS) detection, the particle weight-average molar mass (Mw) was monitored in real-time during the erosion reaction. Reactants were introduced to the MALS detector using the Calypso syringe pump system (Wyatt Technology Corporation, Santa Barbara, CA). ...
... Nanogel erosion was monitored in situ via MALS detection, using a similar method as reported previously. 29 Through this approach, changes in the apparent Mw of nanogels were monitored in real-time, enabling a direct comparison of erosion kinetics for particles in response to DTT and cysteine ( Figure 2). ...
Thermoresponsive hydrogel nanoparticles composed of poly(N-isopropylmethacrylamide) (pNIPMAm) and the disulfide-based cross-linker N,N'-bis(acryloyl)cystamine (BAC) have been prepared using a redox-initiated, aqueous precipitation polymerization approach, leading to improved stability of the disulfide bond compared to traditional thermally-initiated methods. The resultant particles demonstrate complete erosion in response to reducing conditions or thiol competition. This stands in contrast to the behavior of thermally-initiated particles, which retain a cross-linked network following disulfide cleavage due to uncontrolled chain-branching and self-cross-linking side reactions. The synthetic strategy has also been combined with the non-degradable cross-linker N,N-methylenebisacrylamide (BIS) to generate "co-cross-linked" pNIPMAm-BAC-BIS microgels. These particles are redox-responsive, swell upon BAC cross-link scission and present reactive thiols. This pendant thiol functionality was demonstrated to be useful for conjugation of thiol-reactive probes and in reversible network formation by assembling particles cross-linked by disulfide linkages.
... A considerable challenge in characterising the degradation behaviour of nanoparticles is the ability to measure the change in particle sizes whilst simultaneously detecting the formation of any water-soluble products formed as the particles degrade/dissolve. Typically, degradation behaviour is measured in the bulk dispersion using light scattering techniques such as dynamic light scattering (DLS) [19][20][21][22] or multiangle light scattering (MALS) [12,23,24]. However, due to the intensity of scattered light being approximately proportional to the sixth power of the radius, the light scattering from the larger nanoparticles in a distribution can be too intense to allow the detection of the much smaller nanogel fragments or soluble polymers [25]. ...
Nanogels are candidates for biomedical applications, and core-shell nanogels offer the potential to tune thermoresponsive behaviour with the capacity for extensive degradation. These properties were achieved by the combination of a core of poly(N-isopropylmethacrylamide) and a shell of poly(N-isopropylacrylamide), both crosslinked with the degradable crosslinker N,N’-bis(acryloyl)cystamine. In this work, the degradation behaviour of these nanogels was characterised using asymmetric flow field flow fractionation coupled with multi-angle and dynamic light scattering. By monitoring the degradation products of the nanogels in real-time, it was possible to identify three distinct stages of degradation: nanogel swelling, nanogel fragmentation, and nanogel fragment degradation. The results indicate that the core-shell nanogels degrade slower than their non-core-shell counterparts, possibly due to a higher degree of self-crosslinking reactions occurring in the shell. The majority of the degradation products had molecule weights below 10 kDa, which suggests that they may be cleared through the kidneys. This study provides important insights into the design and characterisation of degradable nanogels for biomedical applications, highlighting the need for accurate characterisation techniques to measure the potential biological impact of nanogel degradation products.
... We assume that the broadening of the DLS signal for PNIPAM-based nanogels is related to cleavage of the few existing disulfide bonds under reductive conditions, leading to partial loosening of the network structure and, thus, slight swelling of the nanogels ( Figure 2G). This observation aligns with the behavior of periodate-sensitive microgels [57] and macrosized disulfide-based hydrogels [58] which equally showed gel swelling before full disintegration. ...
Mucosal surfaces pose a challenging environment for efficient drug delivery. Various delivery strategies such as nanoparticles have been employed so far; yet, still yielding limited success. To address the need of efficient transmucosal drug delivery, this report presents the synthesis of novel disulfide‐containing dendritic polyglycerol (dPG)‐based nanogels and their preclinical testing. A bifunctional disulfide‐containing linker is coupled to dPG to act as a macromolecular crosslinker for poly‐N‐isopropylacrylamide (PNIPAM) and poly‐N‐isopropylmethacrylamide (PNIPMAM) in a precipitation polymerization process. A systematic analysis of the polymerization reveals the importance of a careful polymer choice to yield mucus‐degradable nanogels with diameters between 100 and 200 nm, low polydispersity, and intact disulfide linkers. Absorption studies in porcine intestinal tissue and human bronchial epithelial models demonstrate that disulfide‐containing nanogels are highly efficient in overcoming mucosal barriers. The nanogels efficiently degrade and deliver the anti‐inflammatory biomacromolecule etanercept into epithelial tissues yielding local anti‐inflammatory effects. Over the course of this work, several problems are encountered due to a limited availability of valid test systems for mucosal drug‐delivery systems. Hence, this study also emphasizes how critical a combined and multifaceted approach is for the preclinical testing of mucosal drug‐delivery systems, discusses potential pitfalls, and provides suggestions for solutions.
... Since these hydrogels have a high surface area and are subjected to shear forces in the blood, the polymer needs to be stable enough to minimize erosion. For instance, covalently cross-linked PNIPAM resists well to erosion as it is not only covalently cross-linked, but undergoes further self-crosslinking by proton abstraction in the tertiary H of the main chain, while the more biocompatible PVCL is structurally not able to undergo similar self-crosslinking [56]. PVCL is thus more sensitive to shear and tends to decompose starting from the outer corona when subjected to low shear forces [57]. ...
Bio-conjugated hydrogels merge the functionality of a synthetic network with the activity of a biomolecule, becoming thus an interesting class of materials for a variety of biomedical applications. This combination allows the fine tuning of their functionality and activity, whilst retaining biocompatibility, responsivity and displaying tunable chemical and mechanical properties. A complex scenario of molecular factors and conditions have to be taken into account to ensure the correct functionality of the bio-hydrogel as a scaffold or a delivery system, including the polymer backbone and biomolecule choice, polymerization conditions, architecture and biocompatibility. In this review, we present these key factors and conditions that have to match together to ensure the correct functionality of the bio-conjugated hydrogel. We then present recent examples of bio-conjugated hydrogel systems paving the way for regenerative medicine applications.
... It should be noted that the particle radius determined by light scattering did not decrease with the onset of degradation but showed a small increase due to network swelling as consequence of the cleavage of cross-links. Similar obeservations have been found for other degradable microgel systems [52]. From this, we decided to analyze the degradation process by AFM of single deposited particles to obtain more direct visualization of particle degradation. ...
We present a systematic study of self-cross-linked microgels formed by precipitation polymerization of oligo ethylene glycol methacrylates. The cross-linking density of these microgels and, thus, the network flexibility can be easily tuned through the modulation of the reaction temperature during polymerization. Microgels prepared in absence of any difunctional monomer, i.e. cross-linker, show enhanced deformability and particle spreading on solid surfaces as compared to microgels cross-linked with varying amounts of poly(ethylene glycol diacrylate) (PEG-DA) in addition to self-crosslinking. Particles prepared at low reaction temperatures exhibit the highest degree of spreading due to the lightly cross-linked and flexible polymer network. Moreover, AFM force spectroscopy studies suggest that cross-linker-free microgels constitute of a more homogeneous polymer network than PEG-DA cross-linked particles and have elastic moduli at the particle apex that are ~5 times smaller than the moduli of 5 mol-% PEG-DA cross-linked microgels. Resistive pulse sensing experiments demonstrate that microgels prepared at 75 and 80°C without PEG-DA are able to deform significantly to pass through nanopores that are smaller than the microgel size. Additionally, we found that polymer network flexibility of microgels is a useful tool to control the formation of particle dewetting patterns. This offers a promising new avenue for build-up of 2D self-assembled particle structures with patterned chemical and mechanical properties.
