Thermosensitive poly(N-isopropylacrylamide)-b-poly(ε-caprolactone) nanoparticles for efficient drug delivery system

To investigate thermosensitive polymeric nanoparticle, amphiphilic block copolymers of poly(N-isopropylacrylamice)-b-poly(ε-caprolactone) (PNPCL) with different PCL block lengths were synthesized by hydroxy-terminated poly(N-isopropyoacrylamide) (PNiPAAm) initiated ring opening polymerization of ε-caprolactone. Owing to their amphiphilic characteristics, the block copolymers formed self-assembled polymeric nanoparticles in aqueous milieus with thermosensitive PNiPAAm shell compartment. The characterizations of the nanoparticles revealed that the PNPCL nanoparticles showed PCL block length dependent physicochemical characters such as particle sizes, critical aggregation concentrations, and core hydrophobicities. Moreover, the thermosensitive PNiPAAm shells conferred unique temperature responsive properties such as phase transitions with temperature elevation over its lower critical solution temperature (LCST). The temperature induced phase transition resulted in the formation of PNiPAAm hydrogel layer on the PNPCL nanoparticle surface. The drug release tests revealed that the formation of thermosensitive hydrogel layer resulted in the enhanced sustained drug release patterns by acting as an additional diffusion barriers. Therefore, the introduction of thermosensitive polymers on polymeric nanoparticles might be a potential approaches to modulate drug release behaviors.     

Thermosensitive graft copolymers of an amphiphilic macromonomer and N-vinylcaprolactam: synthesis and solution properties in dilute aqueous solutions below and above the LCST

Thermosensitive graft copolymers of N-vinylcaprolactam and poly(ethylene oxide)-alkyl methacrylate macromonomer were synthesised with different grafting densities. Association of the polymers in dilute aqueous solutions was studied below and above the LCST using static and dynamic light scattering, microcalorimetry, pressure perturbation calorimetry (PPC), and fluorescence probe experiments. Owing to the amphiphilicity of the grafts, the most densely grafted polymer forms intrapolymeric structures while the less grafted polymers build up mixtures of intra- and interpolymeric associates at temperatures below LCST. These assemblies solubilise hydrophobic substances such as pyrene. Upon heating, the graft copolymers aggregate in water and form nano-sized particles, mesoglobules. Heat induced particles are exceptionally stable against further aggregation, and the dilution of the solutions has no effect on the particle size or shape. The structure of the particles can be frozen by physically crosslinking the collapsed polymers with a phenol, e.g. 1,2-benzenediol.     

Synthesis and thermosensitive behavior of dextran graft copolymers containing poly (N-vinylcaprolactam) side chains

New graft copolymers were synthesized by grafting N-vinylcaprolactam onto dextran. Their composition and structure were investigated by elemental analyses, infrared spectra and thermogravimetric analyses. By optical transmittance measurements, it was found that the aqueous solutions of these graft copolymers showed a temperature-dependent transmittance change due to the introduction of thermosensitive poly (N-vinylcaprolactam) graft chains. Moreover, the lower critical solution temperature (LCST) of the graft copolymer in aqueous solution was dependent on its grafting extent and concentration. The LCST value was found to increase with the increase of the grafting extent and decrease with the increase of the copolymer concentration. With these stimuli-response properties, such polysaccharide derivative may hold potential applications in biomedicine and biotechnology.     

Thermo-responsive brush copolymers with structure-tunable LCST and switchable surface wettability

Thermo-responsive brush copolymers poly(methyl methacrylate (MMA)-co-2-(2-bromoisobutyryloxy)ethyl methacrylate (BIEM)-graft-(N-isopropyl-acrylamide) (NIPAAm)) were synthesized using Cu-mediated “living” radical polymerization (LRP) approach. Varied grafting densities of the brushes were obtained through adjusting backbone structure as random, gradient and block respectively. The effect of grafting densities on their thermo-responsive phase transition behaviors in aqueous solution and on surface were investigated in detail. The lower critical solution temperature (LCST) of brush copolymers in solution was adjusted as 35, 37 and 38 °C through random, gradient and block backbone structure respectively. Their structure tunable thermo-responsive phase transition in solution were further confirmed by the different micelle aggregation behaviors above LCST which monitored by transmission electron microscopy (TEM) images and dynamic light scattering (DLS). In addition, surfaces modified by the resulted brush copolymers have a temperature tunable wettability based on thermo-responsive phase transition in solid, the similar WCA variation range of three brush copolymers implies that the composition of backbone does not much affect the switchable wettability of surfaces.     

