Thermo-induced Collapse Research Articles

In Situ SERS Sensing by a Laser-Induced Aggregation of Silver Nanoparticles Templated on a Thermoresponsive Polymer.

A stimuli-responsive (pH- and thermoresponsive) micelle-forming diblock copolymer, poly(1,2-butadiene)290-block-poly(N,N-dimethylaminoethyl methacrylate)240 (PB-b-PDMAEMA), was used as a polymer template for the in situ synthesis of silver nanoparticles (AgNPs) through Ag+ complexation with PDMAEMA blocks, followed by the reduction of the bound Ag+ with sodium borohydride. A successful synthesis of the AgNPs on a PB-b-PDMAEMA micellar template was confirmed by means of UV–Vis spectroscopy and transmission electron microscopy, wherein the shape and size of the AgNPs were determined. A phase transition of the polymer matrix in the AgNPs/PB-b-PDMAEMA metallopolymer hybrids, which results from a collapse and aggregation of PDMAEMA blocks, was manifested by changes in the transmittance of their aqueous solutions as a function of temperature. A SERS reporting probe, 4-mercaptophenylboronic acid (4-MPBA), was used to demonstrate a laser-induced enhancement of the SERS signal observed under constant laser irradiation. The local heating of the AgNPs/PB-b-PDMAEMA sample in the laser spot is thought to be responsible for the triggered SERS effect, which is caused by the approaching of AgNPs and the generation of “hot spots” under a thermo-induced collapse and the aggregation of the PDMAEMA blocks of the polymer matrix. The triggered SERS effect depends on the time of a laser exposure and on the concentration of 4-MPBA. Possible mechanisms of the laser-induced heating for the AgNPs/PB-b-PDMAEMA metallopolymer hybrids are discussed.

Temperature-induced unloading of liposomes bound to microgels

Bilayer lipid vesicles (liposomes) composed of zwitter-ionic (electroneutral) egg yolk lecithin and anionic phosphatidylserine were loaded with a water-soluble antitumor antibiotic Dox and electrostatically adsorbed onto the surface of thermo-sensitive microgels synthesized from 3-( N,N -dimethylamino)propylmethacrylamide, N,N -methylenebisacrylamide and 2,2′-azobis(2-methylpropionamidine) dihydrochloride. The resulting saturated microgel-liposomes complex with ultimately adsorbed 40 liposomes retains encapsulated drug in water solution at 25 °C. An increase in temperature induces a collapse of the microgel core and squeezing of the liposome shell, followed by liposome disruption and a release of encapsulated Dox. An intensive Dox leakage begins when temperature reaches 39 °C; a maximum amount of Dox is released within 5 min after starting the temperature trigger. The results are of importance for constricting of thermo-sensitive drug carries and developing protocols for the most productive drug release. • Anionic liposomes preserve their integrity after binding to cationic microgels. • Thermo-induced collapse of microgel core destroys the outer liposome layer. • Liposome disruption is accompanied by a fast release of encapsulated drug. • Sharp rise in the released drug was observed in between 39 and 41 °C. • Rigid latex particles bound to microgels form incompressible outer shell.

Synthesis and characterization of phenylboronic acid-containing polymer for glucose-triggered drug delivery+

ABSTRACT Thermo-, pH- and glucose-responsive polymeric nanoparticles are of great interest in developing a self-regulated drug delivery system. The novel core-shell nanoparticles were synthesized by self-assembly of a phenylboronic acid-based block copolymer poly-(N-isopropylacrylamide)-block-poly(3-acrylamidophenylboronic acid) (PNIPAM136-b-PAPBA16) and a fluorescent complex glucosamine-poly(N-isopropylacrylamide)/Eu(III) (GA-PNIPAM)/Eu(III) based on the cross-linking between PBA- and GA-containing blocks in this work. The nanoparticles can be tuned via thermo-induced collapse or glucose-induced swelling at appropriate pH and temperatures; they had an average kinetic radius was about 80nm, and which showed excellent fluorescence. MTT assays revealed the nanocarriers had no significant cytotoxic response of the micelle when it was observed in the cell line over the concentration range from 0.1 to 1000 μg/ml at any exposure times.