... Microgels are physically different from macrogels even though internally have the same gel structure. Indeed, as the high surface to volume ratios are several orders of magnitude larger than those in macrogels, microgels can present a non-uniform distribution of polymer chains throughout the network [23][24][25]. ...
Hydrogels, and in particular microgels, are playing an increasing important role in diverse range of applications due to their hydrophilic, biocompatible, and highly flexible chemical characteristics. On this basis, solution-like environment, non-fouling nature, easy probe accessibility and target diffusion, effective inclusion of reporting moieties can be achieved, making them ideal substrates for bio-sensing applications. In fact, hydrogels are already successfully used in immunoassays as well as sensitive nucleic acid assays, also enabling hydrogel-based suspension arrays. In this review we discuss key parameters of hydrogels in the form of micron-sized particles to be used in sensing applications, paying attention to protein and oligonucleotide (i.e. miRNAs) targets as most representative kind of biomarkers.
... 12,13 They have been demonstrated to be benecial in a wide array of biological applications, including tumor targeting for delivery of therapeutic agents, 14 bioresponsive microlenses, 15 articial platelets 16 and in non-fouling coatings. 17 The versatility in their synthesis also makes it possible to make them more 'biofriendly' through the utilization of biocompatible constituent polymers 18 and degradable crosslinkers, 19,20 further enhancing their suitability for use in biological systems. ...
We present the development and detailed characterization of a range of amine functionalized microgels for utilization in conjugation reactions. Cationic N-isopropylmethacrylamide (NIPMAm) based microgels were synthesized through copolymerization with a primary amine containing monomer, N-(3-aminopropyl)methacrylamide hydrochloride (APMA). A range of synthesis conditions and monomer feed ratios generated microgels of diverse architectures, in different size ranges and with varying amounts of incorporated primary amines. The efficiency of amine incorporation was quantified using a fluorescence-based assay in order to determine the potential applicability of these particles for controlled bioconjugation reactions. The pH responsivity of all microgels was studied via dynamic light scattering and their height profile was investigated through atomic force microscopy following deposition on a functionalized flat substrate. Tunable resistive pulse sensing was employed to characterize microgels with respect to their number densities and molecular weights. These microgels were then conjugated to two dyes, malachite green and rose bengal with the purpose of investigating accessibility of primary amine groups for conjugation reactions. The microgel–dye constructs were then analyzed for dye content/microgel. Finally, the viability of NIH 3T3 fibroblasts incubated in the presence of varying concentrations of non-conjugated and dye conjugated microgels was studied. Confocal imaging revealed low cellular toxicity under conditions of incubation with low concentrations of microgel–dye conjugates, which is promising for eventual utilization of these constructs in bioimaging applications.
... This may be attributed to the absence of tert-C of the polymer chain, which restrains the chain transfer reaction. 38,39 The degraded short polymer chains are easy to be eliminated from the body through the excretion pathway, thereby reducing the cytotoxicity of the materials. 36 The highly sensitive redox-triggered degradation of P(MEO 2 MA-s-s-OEGMA) nanogels demonstrated by the above results offers the possibility of efficient triggered release of payloads in a reducing environment, such as the intracellular space of cancer cells. ...
Stimuli-responsive nanomaterials have a promising prospect of application in controlled intracellular drug delivery. In this paper, we fabricated thermo- and redox-responsive biodegradable nanogels by precipitation copolymerization of 2-(2-methoxyethoxy) ethyl methacrylate, oligo(ethylene glycol) methacrylate, and a disulfide-containing crosslinker N,N’-bis(acryloyl) cystamine. The poly(oligo(ethylene glycol) methacrylate) (POEGMA)-based nanogels exhibit a sharp volume collapse at their volume phase transition temperatures (VPTT), which are tunable in a wide temperature range. By incorporating disulfide bond into polymer networks, the nanogels are endowed with an excellent redox-labile property that they can degrade efficiently into short polymer chains (Mw < 2000) in the presence of reducing agent (glutathione or dithiothreitol). The anticancer drug (doxorubicin, DOX) loaded nanogels display a well-controlled release behavior, that is, low leakage of DOX in physiological condition (only 8.1% in 48 h), while rapid and sufficient release of DOX in reducing environment (92.2% in 48 h). Cell viability assays reveal that the blank nanogels have negligible cytotoxicity against normal cells (HEK-293T cells), while DOX-loaded nanogels present significant inhibitive effect on tumor cells (HeLa cells).
... Previous microgel degradation studies in our lab have revealed that microgel network structure is dictated in some cases by the parent monomer. 34 These studies indicate that microgels composed of pNIPAm exhibit a heterogeneous cross-linker distribution, containing a densely cross-linked core surrounded by a loosely cross-linked periphery. In contrast, microgels composed of pNIPMAm exhibit a more homogeneous cross-linker distribution. ...
We investigate the influence of microgel composition on phase behavior of binary microgel dispersions using poly(N-isopropylacrylamide) microgels cross-linked with 5mol% and 1mol% N,N'-methylenebis(acrylamide), or poly(N-isopropylmethacrylamide) microgels cross-linked with 5mol% N,N'-methylenebis(acrylamide). We then explore the dispersion phase behavior in the context of microgel deposition at a planar interface. These results are then compared to the observed assembly of microgels at curved interfaces, in the form of raspberry-like patchy particles (RLPPs) consisting of a polystyrene core surrounded by a (two-component) microgel shell. Results suggest that microgel composition has a large influence on the ability of binary dispersions to coat planar and curved interfaces. In particular, we demonstrate that binary dispersions of microgels containing higher cross-linker content exhibit decreased packing densities that are very pronounced at a curved interface. To enhance packing density we also explore the use of a two-step coating process to fabricate RLPPs with enhanced control over topography. Development of these complex vehicles is potentially beneficial in the modulation of biological systems where spatial and temporal presentation of molecules can have a large influence on cellular behavior.
Copyright © 2015. Published by Elsevier Inc.
High-speed atomic force microscopy (AFM) is a technique that enables real-time imaging of nanoscale phenomena in solution. It was originally developed to visualize biomolecules, whose dynamics in solution significantly affect the manifestation of their functions, and has contributed to the understanding of molecular mechanisms based on the observation of single-molecule dynamics of proteins. In recent years, its application has broadened to include not only biomolecules, but also the structural dynamics of supramolecular assemblies that associate and dissociate in solution, as well as the evaluation of synthetic molecules such as polymer gels that swell in solution. In this paper, we review some of our recent studies on the application of high-speed AFM to supramolecular polymers and hydrogel particles.
Advancements in nanogel (NG) applications require of precise control over their size, structure, and functionalization. However, synthesis methods have limitations which hinder the incorporation of some functional groups and hamper...
Although the degradation of colloidal particles is one of the most attractive phenomena in the field of biological and environmental science, the degradation mechanism of single particles remains to be elucidated. In this study, in order to clarify the impact of the structure of a single particle on the oxidative degradation processes, thermoresponsive colloidal particles with chemical cleavage points were synthesized as a model, and their degradation behavior was evaluated using high-speed atomic force microscopy (HS-AFM) as well as conventional scattering techniques. The real-time observation of single-particle degradation revealed that the degradation behavior of microgels is governed by their inhomogeneous nanostructure, which originates from the polymerization method and their hydrophilicity. Our findings can be expected to advance the design of carriers for drug-delivery and the understanding of the formation processes of micro (nano)plastics.