Toward an understanding of thermoresponsive transition behavior of hydrophobically modified N-isopropylacrylamide copolymer solution

Poly(N-isopropylacrylamide-co-vinyl laurate)(PNIPAAm-co-VL) copolymers were prepared at various feed ratios via conventional radical random copolymerization. The formation, composition ratios and molecular weight of copolymers were examined. The thermoresponsive behaviors of PNIPAAm and PNIPAAm-co-VL solutions at low and high concentrations were intensively investigated by turbidity measurement, Micro-DSC, temperature-variable state fluorescence, ¹H NMR and dynamic light scattering (DLS). Several important results were obtained that (1) incorporation of PVL results in much lower and broader LCST regions of the copolymer solutions, and facilitates the formation of hydrophobic microdomains far below LCST, causing a pronounced aggregation in solutions (2) temperature-variable ¹H NMR spectra shows that during the phase transition, the ‘penetration’ of PNIPAAm into the hydrophobic core is a process accompanied with a transition of isopropyl from hydration to dehydration as well as a self-aggregation of hydrophobic chains at different temperature stages (3) according to the ¹H NMR spectra of polymer solutions obtained at varied temperatures, the microdomains from hydrophobic VL moieties have a different accessibility for isopropyl groups and the entire chains during phase transition (4) temperature-variable DLS demonstrates that the temperature-induced transition behavior of copolymers is supposedly divided into three stages: pre-LCST aggregation (<20 °C), coil-globule transition at LCST (20-25 °C) and post-LCST aggregation (>25 °C).     

Poly(N‐isopropylacrylamide‐co‐hydroxyethyl methacrylate) graft copolymers and their application as carriers for drug delivery system

Poly(N‐isopropylacrylamide‐co‐hydroxyethyl methacrylate) [P(NIPAM‐co‐HEMA)] copolymer was synthesized by controlled radical polymerization from respective N‐isopropylacrylamide (NIPAM) and hydroxyethyl methacrylate (HEMA) monomers with a predetermined ratio. To prepare the thermosensitive and biodegradable nanoparticles, new thermosensitive graft copolymer, poly(L ‐lactide)‐graft‐poly(N‐isoporylacrylamide‐co‐hydroxyethyl methacrylate) [PLLA‐g‐P(NIPAM‐co‐HEMA)], with the lower critical solution temperature (LCST) near the normal body temperature, was synthesized by ring opening polymerization of L ‐lactide in the presence of P(NIPAM‐co‐HEMA). The amphiphilic property of the graft copolymers was formed by the grafting of the PLLA hydrophobic chains onto the PNIPAM based hydrophilic backbone. Therefore, the graft copolymers can self‐assemble into uniformly spherical micelles ò about 150–240 nm in diameter as observed by the field emission scanning electron microscope and dynamic light scattering. Dexamethasone can be loaded into these nanostructures during dialysis with a relative high loading capacity and its in vitro release depends on temperature. Above the LCST, most of the drugs were released from the drug‐loaded micelles, whereas a large amount of drugs still remains in the micelles after 48 h below the LCST. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Fabrication of an asymmetric hollow particle with a thermo-sensitive PNIPAM inside corona

Asymmetric hollow particles were fabricated from the self-assembly of block copolymers poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine) (PNIPAM-b-P4VP) and poly(ethylene glycol)-block-poly(acrylic acid) (PEG-b-PAA) in water. The shell of the asymmetric hollow particle was a polyion complex layer which acted as a semipermeable membrane. Outside the shell were PEG hydrophilic layers and inside were thermo-sensitive PNIPAM chains. When temperature was higher than the lower critical solution temperature (LCST) of PNIPAM, it became insoluble and collapsed onto the shrinking shell to form a hydrophobic lumen. The whole process was characterized by dynamic light scattering (DLS), static light scattering (SLS), transmission electron microscopy (TEM), atom force microscopy (AFM) and nuclear magnetic resonance (NMR).     