1H NMR study of thermo-induced collapse of polyelectrolyte microgels

1H NMR study of thermo-induced collapse of polyelectrolyte microgels

Payload release by liposome burst: Thermal collapse of microgels induces satellite destruction

We present a smart liposome carrier system for stimulated release, consisting of cationic, thermo-responsive microgels. At low temperature, the swollen microgels adsorb about 200 anionic liposomes, 50 nm in diameter, per microgel. When heated from 39 °C to 41 °C, the microgel–liposome complex particles collapse from approx. 370 nm down to approx. 270 nm. Upon the thermo-induced collapse, the adsorbed liposome satellite layer is squeezed until the initially spherical liposomes explode and release their payload (antitumor drug doxorubicin) into the surrounding. This burst release mechanism, taking place over a narrow temperature range, is newly reported and of possible biomedical importance.

Schizophrenic Core–Shell Microgels: Thermoregulated Core and Shell Swelling/Collapse by Combining UCST and LCST Phase Transitions

A variety of slightly cross-linked poly(2-vinylpyridine)-poly(N-isopropylacrylamide) (P2VP-PNIPAM) core-shell microgels with pH- and temperature-responsive characteristic were prepared via seeded emulsion polymerization. Negatively charged sodium 2,6-naphthalenedisulfonate (2,6-NDS) could be internalized into the inner core, followed by formation of (P2VPH(+)/SO3(2-)) supramolecular complex through the electrostatic attractive interaction in acid condition. The thermoresponsive characteristic feature of the (P2VPH(+)/SO3(2-))-PNIPAM core-shell microgels was investigated by laser light scattering and UV-vis measurement, revealing an integration of upper critical solution temperature (UCST) and lower critical solution temperature (LCST) behaviors in the temperature range of 20-55 °C. The UCST performance arised from the compromised electrostatic attractive interaction between P2VPH(+) and 2,6-NDS at elevated temperatures, while the subsequent LCST transition is correlated to the thermo-induced collapse of PNIPAM shells. The controlled release of 2,6-NDS was monitored by static fluorescence spectra as a function of temperature change. Moreover, stopped-flow equipped with a temperature-jump accessory was then employed to assess the dynamic process, suggesting a millisecond characteristic relaxation time of the 2,6-NDS diffusion process. Interestingly, the characteristic relaxation time is independent of the shell cross-link density, whereas it was significantly affected by shell thickness. We believe that these dual thermoresponsive core-shell microgels with thermotunable volume phase transition may augur promising applications in the fields of polymer science and materials, particularly for temperature-triggered release.

Synthesis of Amphiphilic Tadpole-Shaped Linear-Cyclic Diblock Copolymers via Ring-Opening Polymerization Directly Initiating from Cyclic Precursors and Their Application as Drug Nanocarriers

We report on the facile synthesis of well-defined amphiphilic and thermoresponsive tadpole-shaped linear-cyclic diblock copolymers via ring-opening polymerization (ROP) directly initiating from cyclic precursors, their self-assembling behavior in aqueous solution, and the application of micellar assemblies as controlled release drug nanocarriers. Starting from a trifunctional core molecule containing alkynyl, hydroxyl, and bromine moieties, alkynyl-(OH)-Br, macrocyclic poly(N-isopropylacrylamide) (c-PNIPAM) bearing a single hydroxyl functionality was prepared by atom transfer radical polymerization (ATRP), the subsequent end group transformation into azide functionality, and finally the intramacromolecular ring closure reaction via click chemistry. The target amphiphilic tadpole-shaped linear-cyclic diblock copolymer, (c-PNIPAM)-b-PCL, was then synthesized via the ROP of ε-caprolactone (CL) by directly initiating from the cyclic precursor. In aqueous solution at 20 °C, (c-PNIPAM)-b-PCL self-assembles into spherical micelles consisting of hydrophobic PCL cores and well-solvated coronas of cyclic PNIPAM segments. For comparison, linear diblock copolymer with comparable molecular weight and composition, (l-PNIPAM)-b-PCL, was also synthesized. It was found that the thermoresponsive coronas of micelles self-assembled from (c-PNIPAM)-b-PCL exhibit thermoinduced collapse and aggregation at a lower critical thermal phase transition temperature (T(c)) compared with those of (l-PNIPAM)-b-PCL. Temperature-dependent drug release profiles from the two types of micelles of (c-PNIPAM)-b-PCL and (l-PNIPAM)-b-PCL loaded with doxorubicin (Dox) were measured, and the underlying mechanism for the observed difference in releasing properties was proposed. Moreover, MTT assays revealed that micelles of (c-PNIPAM)-b-PCL are almost noncytotoxic up to a concentration of 1.0 g/L, whereas at the same polymer concentration, micelles loaded with Dox lead to ∼60% cell death. Overall, chain topologies of thermoresponsive block copolymers, that is, (c-PNIPAM)-b-PCL versus (l-PNIPAM)-b-PCL, play considerable effects on the self-assembling and thermal phase transition properties and their functions as controlled release drug nanocarriers.