Via mesoscale simulations, we characterize the process of controlled degradation of nanogels suspended in a single solvent and those adsorbed at the liquid-liquid interface between two incompatible fluids. Controlled degradation is of interest since it can be used to dynamically tailor size, shape, and transport properties of these soft particles. For the nanogels adsorbed at the liquid-liquid interfaces, controlled degradation can provide a means to dynamically tailor interfacial properties on the nanoscale. To characterize the degradation process, we track the structural characteristics of the remnant nanogel, such as its radius of gyration and shape anisotropy, and spatiotemporal distribution of the broken-off fragments. We use the dissipative particle dynamics approach with an adapted form of the modified segmental repulsive potential. We identify the reverse gel point and characterize the scaling of this point with the finite number of polymer precursors in the system. Furthermore, we characterize the effects of polymer-solvent interactions on the evolution of shape and effective size of the nanogel during the degradation process. We show that for the nanogel adsorbed onto the liquid-liquid interface, the extent of spreading is controlled by the relative extent of degradation. We demonstrate that depending on the properties of the soft interface, broken-off fragments can either disperse into one of the phases or adsorb onto the interface, enhancing the interfacial coverage and controlling interfacial properties on the nanoscale. Our study provides insights into using controlled degradation to dynamically tune shapes of nanocarriers and nanoscale topography at the liquid-liquid interfaces.
Peptide-polymer complementary pairs can provide useful tools for isolating, organizing, and separating biomacromolecules. We describe a procedure for selecting a high affinity complementary peptide-polymer nanoparticle (NP) pair using phage display. A hydrogel copolymer nanoparticle containing a statistical distribution of negatively charged and hydrophobic groups was used to select a peptide sequence from a phage displayed library of >1010 peptides. The NP has low nanomolar affinity for the selected cyclic peptide and exhibited low affinity for a panel of diverse proteins and peptide variants. Affinity arises from the complementary physiochemical properties of both NP and peptide as well as the specific peptide sequence. Comparison of linear and cyclic variants of the peptide established that peptide structure also contributes to affinity. These findings offer a general method for identifying polymer-peptide complementary pairs. Significantly, precise polymer sequences (proteins) are not a requirement, a low information statistical copolymer can be used to select for a specific peptide sequence with affinity and selectivity comparable to that of an antibody. The data also provides evidence for the physiochemical and structural contributions to binding. The results confirm the utility of abiotic, statistical, synthetic copolymers as selective, high affinity peptide affinity reagents.
The preparation of millimeter‐sized poly(acrylamide‐co‐acrylic acid) hydrogel beads via inverse Pickering emulsion polymerization using starch‐based nanoparticles (SNPs) as stabilizers is reported. Amphiphilic starch is fabricated by the introduction of butyl glycidyl ether groups and palmitate groups, and the hydrophobically modified SNPs are fabricated by a nanoprecipitation process. The obtained SNPs could adsorb at oil‐water interfaces to stabilize an inverse Pickering emulsion, and the effects of oil/water volume fraction ratio and SNP concentration on emulsions are comprehensively studied. Poly(acrylamide‐co‐acrylic acid) hydrogel beads with a size of approximately 1 mm are obtained by inverse Pickering emulsion polymerization stabilized by SNPs. The morphology and structure of hydrogel beads are extensively investigated, which confirms that SNPs locate on the surface of hydrogel beads and act as emulsifiers and network structures present inside the beads. Polymerization is also detected to investigate the potential formation mechanism of hydrogel beads. The pH‐responsive property of hydrogel beads and its potential application for drug delivery are also explored.
Control over the size and functional group distribution of soft responsive hydrogel particles is essential for applications such as drug delivery, catalysis and chemical sensing. Traditionally, targeted functional group distributions are achieved with semi-batch techniques which require specialized equipment, while the preparation of size-tailored particles typically involves the use of surfactants. Herein, we present a simple and robust surfactant-free method for the modulation of size and carboxylic acid functional group distribution in poly(N-isopropylacrylamide) thermoresponsive microgels, employing reaction pH as the single experimental parameter. The varying distributions of carboxylic acid residues arise due to differences in kinetic reactivity, which are a function of the degree of dissociation of methacrylic acid, and thus of reaction pH. Incorporated charged residues induce a surfactant-like action during the particle nucleation stage, and impact the final particle size. Characterization with dynamic light scattering, and electron microscopy consistently supports the pH-tailored morphology of the microgels. A mathematical model which accounts for particle deformation on the imaging substrate also shows excellent agreement with the experimental results.
Degradable and thermo-sensitive microgels were successfully prepared via simultaneous quaternization and siloxane condensation during surfactant-free emulsion polymerization with N-vinylcaprolactam (NVCL) as main monomer, and 1-vinylimidazole (VIM) as co-monomer in the presence of (3-bromopropyl)trimethoxysilane (BPTMOS). The formation mechanism of cross-linking network was attributed to the hydrolysis and condensation of the methoxysilyl groups of BPTMOS and the quaternization of imidazole moiety of VIM by the bromine group of BPTMOS, leading to the microgels. The microgels were spherical shape with narrow size distribution, stable in acidic buffer solution, but degradable in neutral and alkaline solutions. The presence of quaternized imidazolium in the same chain segment of Si-O-Si cross-linking points promoted the decomposition of Si-O-Si bonds and hence the degradation of the microgels. The obtained microgels could load and release the model drug, doxorubicin. The size, thermo-sensitivity, stability, degradation rate, and drug release behavior of the resultant microgels could be tuned by controlling the cross-linking degree, chemical composition, and degradation medium.
Microgels constitute a class of materials that have increasingly proven interesting for utilization in biological applications. Due to the versatility provided by microgel constructs with regards to their dimensions, functionality and mechanical properties, their use as building blocks at biological interfaces has been a field of great interest for numerous researchers. In this review, we summarize the advantages that microgel‐based systems provide, when employed for the decoration of biointerfaces. These include control over the chemical structure, crosslink density and thickness of coatings fabricated using microgels. We also review the current state of affairs in the design of microgel‐laden biointerfaces and the challenges that remain unmitigated. Lastly, we provide some examples of current and future work being undertaken and developed with the goal of resolution of some of these issues.
We describe the influence of microgel packing on colloidal-phase mediated heteroaggregation using poly(N-isopropylacrylamide) and poly(N-isopropylmethacrylamide) microgels with 1% mol or 5% mol N,N′-methylenebis(acrylamide) cross-linker. This system is uniquely designed to interrogate the influence of microgel structure and stiffness on microgel deformation at a curved interface by elminating the necessity of electrostatic charge pairing. Microgel monomer and cross-linker content is expected to influence deformation at a curved interface. Microgel deformation and swelling were characterized via atomic force microscopy (AFM) and viscometry. A systematic study of colloidal-phase mediated heteroaggregation was performed at varied effective volume fractions with all microgel compositions. Scanning electron microscopy (SEM) and qNano pore translocation experiments were used to asses the microgel coverage on the resultant raspberry-like particles (RLPs). Results reveal that microgel composition has a strong influence on the efficiency (as determined by microgel coverage) of RLP fabrication. The compositional effects appear to be related to the degree of microgel spreading/deformation at the interface, which is coupled to the influence of packing on assembly fidelity. These findings are widely applicable to systems where microgel deformation occurs at a curved interface. We also demonstrate that qNano pore translocation experiments can be used as a high-throughput method to analyze RLP microgel coverage.