Synthesis and self-assembly of a new amphiphilic thermosensitive poly(N-vinylcaprolactam)/poly(ε-caprolactone) block copolymer

New amphiphilic thermosensitive poly(N-vinylcaprolactam)/poly(ε-caprolactone) (PNVCL-b-PCL) block copolymers were synthesized by ring-opening polymerization of ε-caprolactone with hydroxy-terminated poly(N-vinylcaprolactam) (PNVCL-OH) as a macroinitiator. The structures of the polymers were confirmed by IR, ¹H NMR and GPC. The critical micelle concentrations of copolymer in aqueous solution measured by the fluorescence probe technique reduced with the increasing of the proportion of hydrophobic parts, so did the diameter and distribution of the micelles determined by dynamic light scattering. The shape observed by transmission electron microscopy (TEM) demonstrated that the micelles are spherical. On the other hand, the UV–vis measurement showed that polymers exhibit a reproducible temperature-responsive behavior with a lower critical solution temperature (LCST). The LCST of PNVCL-OH can be adjusted by controlling the molecular weights, and that of copolymers can be adjusted by controlling the compositions and the concentration. Variable temperature TEM measurements demonstrated that LCST transition was the result of transition of individual micelles to larger aggregates.     

Light scattering and microcalorimetry studies on aqueous solutions of thermo-responsive PVCL-g-PEO copolymers

Dilute aqueous solutions of thermo-responsive poly(N-vinyl caprolactam)-graft-polyethylene oxide (PVCL-g-PEO) copolymers were studied by light scattering and high sensitivity differential scanning microcalorimetry. These copolymers are double hydrophilic at low temperatures, but become amphiphilic upon heating the solutions above the cloud point temperature of the PVCL segments (T_CP). The self-assembly properties of the copolymers are investigated by dynamic light scattering as a function of the temperature, degree of grafting and concentration. It was found that a certain critical polymer concentration is needed for the polymers to form stable aggregates. These structures are expected to consist of a hydrophobic PVCL core, stabilized by a hydrophilic PEO shell. The size of these aggregates increases with the degree of grafting. Microcalorimetry results revealed that the grafting of PVCL with hydrophilic PEO does not influence the phase transition enthalpy of PVCL.     

Electrostatic self-assembly of thermally responsive zwitterionic poly(N-isopropylacrylamide) and poly(ethylene oxide) modified with ionic groups

The electrostatic self-assembly of thermally responsive copolymers of N-isopropylacrylamide (NIPAM) containing up to 10 mol% of the sulfobetaine monomer 3-[N-(3-methacrylamidopropyl)-N,N-dimethyl]ammoniopropane sulfonate) (SPP) and poly(ethylene oxide) modified with terminal cationic or anionic groups (IMPEO) was studied in methanol and aqueous solutions by static light scattering, turbidimetry, viscometry, and rheological measurements. The formation of graft-like complexes at stoichiometric dipole-ion ratio and their self-association was detected in the dilute and semidilute regime at temperatures below and above the lower critical solution temperature (LCST). The ability of the graft-like complexes to associate below the LCST depended on the sulfobetaine content of the copolymers, the functionality of IMPEO, and the polymer concentration. The effect of the IMPEO terminal group on the solution behavior of the graft-like complexes was less pronounced. With increasing temperature their semidilute aqueous solutions form gels, stable over a wide temperature range.     

Thermo-sensitive polymers based on graft polysiloxanes

The synthesis of novel polymers obtained by grafting poly(dimethyl siloxane) with NIPAM, N,N′-dimethyl acrylamide (DMA) and copolymers of NIPAM with DMA and butyl acrylate using SET-LRP technique is presented. The polymers were characterized by ¹H NMR, fluorescence spectroscopy, and DSC. The thermo-sensitivity and the LCST as well as the aggregation phenomena during phase transition are evidenced by dynamic light scattering (DLS) and rheology coupled with small angle light scattering (SALS). Rheological and Rheo-SALS measurements proved to be useful tools to characterize the macroscopic behavior but also to evidence structural changes below and above the LCST for the analyzed systems. Good correlation was found between rheological, rheo-SALS and DLS data.     