Thermo- and light-regulated fluorescence resonance energy transfer processes within dually responsive microgels

We report on the fabrication of thermo- and light-responsive P(NIPAM-DMNA-NBDAE-RhBEA) microgels consisting of N-isopropylacrylamide (NIPAM), photocleavable moieties, 5-(2′-(dimethylamino)ethoxy)-2-nitrobenzyl acrylate (DMNA), fluorescence resonance energy transfer (FRET) donors, 4-(2-acryloyloxyethylamino)-7-nitro-2,1,3-benzoxadiazole (NBDAE), and rhodamine B-based FRET acceptors (RhBEA) via the free radical emulsion polymerization technique. Thermo-induced collapse and swelling of responsive microgels above and below the lower critical solution temperatures (LCSTs), respectively, can finely tune the spatial proximity between NBDAE and RhBEA dyes, leading to the facile modulation of FRET efficiencies. Upon UV irradiation (pH 8.5), DMNA moieties within microgels undergo photolysis reactions and the formation of sodium carboxylate residues on microgel scaffolds results in elevated LCST. Thus, UV irradiation of microgel dispersions in the intermediate temperature range (between the LCST of original microgels and that of UV-irradiated microgels) can directly lead to the re-swelling of initially collapsed microgels. The incorporation of FRET pairs (NBDAE and RhBEA dyes) allow for the in situ monitoring of thermo- and UV irradiation-induced volume phase transitions (VPTs) of the reported dually responsive microgels. This work represents the first report of thermoresponsive microgels with VPTs tunable by photolabile 2-nitrobenzyl ester moieties.

FRET-Derived Ratiometric Fluorescent K+ Sensors Fabricated from Thermoresponsive Poly(N-isopropylacrylamide) Microgels Labeled with Crown Ether Moieties

We report on the fabrication of ratiometric fluorescent K(+) sensors based on thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) microgels covalently incorporated with K(+)-recognizing 4-acrylamidobenzo-18-crown-6 residues (B18C6Am), fluorescence resonance energy transfer (FRET) donor dyes, 4-(2-acryloyloxyethylamino)-7-nitro-2,1,3-benzoxadiazole (NBDAE), and rhodamine-B-based FRET acceptors (RhBEA) by utilizing K(+)-induced changes in microgel volume phase transition (VPT) temperatures. P(NIPAM-B18C6Am-NBDAE-RhBEA) microgels were synthesized via the free radical emulsion copolymerization technique. The spatial proximity between FRET pairs (NBDAE and RhBEA dyes) within microgels can be tuned via thermoinduced collapse and swelling of thermoresponsive microgels above and below VPT temperatures, leading to the facile modulation of FRET efficiencies. B18C6Am moieties within P(NIPAM-B18C6Am-NBDAE-RhBEA) microgels can preferentially capture K(+) via the formation of 1:1 molecular recognition complexes, resulting in the enhancement of microgel hydrophilicity and elevated VPT temperatures. Thus, the gradual addition of K(+) into microgel dispersions at intermediate temperatures, i.e., between VPT temperatures of P(NIPAM-B18C6Am-NBDAE-RhBEA) microgels in the absence and presence of K(+) ions, respectively, can directly lead to the reswelling of initially collapsed microgels. This process can be monitored by changes in fluorescence intensity ratios, i.e., FRET efficiencies. The presence of FRET pairs within P(NIPAM-B18C6Am-NBDAE-RhBEA) microgels allows for the facile in situ monitoring of thermoinduced and K(+)-induced VPTs of dually responsive microgels. The response time for fluorescent K(+)-sensing was further investigated via the stopped-flow technique, which reveals that the process completes within ∼4 s. This work represents the first report of thermoresponsive microgel-based ratiometric fluorescent sensors for both K(+) ions and temperatures.