Crosslinker-free poly(n-isopropylacrylamide) (polyNIPAM) particles produced by conventional emulsifier-free heterophase polymerisations contain gels and do not easily and completely disintegrate in water, if at all. These particles, when cooled below lower critical solution temperature (LCST) swell first and then gradually shrink, due to their slow rate of disintegration. We first show that only particles formed using very low monomer concentration, which have a low molecular weight, are fully soluble in water. Then, we describe a seeded semicontinuous route which was designed in order to be able to maintain a low monomer concentration in water in the course of reaction and control the length and location of growing chains. Nanoparticles produced via semicontinuous approach not only disintegrated in water very quickly but also dissolved in water completely as soon as LCST was reached. This finding may also find applications in technologically important processes for dissolution of macromolecules in solvents.
Figure
Schematics of dissolution of polyNIPAM nanoparticles produced via (left) batch process and (right) semicontinuous process in water when the temperature falls below LCST
The field of polymeric biomaterials has received much attention in recent years due to its potential for enhancing the biocompatibility of systems and devices applied to drug delivery and tissue engineering. Such applications continually push the definition of biocompatibility from relatively straightforward issues such as cytotoxicity to significantly more complex processes such as reducing foreign body responses or even promoting/recapitulating natural body functions. Hydrogels and their colloidal analogues, microgels, have been and continue to be heavily investigated as viable materials for biological applications because they offer numerous, facile avenues in tailoring chemical and physical properties to approach biologically harmonious integration. Mechanical properties in particular are recently coming into focus as an important manner in which biological responses can be altered.
Polyglycerol based nanogels (nPG) can function as cellular delivery systems. These nPGs are synthesized with different amine densities (nPG amines) by acid-catalyzed epoxide-opening polymerization using a mini-emulsion approach and surface modification. All the synthesized nanogels are characterized by NMR, dynamic light scattering, and ζ-potential, showing slightly positive surface charge and a homogeneous size of ≈100 nm. The use of these systems for delivery applications is demonstrated with regard to polyplex formation, cytotoxicity, and cellular uptake studies. It is depicted that the CE50 value of the high loaded nPG amines is eight times higher than the low loaded ones. The influence of the amine loading percentage on the nanogel and the effects of polyvalency in these architecture is discussed.
Multilayer coatings made from hydrogel microparticles (microgels) are conceptually very simple materials: thin films composed of microgel building blocks held together by polyelectrolyte "glue". However, the apparent simplicity of their fabrication and structure belies extremely complex properties, including those of "dynamic" coatings that display rapid self-healing behavior in the presence of solvent. This contribution covers our work with these materials, and highlights some of the key findings regarding damage mechanisms, healing processes, film structure/composition, and how the variation of fabrication parameters can impact self-healing behavior.
Microgels based on thermally responsive polymers have been widely investigated in the context of controlled release applications, with increasing recent interest on developing a clearer understanding of what physical, chemical, and biological parameters must be considered to rationally design a microgel to deliver a specific drug at a specific rate in a specific physiological context. In this contribution, we outline these key design parameters associated with engineering responsive microgels for drug delivery and discuss several recent examples of how these principles have been applied to the synthesis of microgels or microgel-based composites. Overall, we suggest that in vivo assessment of these materials is essential to bridge the existing gap between the fascinating properties observed in the lab and the practical use of microgels in the clinic. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3027–3043
The synthesis and characterization of solution-cast, molded gels of N-vinyl formamide (NVF) has not been previously reported even though NVF is an isomer of acrylamide (AAm) and polyacrylamide (PAAm) hydrogels have many commercial applications. Aqueous NVF solutions were cross-linked into gels using a novel cross-linker, 2-(N-vinylformamido)ethylether, and the thermally-activated initiator VA-044. For a given formulation, PNVF gels swell up to twice that of PAAm gels cross-linked with N,N′-methylenebisacrylamide. From swelling and compression measurements, PNVF gels were found to be more hydrophilic than PAAm gels. Flory-Huggins solubility parameters were χ = 0.38ϕ2 + 0.48 for PNVF and χ = 0.31ϕ2 + 0.49 for PAAm, where ϕ2 is the polymer volume fraction. The shear moduli for PNVF and PAAm scale with ϕ and ϕ respectively, consistent with good solvent behavior, also suggesting PNVF is more hydrophilic than PAAm. Similarity of mechanical properties for both gels as a function of ϕ2 suggests that network structures of PNVF and PAAm gels are similar. Fracture strains of both gels declined with ϕ2 by the same linear function while fracture stresses were about 500 kPa regardless of formulation. Since NVF is a liquid monomer, less toxic than AAm and can be hydrolyzed to a cationic form, PNVF gels could become technologically significant. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013
Thermoresponsive microgels consisting of poly(N-isopropylacrylamide) cores and poly(N-isopropylmethacrylamide) shells cross-linked with the hydrolytically degradable cross-linker N,O-dimethacryloyl hydroxylamine were synthesized. Their swelling and erosion properties were characterized using a variety of analytical tools including dynamic light scattering, asymmetrical flow field-flow fractionation–multiangle light scattering, and atomic force microscopy. Shell addition leads to particle densification due to the added polymer and the mechanical, compressive force applied by the shell. Upon hydrolytic degradation of the shell cross-links, mechanical and chemical changes occur throughout the core and shell, leading to softer and more porous shells that permit greater core swelling. Such changes, which are triggered on exposure to physiologic conditions, are of potential utility within the realm of triggered drug delivery.
In this work, a novel thermo and pH responsive magnetic hydrogel nanosphere poly(N-isopropylacrylamide-co-acrylic acid)/Fe(3)O(4) (poly(NIPAAm-co-AA)/Fe(3)O(4)) has been successfully prepared. The magnetic hydrogel nanospheres with thermo and pH-sensitivity were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared-spectrometer (FT-IR), UV-vis absorption spectroscopy, and vibrating sample magnetometer (VSM). The magnetic hydrogel nanospheres exhibited uniform sphere structures and superparamagnetic property. Finally, the drug loading capacities and the releasing behavior of the magnetic hydrogel nanospheres were investigated with doxorubicin hydrochloride (DOX) as an anticancer drug model. The resulting magnetic hydrogel nanospheres exhibited high encapsulation efficiency (95%) to DOX under an appropriate condition. In vitro release experiments revealed that release was faster at pH 5.3 (37°C) than at pH 7.4 (25°C) or pH 7.4 (37°C). The DOX-loaded magnetic hydrogel nanospheres also showed enhanced anticancer effect compared with the free drug in vitro. These presented results suggested that the magnetic hydrogel nanospheres have a potential as tumor targeting drug carrier.
In this study we report the preparation of a new family of core-shell microgels that are water-swellable and have a morphology that is controllable by particle composition. Here, nearly monodisperse core-shell PNVF-xGMA [poly(N-vinylformamide-co-glycidyl methacrylate)] particles (where x is the weight fraction of GMA used) were prepared via nonaqueous dispersion (NAD) polymerization in one step. The shells were PGMA-rich and were cross-linked by reaction of epoxide groups (from GMA) with amide groups (from NVF). The core of the particles was PNVF-rich. A bifunctional cross-linking monomer was not required to prepare these new microgels. The particles had a remarkable "cane-ball"-like morphology with interconnected ridges, and this could be controlled by the value for x. The particle size was tunable over the range 0.8-1.8 μm. Alkaline hydrolysis was used to hydrolyze the PNVF segments to poly(vinylamine), PVAM. The high swelling pressure of the cationic cores caused shell fragmentation and release of some of the core polymer when the hydrolyzed particles were dispersed in pure water. The extent to which this occurred was controllable by x. Remarkably, the PGMA-rich shells could be detached from the hydrolyzed particles by dispersion in water followed by drying. The hydrolyzed PNVF-0.4GMA particles contained both positively and negatively charged regions and the dispersions appeared to exhibit charge-patch aggregation at low ionic strengths. The new cross-linking strategy used here to prepare the PNVF-xGMA particles should be generally applicable for amide-containing monomers and may enable the preparation of a range of new water-swellable microgels.
The application of RNA interference to treat disease is an important yet challenging concept in modern medicine. In particular, small interfering RNA (siRNA) have shown tremendous promise in the treatment of cancer. However, siRNA show poor pharmacological properties, which presents a major hurdle for effective disease treatment especially through intravenous delivery routes. In response to these shortcomings, a variety of nanoparticle carriers have emerged, which are designed to encapsulate, protect, and transport siRNA into diseased cells. To be effective as carrier vehicles, nanoparticles must overcome a series of biological hurdles throughout the course of delivery. As a result, one promising approach to siRNA carriers is dynamic, versatile nanoparticles that can perform several in vivo functions. Over the last several years, our research group has investigated hydrogel nanoparticles (nanogels) as candidate delivery vehicles for therapeutics, including siRNA. Throughout the course of our research, we have developed higher order architectures composed entirely of hydrogel components, where several different hydrogel chemistries may be isolated in unique compartments of a single construct. In this Account, we summarize a subset of our experiences in the design and application of nanogels in the context of drug delivery, summarizing the relevant characteristics for these materials as delivery vehicles for siRNA. Through the layering of multiple, orthogonal chemistries in a nanogel structure, we can impart multiple functions to the materials. We consider nanogels as a platform technology, where each functional element of the particle may be independently tuned to optimize the particle for the desired application. For instance, we can modify the shell compartment of a vehicle for cell-specific targeting or evasion of the innate immune system, whereas other compartments may incorporate fluorescent probes or regulate the encapsulation and release of macromolecular therapeutics. Proof-of-principle experiments have demonstrated the utility of multifunctional nanogels. For example, using a simple core/shell nanogel architecture, we have recently reported the delivery of siRNA to chemosensitize drug resistant ovarian cancer cells. Ongoing efforts have resulted in several advanced hydrogel structures, including biodegradable nanogels and multicompartment spheres. In parallel, our research group has studied other properties of the nanogels, including their behavior in confined environments and their ability to translocate through small pores.
Temperature responsive poly( N ‐isopropylmethacrylamide) (pNIPMAm) microgel capsules around 1 µm containing multiple poly( N ‐isopropylacrylamide) (pNIPAm) nanoinclusions were prepared. This structure was achieved through the addition of a cross‐linked pNIPMAm shell to stable, monodispersed aggregates of pNIPAm chains. This one‐pot synthetic approach resulted in core/shell microgels at high temperature wherein only the shell (pNIPMAm) component contained stable, covalent cross‐links between chains. Thus, upon decreasing the temperature following synthesis, the majority of the encapsulated pNIPAm chains escaped from the shell, resulting in nearly hollow microcapsules. Remnant pNIPAm segments in the microcapsule then form nanoparticulate inclusions upon raising the temperature.
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This paper develops a non‐spherical polymeric micelle using an amphiphilic block copolymer and a porphyrin crystalline structure. The nanoscale polymer micelles were characterized by transmission electron microscopy (TEM) and atomic force microscopy (AFM), revealing particle sizes of approximately 150 nm with a particular shape in the hexagonal lattice. The shape shows the selective uptake efficacy for the HeLa and macrophage cells, and inhibits phagocytosis against the macrophage.
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Conversion versus time curves were measured for poly(N-isopropylacrylamide) microgel latexes prepared by polymerization in water with sodium dodecyl sulfate, SDS. Polymerization rates increased with temperature with methylenebisacrylamide crosslinking monomer consumed faster thanN-isopropylacrylamide. The particle diameter decreased with increasing concentrations of SDS in the polymerization recipe and there was evidence that the rate of polymerization increased somewhat with SDS concentration. Particle formation occurred by homogeneous nucleation as micelles were absent.
Comparison of particle size distributions from dynamic light scattering to those from a centrifugal sizer led to the conclusion that larger particles within a specific latex were less swollen with acetonitrile than were the smaller ones. This was interpreted as evidence for the polymer in larger particles having a higher crosslink density. Particle swelling was estimated from swelling ratios defined as the particle volume at 25 °C divided by the volume at 50 °C. In the absence of crosslinking poly(N-isopropylacrylamide) linear chains would disolve at 25 °C. The swelling results indicated that the average crosslink density in the particles decreased with conversion. This was explained by the observation that the methylenebisacrylamide was consumed more quickly and is typical of crosslinking in emulsion polymerization where polymer particles have high polymer concentrations at their birth.
Surfactant-free, radical precipitation co-polymerization of N-isopropylmethacrylamide (NIPMAm) and the cationic co-monomer N-(3-aminopropyl) methacrylamide hydrochloride (APMH) was carried out to prepare microgels functionalized with primary amines. The morphology and hydrodynamic diameter of the microgels were characterized by atomic force microscopy (AFM) and photon correlation spectroscopy (PCS), with the effect of NaCl concentration and initiator type on the microgel size and yield being investigated. When a V50-initiated reaction was carried out in pure water, relatively small microgels (~160 nm diameter) were obtained in low yield (~20%). However, both the yield and size increased if the reaction was carried out in saline or by using APS as initiator instead of V50. Stable amine-laden microgels in the range from 160 nm to 950 nm in diameter with narrow size distributions were thus produced using reaction media with controlled salinity. Microgel swelling and electrophoretic mobility values as a function of pH, ionic strength and temperature were also studied, illustrating the presence of cationic sidechains and their influence on microgel properties. Finally, the availability of the primary amine groups for post-polymerization modification was confirmed via modification with fluorescein-NHS.
Background
Griseofulvin, an antifungal drug, has recently been shown to inhibit proliferation of various types of cancer cells and to inhibit tumor growth in athymic mice. Due to its low toxicity, griseofulvin has drawn considerable attention for its potential use in cancer chemotherapy. This work aims to understand how griseofulvin suppresses microtubule dynamics in living cells and sought to elucidate the antimitotic and antiproliferative action of the drug.
Methods
The effects of griseofulvin on the dynamics of individual microtubules in live MCF-7 cells were measured by confocal microscopy. Immunofluorescence microscopy, western blotting and flow cytometry were used to analyze the effects of griseofulvin on spindle microtubule organization, cell cycle progression and apoptosis. Further, interactions of purified tubulin with griseofulvin were studied in vitro by spectrophotometry and spectrofluorimetry. Docking analysis was performed using autodock4 and LigandFit module of Discovery Studio 2.1.
Results
Griseofulvin strongly suppressed the dynamic instability of individual microtubules in live MCF-7 cells by reducing the rate and extent of the growing and shortening phases. At or near half-maximal proliferation inhibitory concentration, griseofulvin dampened the dynamicity of microtubules in MCF-7 cells without significantly disrupting the microtubule network. Griseofulvin-induced mitotic arrest was associated with several mitotic abnormalities like misaligned chromosomes, multipolar spindles, misegregated chromosomes resulting in cells containing fragmented nuclei. These fragmented nuclei were found to contain increased concentration of p53. Using both computational and experimental approaches, we provided evidence suggesting that griseofulvin binds to tubulin in two different sites; one site overlaps with the paclitaxel binding site while the second site is located at the αβ intra-dimer interface. In combination studies, griseofulvin and vinblastine were found to exert synergistic effects against MCF-7 cell proliferation.