Metal-Chelating and Dansyl-Labeled Poly(N-isopropylacrylamide) Microgels as Fluorescent Cu2+ Sensors with Thermo-Enhanced Detection Sensitivity

We report on the fabrication of Cu2+-sensing thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) microgels labeled with metal-chelating acceptor and fluorescent reporter moieties. Cu2+ detection sensitivity can be considerably enhanced via thermo-induced collapse of the sensing matrix, which can easily optimize the relative spatial distribution of Cu2+-binding sites and fluorescence readout functionalities. A novel picolinamine-containing monomer with Cu2+-binding capability, N-(2-(2-oxo-2-(pyridine 2-yl-methylamino)ethylamino)ethyl)acrylamide (PyAM, 3), was synthesized at first. Nearly monodisperse Cu2+-sensing microgels were prepared via emulsion polymerization of N-isopropylacrylamide (NIPAM) in the presence of a nonionic surfactant, N,N'-Methylene-bis(acrylamide) (BIS), PyAM (3), and fluorescent dansylaminoethyl- acrylamide (DAEAM, 5) monomers at around neutral pH and 70 degrees C. At 20 degrees C, as-synthesized microgels in their swollen state can selectively bind Cu2+ over other metal ions (Hg2+, Mg2+, Zn2+, Pb2+, Ag+, and Al3+), leading to prominent quenching of fluorescence emission intensity. Above the volume phase transition temperature, P(NIPAM-co-PyAM-co-DAEAM) microgels exhibit increased fluorescence intensity. It was observed that Cu2+ detection sensitivity can be dramatically enhanced via thermo-induced microgel collapse at elevated temperatures. At a microgel concentration of 3.0x10(-6) g/mL, the detection limit drastically improved from approximately 46 nM at 20 degrees C to approximately 8 nM at 45 degrees C. The underlying mechanism for this novel type of sensor with thermotunable detection sensitivity was tentatively proposed.

Real-time measurement of the mass of water expelled by poly(N-isopropylacrylamide) brushes upon thermo-induced collapse

An impedance analysis of quartz crystal microbalance data reveals the mass of water expelled by poly(N-isopropylacrylamide) brushes upon the thermo-induced collapse.

Thermo-Induced Formation of Unimolecular and Multimolecular Micelles from Novel Double Hydrophilic Multiblock Copolymers of N,N-Dimethylacrylamide and N-Isopropylacrylamide

Two novel double hydrophilic multiblock copolymers of N,N-dimethylacrylamide and N-isopropylacrylamide, m-PDMAp-PNIPAMq, with varying degrees of polymerization (DPs) for PDMA and PNIPAM sequences (p and q) were synthesized via consecutive reversible addition-fragmentation chain transfer (RAFT) polymerizations using polytrithiocarbonate (1) as the chain transfer agent (Scheme 1), where PDMA is poly(N,N-dimethylacrylamide) and PNIPAM is poly(N-isopropylacrylamide). The DPs of PDMA and PNIPAM sequences were determined by 1H NMR, and the block numbers, i.e., number of PDMAp-PNIPAMq sequences (n), were obtained by comparing the molecular weights of multiblock copolymers to that of cleaved products as determined by gel permeation chromatography (GPC). m-PDMA42-PNIPAM37 and m-PDMA105-PNIPAM106 multiblock copolymers possess number-average molecular weights (Mn) of 4.62x10(4) and 9.53x10(4), respectively, and the polydispersities (Mw/Mn) are typically around 1.5. Block numbers of the obtained multiblock copolymers are ca. 4, which are considerably lower than the numbers of trithiocarbonate moieties per chain of 1 (approximately 20) and m-PDMAp precursors (approximately 6-7). PDMA homopolymer is water soluble to 100 degrees C, while PNIPAM has been well known to exhibit a lower critical solution temperature (LCST) at ca. 32 degrees C. In aqueous solution, m-PDMA42-PNIPAM37 and m-PDMA105-PNIPAM106 multiblock copolymers molecularly dissolve at room temperature, and their thermo-induced collapse and aggregation properties were characterized in detail by a combination of optical transmittance, fluorescence probe measurements, laser light scattering (LLS), and micro-differential scanning calorimetry (micro-DSC). It was found that chain lengths of PDMA and PNIPAM sequences exert dramatic effects on their aggregation behavior. m-PDMA105-PNIPAM106 multiblock copolymer behaves as protein-like polymers and exhibits intramolecular collapse upon heating, forming unimolecular flower-like micelles above the thermal phase transition temperature. On the other hand, m-PDMA42-PNIPAM37 multiblock copolymer exhibits collapse and intermolecular aggregation, forming associated multimolecular micelles at elevated temperatures. The intriguing aggregation behavior of this novel type of double hydrophilic multiblock copolymers argues well for their potential applications in many fields such as biomaterials and biomedicines.