Conclusions
The study provided evidence suggesting that griseofulvin shares its binding site in tubulin with paclitaxel and kinetically suppresses microtubule dynamics in a similar manner. The results revealed the antimitotic mechanism of action of griseofulvin and provided evidence suggesting that griseofulvin alone and/or in combination with vinblastine may have promising role in breast cancer chemotherapy.
To investigate the outcome of locoregionally advanced nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT) after induction chemotherapy, with or without concomitant chemotherapy.
Between August 2003 and March 2007, 370 patients with locoregionally advanced NPC were treated with IMRT. Presenting stages were stage IIB in 62, stage III in 197, and stage IVA/B in 111 patients. All patients except for 36 patients with cervical lymphadenopathy of 4 cm or less in diameter received 2 cycles of cisplatin-based neoadjuvant chemotherapy. Forty-eight patients received cisplatin-based concurrent chemotherapy as well.
With a median follow-up time of 31 months (range 5 to 61 months), the 3-year local control, regional control, metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS) rates were 95%, 97%, 86%, 81% and 89%, respectively. Multivariate analyses revealed that both age (< or = 60 vs. >60) and N-classification are significant prognosticators for OS (P = 0.001, hazard ratio [HR] 2.395, 95% confidence interval [CI] 1.432-4.003; P = 0.012, hazard ratio [HR] 2.614, 95% confidence interval [CI] 1.235-5.533); And N-classification is the only significant predicative factor for MFS (P = 0.002, [HR] 1.99, 95% CI 1.279-3.098). T-classification and concurrent chemotherapy were not significant prognostic factors for local/regional control, MFS, DFS, or OS. Subgroup analysis revealed that concurrent chemotherapy provided no significant benefit to IMRT in locoregionally advanced NPC, but was responsible for higher rates of grade 3 or 4 acute toxicities (50% vs. 29.8%, P < 0.005). No grade 3 or 4 late toxicity including xerostomia was observed. However, two patients treated with IMRT and neoadjuvant but without concurrent and adjuvant chemotherapy died of treatment related complications.
IMRT following neoadjuvant chemotherapy produced a superb outcome in terms of local control, regional control, MFS, DFS, and OS rates in patients with stage IIB to IVB NPC. Effective treatment strategy is urgently needed for distant control in patients diagnosed with locoregionally advanced NPC.
Chemoresistance is a major obstacle in cancer treatment. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such as the epidermal growth factor receptor (EGFR), which has been shown to increase the sensitivity of cancer cells to taxane chemotherapy. However, delivery represents the main hurdle for the broad development of RNAi therapeutics.
We report here the use of core/shell hydrogel nanoparticles (nanogels) functionalized with peptides that specially target the EphA2 receptor to deliver small interfering RNAs (siRNAs) targeting EGFR. Expression of EGFR was determined by immunoblotting, and the effect of decreased EGFR expression on chemosensitization of ovarian cancer cells after siRNA delivery was investigated.
Treatment of EphA2 positive Hey cells with siRNA-loaded, peptide-targeted nanogels decreased EGFR expression levels and significantly increased the sensitivity of this cell line to docetaxel (P < 0.05). Nanogel treatment of SK-OV-3 cells, which are negative for EphA2 expression, failed to reduce EGFR levels and did not increase docetaxel sensitivity (P > 0.05).
This study suggests that targeted delivery of siRNAs by nanogels may be a promising strategy to increase the efficacy of chemotherapy drugs for the treatment of ovarian cancer. In addition, EphA2 is a viable target for therapeutic delivery, and the siRNAs are effectively protected by the nanogel carrier, overcoming the poor stability and uptake that has hindered clinical advancement of therapeutic siRNAs.
Nanoparticles in a biological fluid (plasma, or otherwise) associate with a range of biopolymers, especially proteins, organized into the “protein corona” that is associated with the nanoparticle and continuously exchanging with the proteins in the environment. Methodologies to determine the corona and to understand its dependence on nanomaterial properties are likely to become important in bionanoscience. Here, we study the long-lived (“hard”) protein corona formed from human plasma for a range of nanoparticles that differ in surface properties and size. Six different polystyrene nanoparticles were studied: three different surface chemistries (plain PS, carboxyl-modified, and amine-modified) and two sizes of each (50 and 100 nm), enabling us to perform systematic studies of the effect of surface properties and size on the detailed protein coronas. Proteins in the corona that are conserved and unique across the nanoparticle types were identified and classified according to the protein functional properties. Remarkably, both size and surface properties were found to play a very significant role in determining the nanoparticle coronas on the different particles of identical materials. We comment on the future need for scientific understanding, characterization, and possibly some additional emphasis on standards for the surfaces of nanoparticles.
• bionanoscience
• mass spectrometry
• interactions
• proteomics
• human plasma
Due to their small size, nanoparticles have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technology. Despite the remarkable speed of development of nanoscience, relatively little is known about the interaction of nanoscale objects with living systems. In a biological fluid, proteins associate with nanoparticles, and the amount and presentation of the proteins on the surface of the particles leads to an in vivo response. Proteins compete for the nanoparticle "surface," leading to a protein "corona" that largely defines the biological identity of the particle. Thus, knowledge of rates, affinities, and stoichiometries of protein association with, and dissociation from, nanoparticles is important for understanding the nature of the particle surface seen by the functional machinery of cells. Here we develop approaches to study these parameters and apply them to plasma and simple model systems, albumin and fibrinogen. A series of copolymer nanoparticles are used with variation of size and composition (hydrophobicity). We show that isothermal titration calorimetry is suitable for studying the affinity and stoichiometry of protein binding to nanoparticles. We determine the rates of protein association and dissociation using surface plasmon resonance technology with nanoparticles that are thiol-linked to gold, and through size exclusion chromatography of protein-nanoparticle mixtures. This method is less perturbing than centrifugation, and is developed into a systematic methodology to isolate nanoparticle-associated proteins. The kinetic and equilibrium binding properties depend on protein identity as well as particle surface characteristics and size.
Nanosized hydrogels (nanogels) have attracted considerable attention as multifunctional polymer-based drug delivery systems. Their versatility is demonstrated both in drug encapsulation and drug release. Nanogels can be designed to facilitate the encapsulation of diverse classes of bioactive compounds. With optimization of their molecular composition, size and morphology, nanogels can be tailor-made to sense and respond to environmental changes in order to ensure spatial and stimuli-controlled drug release in vivo. This manuscript aims to highlight recent advances in the interface between biology and nanomedicine with the emphasis on nanogels as carriers for controlled drug delivery.
The crosslinking copolymerization of acrylamide (AA) and N,N′-methylene-bis-acrylamide (BA) has been studied by high resolution 1H-NMR with copolymerization in situ. This procedure allows calculation of the copolymer composition at zero degree of conversion and as a function of the polymerization time. Monomer reactivity ratios were calculated by the Kelen-Tüdös method in the pre-gel state and during gelation. Sequence distributions of both comonomers were then characterized.
Microgels/nanogels are crosslinked polymeric particles, which can be considered as hydrogels if they are composed of water soluble/swellable polymer chains. They possess high water content, biocompatibility, and desirable mechanical properties. They offer unique advantages for polymer-based drug delivery systems (DDS): a tunable size from nanometers to micrometers, a large surface area for multivalent bioconjugation, and an interior network for the incorporation of biomolecules. Present and future microgel applications require a high degree of control over properties. They include stability for prolonged circulation in the blood stream, novel functionality for further bioconjugation, controlled particle size with uniform diameter, and biodegradability for sustained release of drugs for a desired period of time and facile removal of empty devices. This review describes the recent developments of microgel/nanogel particles as drug delivery carriers for biological and biomedical applications. Various synthetic strategies for the preparation of microgels/nanogels are detailed, including photolithographic and micromolding methods, continuous microfluidics, modification of biopolymers, and heterogeneous free radical and controlled/living radical polymerizations.
The synthesis and characterization of base labile Poly(N- isopropylacrylamide) networks utilizing a reactive cross linker was performed in the study. PNIPAm hydrogels were prepared by radical polymerization using hydrogels with different compositions of cross-linker and the degree of swelling as well as the stimuli-responsive behavior with temperature was analyzed. The thermal behavior of the hydrogel in water was studied by demonstrating the utility of the 2,3,4,5,6-tetrafluoro-1,4-phenylene diacrylate as a degradable cross linker under basic conditions. The water-swollen PNIPAm gel was treated with different kinds of nucleophilic agents, as ammonia, and their dissolution by amines was indicated by deep purple coloration of the resulting polymer solution. The color change is added in the advantage of a base-labile cross-linker that enables the dissolution of the hydrogel under certain biological conditions with applications in sensing devices.
A series of novel nanogels with both thermoresponsive and hydrolytically degradable properties were synthesized by emulsion polymerization of N-isopropylacrylamide (NIPAAm) and dextran-lactate-2-hydroxyethyl methacrylate (DEXlactateHEMA), a hydrolytically degradable and cross-linkable dextran derivative, without using low molar mass surfactants. Various lengths of degradable oligolactate units and different precursor feeding ratios between NIPAAm and DEXlactateHEMA were used to synthesize the nanogels. FTIR measurements confirmed the chemical compositions and hydrolytic degradation of the synthesized nanogels. Dynamic light scattering measurements of the hydrodynamic radii of the nanogels in phosphate buffer saline (PBS, pH 7.4) against temperature and angle revealed that the nanogels were thermoresponsive with a lower critical solution temperature (LCST) of 32 °C. The size and morphology changes of the nanogels with degradation were investigated by using transmission electron microscopy, atomic force microscopy, and static light scattering techniques. AFM image analysis and Holtzer plots revealed that the nanogels became more rigid with degradation in water solutions.
Degradable hydrogel particles have been integrated into a variety of biomedical applications, but there are no studies to date illustrating the detailed morphological changes that occur in single microgels during erosion in complex media. Herein, we use ambient and in-liquid atomic force microscopy (AFM) to interrogate changes in morphology of substrate-supported microgels synthesized from poly(N-isopropylmethacrylamide-co-acrylic acid) cross-linked with a hydrolyzable cross-linker (N,O-dimethacryloyl hydroxylamine). Erosion was monitored under physiological conditions (37 °C in serum-supplemented PBS). At early time points of erosion, the microgel swelling capacity increases due to the hydrolysis of the cross-linker and a concomitant decrease in network connectivity. After longer erosion times and extensive polymer loss, the remnant degraded microgel reveals a high polymer density toward the center of the particle with a low-density corona, which most likely results from internal cross-linking of the polymer. These detailed morphological changes illustrate the complex nature of erodible microgels, which would be difficult to observe using ensemble-averaged analyses.
We have explored a synthetic route toward poly(N-isopropylacrylamide) (pNIPAm) nanogels by growing a pNIPAm shell onto a metal nanoparticle seed. Nuclei compatible with precipitation polymerization of thermoresponsive polymers were formed by adsorption of NH2-terminated pNIPAm on Au nanoparticles. The adsorbed pNIPAm layer, when heated above the LCST, collapses onto the Au nanoparticle surface. This polymer layer thus serves as a hydrophobic nucleus for growing pNIPAm oligoradicals during polymer synthesis, resulting in the formation of a pNIPAm shell. Etching of the Au core from the polymer-coated particles with KCN results in hollow hydrogel nanoparticles. The rate of Au core etching as studied by the decrease in Au nanoparticle plasmon absorbance was shown to depend on polymer shell composition, shell thickness, and the thermosensitivity of the polymer. Efficient quenching of fluorophores incorporated in the polymer shell by the core Au nanoparticles was observed; however, the shell fluorescence was regained after core dissolution. Future studies are aimed at understanding the encapsulation of small molecules and proteins within the nanocapsule structure.
Thermosensitive crosslinked polymer latexes have been synthesized by precipitation polymerization of N-isopropylmethacrylamide (NIPMAM) as a main monomer, methylene bis-acrylamide (MBA) as a crosslinker, and potassium persulfate (KPS) as the initiator. Polymerizations kinetics were first investigated by studying both the influence of crosslinker (MBA) and initiator (KPS) concentrations and temperature effects on the polymerization conversion, the particle size, and water-soluble polymer (WSP) as a function of time. Particle size analysis by Scanning Electron Microscopy (SEM) showed that a short nucleation step afforded the synthesis of highly monodispersed latexes. In addition, a strong dependence of WSP formation on MBA and KPS concentration and polymerization temperature was found, as well. Comparison of particle size by SEM and quasielastic light scattering clearly evidenced the dramatic effect of temperature on particle size. Lower critical solubility temperatures (LCST) of latexes were determined and compared. Finally, based on these results, the mechanism of particle formation in this polymerization process is discussed. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1823–1837, 1999
Self-rupturing microcapsules are prepared by layer-by-layer coating of degradable dextran-hydroxyethyl methacrylate microgels with the polyelectrolytes poly(allylamine hydrochloride) and sodium poly(styrene sulfonate). When the microgel core degrades, the swelling pressure increases and, at a critical value of the swelling pressure, the surrounding membrane suddenly ruptures (see Figure). This type of microcapsule could be very promising for pulsed drug delivery.
We have found that the free-radical polymerization of N-isopropylacrylamide (NIPAM) in water initiated by potassium persulfate at temperatures well above the phase transition temperature leads to the formation of gel nanospheres instead of linear chains even in the absence of added cross-linker. These particles, with radii of several hundred nanometers, resemble normal NIPAM microgels in every aspect except that they are characterized by lower solid contents and larger swelling ratios than N,N′-methylene bis(acrylamide) cross-linked microgels synthesized under similar conditions. Without added cross-linker, the formation of gel nanospheres is attributed to self-cross-linking by chain transfer reaction during and after polymerization.
We describe the synthesis and characterization of degradable nanogels that display bulk erosion under physiologic conditions (pH = 7.4, 37 degrees C). Erodible poly(N-isopropylmethacrylamide) nanogels were synthesized by copolymerization with N,O-(dimethacryloyl) hydroxylamine, a cross-linker previously used in the preparation of nontoxic and biodegradable bulk hydrogels. To monitor particle degradation, we employed multiangle light scattering and differential refractometry detection following asymmetrical flow field-flow fractionation. This approach allowed the detection of changes in nanogel molar mass and topology as a function of both temperature and pH. Particle erosion was evident from both an increase in nanogel swelling and a decrease in scattering intensity as a function of time. Following these analyses, the samples were recovered for subsequent characterization by direct particle tracking, which yields hydrodynamic size measurements and enables number density determination. Additionally, we confirmed the conservation of nanogel stimuli-responsivity through turbidity measurements. Thus, we have demonstrated the synthesis of degradable nanogels that erode under conditions and on time scales that are relevant for many drug delivery applications. The combined separation and light scattering detection method is demonstrated to be a versatile means to monitor erosion and should also find applicability in the characterization of other degradable particle constructs.
Degradable polymers are beginning to play an increasing role as materials for environmental and medical applications. Understanding factors that control erosion, such as bond cleavage and the dissolution and diffusion of degradation products, will be critical to the future development of these materials. Erosion kinetics, photomicroscopy, and infrared spectroscopy were used to understand the erosion mechanism of two families of degradable polymers, polyanhydrides and polyesters. Polyanhydrides exhibit behavior more characteristic of surface erosion, whereas the polyesters exhibit bulk erosion patterns. Control of erosion times from a few days to several years can be achieved by a judicious choice of monomer units and bond selection.
The development of protein-based vaccines remains a major challenge in the fields of immunology and drug delivery. Although numerous protein antigens have been identified that can generate immunity to infectious pathogens, the development of vaccines based on protein antigens has had limited success because of delivery issues. In this article, an acid-sensitive microgel material is synthesized for the development of protein-based vaccines. The chemical design of these microgels is such that they degrade under the mildly acidic conditions found in the phagosomes of antigen-presenting cells (APCs). The rapid cleavage of the microgels leads to phagosomal disruption through a colloid osmotic mechanism, releasing protein antigens into the APC cytoplasm for class I antigen presentation. Ovalbumin was encapsulated in microgel particles, 200-500 nm in diameter, prepared by inverse emulsion polymerization with a synthesized acid-degradable crosslinker. Ovalbumin is released from the acid-degradable microgels in a pH-dependent manner; for example, microgels containing ovalbumin release 80% of their encapsulated proteins after 5 h at pH 5.0, but release only 10% at pH 7.4. APCs that phagocytosed the acid-degradable microgels containing ovalbumin were capable of activating ovalbumin-specific cytoxic T lymphocytes. The acid-degradable microgels developed in this article should therefore find applications as delivery vehicles for vaccines targeted against viruses and tumors, where the activation of cytoxic T lymphocytes is required for the development of immunity.
Plasmid DNA was directly encapsulated into biocompatible polymer microparticles via radical polymerization in an inverse emulsion system. Acrylamide-based microspheres 0.2-1 microm in diameter were prepared using an acid-cleavable difunctional monomer. Retention of the DNA payload at physiological pH with complete release under acidic conditions at lysosomal pH was demonstrated. By trapping the plasmid DNA within the cross-linked microparticle, enzymatic degradation was prevented when exposed to serum nucleases. For vaccine development, these delivery vehicles were also investigated for their ability to generate immune responses when delivered to phagocytic cells of the immune system. Encapsulated plasmid DNA demonstrated immunostimulatory activity in macrophages, leading to cytokine secretion of IL-6 with a response approximately 40-fold higher than that achieved with DNA alone.
The structure of temperature-sensitive poly(N-isopropylacrylamide) microgels in dilute suspension was investigated by means of small-angle neutron scattering. A direct modeling expression for the scattering intensity distribution was derived which describes very well the experimental data at all temperatures over an extensive q range. The overall particle form as well as the internal structure of the microgel network is described by the model. The influence of temperature, cross-linking density, and particle size on the structure was revealed by radial density profiles and clearly showed that the segment density in the swollen state is not homogeneous, but gradually decays at the surface. The density profile reveals a box profile only when the particles are collapsed at elevated temperatures. An increase of the cross-linking density resulted in both an increase of the polymer volume fraction in the inner region of the particle and a reduction of the smearing of the surface. The polymer volume fraction inside the colloid decreased with increasing particle size. The structural changes are in good agreement with the kinetics of the emulsion copolymerization used to prepare the microgel colloids.
This investigation presents a study of the internal structure of poly(NIPAM/xBA) microgel particles (NIPAM and BA are N-isopropylacrylamide and N,N'-methylene bisacrylamide, respectively). In this study, x is the wt % of BA used during microgel synthesis. Two values of x were used to prepare the microgels, 1 and 10. The microgel dispersions were investigated using photon correlation spectroscopy (PCS) and small-angle neutron scattering (SANS). These measurements were made as a function of temperature in the range 30-50 degrees C. Scattering maxima were observed for the microgels when the dispersion temperatures were less than their volume phase transition temperatures. The SANS data were fitted using a model which consisted of Porod and Ornstein-Zernike form factors. The analysis showed that the macroscopic hydrodynamic diameter of the microgel particles and the submicroscopic mesh size of the network are linearly related. This is the first study to demonstrate affine swelling for poly(NIPAM/xBA) microgels. Furthermore, the mesh size does not appear to be strongly affected by x. The data suggest that the swollen particles have a mostly homogeneous structure, although evidence for a thin, low segment density shell is presented. The study confirms that poly(NIPAM/xBA) microgel particles have a core-shell structure. The shell has an average thickness of approximately 20 nm for poly(NIPAM/1BA) particles which appears to be independent of temperature over the range studied. The analysis suggests that the particles contained approximately 50 vol % water at 50 degrees C. The molar mass of the poly(NIPAM/1BA) microgel particles was estimated as 6 x 10(9) g mol(-1).
The last decade of research in the physical sciences has seen a dramatic increase in the study of nanoscale materials. Today, "nanoscience" has emerged as a multidisciplinary effort, wherein obtaining a fundamental understanding of the optical, electrical, magnetic, and mechanical properties of nanostructures promises to deliver the next generation of functional materials for a wide range of applications. While this range of efforts is extremely broad, much of the work has focused on "hard" materials, such as Buckyballs, carbon nanotubes, metals, semiconductors, and organic or inorganic dielectrics. Meanwhile, the soft materials of current interest typically include conducting or emissive polymers for "plastic electronics" applications. Despite the continued interest in these established areas of nanoscience, new classes of soft nanomaterials are being developed from more traditional polymeric constructs. Specifically, nanostructured hydrogels are emerging as a promising group of materials for multiple biotechnology applications as the need for advanced materials in the post-genomic era grows. This review will present some of the recent advances in the marriage between water-swellable networks and nanoscience.
Thermoresponsive poly(N-isopropyl acrylamide) (pNIPAm) microgels possessing a hollow structure have been synthesized from core-shell nanoparticles upon oxidation of the particle core, followed by removal of the produced polymer segments by centrifugation. N,N'-(1,2-dihydroxyethylene)bisacrylamide (DHEA) is used as a cross-linker for preparing the degradable core, whereas N,N'-methylenebis(acrylamide) (BIS) is used as a cross-linker to add a nondegradable pNIPAm shell. Addition of NaIO(4) to a suspension of these particles in water leads to controlled degradation of the particle core by cleavage of the 1,2-glycol bond in DHEA. Fluorescence spectroscopy, UV/Vis spectroscopy, and photon correlation spectroscopy are used to characterize the hollow particles produced.
Poly(N-isopropylmethacrylamide) (PiPMA) has one more methyl group at each monomeric unit than poly(N-isopropylacrylamide) (PiPA). By use of laser light scattering (LLS) and ultrasensitive differential scanning calorimetry (US-DSC) we have investigated the association and dissociation of PiPMA chains in water. LLS studies reveal that PiPMA chains form larger aggregates at a temperature above its lower critical solution temperature (LCST) as the chain molar mass (Mw) decreases. In comparison with PiPA aggregates, PiPMA aggregates show a larger ratio of average radius of gyration to average hydrodynamic radius ( / ), indicating that PiPMA aggregates are looser. US-DSC studies show PiPMA chains have smaller enthalpy change (DeltaH) and entropy change (DeltaS) than PiPA chains during the phase transition, indicating that PiPMA chains have smaller conformational change. Our experiments demonstrate that the additional methyl groups in PiPMA chains restrain the intrachain collapse and interchain association, leading the phase transition to occur at a higher temperature.
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