Synthesis and thermosensitive behavior of dextran graft copolymers containing poly(N-vinylcaprolactam) side chains

New graft copolymers were synthesized by grafting N-vinylcaprolactam onto dextran. Their composition and structure were investigated by elemental analyses, infrared spectra and thermogravimetric analyses. By optical transmittance measurements, it was found that the aqueous solutions of these graft copolymers showed a temperature-dependent transmittance change due to the introduction of thermosensitive poly(N-vinylcaprolactam) graft chains. Moreover, the lower critical solution temperature (LCST) of the graft copolymer in aqueous solution was dependent on its grafting extent and concentration. The LCST value was found to increase with the increase of the grafting extent and decrease with the increase of the copolymer concentration. With these stimuli-response properties, such polysaccharide derivative may hold potential applications in biomedicine and biotechnology. Translated from Acta Scientiarum Naturalium Universitatis Sunyatseni, 2006, 45(1): 50–52 [译自: 中山大学学报 (自然科学版)]     

Thermoresponsive core-shell-corona micelles of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene

Core-shell-corona micelles with a thermoresponsive shell self-assembled by triblock copolymer of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene (PEG₄₅-b-PNIPAM₁₆₈-b-PS₄₆) are studied by ¹H NMR, light scattering and atomic force microscopy. The thermoresponsive triblock copolymer, which has a relatively short hydrophobic PS block, can disperse in water at room temperature to form core-shell-corona micelles with the hydrophobic PS block as core, the thermoresponsive PNIPAM block as shell and the hydrophilic PEG block as corona. At temperature above lower critical solution temperature (LCST) of the PNIPAM block, the PNIPAM chains gradually collapse on the PS core to shrink the size and change the structure of the resultant core-shell-corona micelles with temperature increasing. It is found that there possibly exists an interface between the PNIPAM shell and PEG corona of the core-shell-corona micelles at temperature above LCST of the PNIPAM block.     

Effect of intermolecular and intramolecular forces on hydrodynamic diameters of poly(N‐isopropylacrylamide) copolymers in aqueous solutions

A novel copolymer, poly(N‐isopropylacrylamide‐co‐hydroxypropyl methacrylate‐co‐3‐trimethoxysilypropyl methacrylate) has been synthesized and the hydrodynamic diameters in various aqueous solutions under different temperatures are determined by dynamic light scattering. The results show that the hydrodynamic diameters of copolymers have no obvious change in each working solution below lower critical solution temperature (LCST); across LCST, the diameters increased suddenly at different initial temperature in various aqueous solutions; above LCST, they decreased slightly as the temperature increased in UHQ water, and increased continuously with increasing temperature or salt concentration in saline solutions, and reduced with the rising of pH value in pH buffer. These are attributed to different intermolecular and intramolecular forces leading to disparity in dimension, conformation, and LCST of copolymers. The hydrogen bonding between water molecules and copolymer chains could maintain size and conformation of copolymer single chain; the hydrogen bonding between amide linkages and hydrophobic interactions between isopropyl groups result in intramolecular collapse and intermolecular aggregation; the electrostatic repulsion weakens aggregation extent of copolymers. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Association behavior of thermo-responsive block copolymers based on poly(vinyl ethers)

Thermo-sensitive nanosized structures have been prepared in water from poly(methyl vinyl ether)-block-poly(isobutyl vinyl ether) (PMVE-b-PIBVE) block copolymers. The composition and the architecture (diblock and triblock architectures) of the PMVE-b-PIBVE copolymers have been varied. The investigated copolymers had an asymmetric composition with a major PMVE block. While the PIBVE blocks are hydrophobic, the PMVE blocks are hydrophilic at room temperature and become hydrophobic above their demixing temperature (around 36 °C) as a result of the lower critical solution temperature (LCST) behavior. At room temperature, the amphiphilic copolymers aggregate in water above a critical micelle concentration, which has been experimentally measured by hydrophobic dye solubilization. The hydrodynamic diameter of the structures formed above the cmc has been measured by dynamic light scattering (DLS) while their morphology has been studied by transmission electron microscopy (TEM). ¹H NMR measurements in D₂O at room temperature reveal that the aggregates contain PIBVE insoluble regions surrounded by solvated PMVE chains. These investigations have shown that polydisperse spherical micelles are formed for asymmetric PMVE-b-PIBVE copolymers containing at least 9 IBVE units. For copolymers containing less IBVE units, loose aggregates are formed.Finally, the thermo-responsive, reversible properties of these structures have been investigated. Above the cloud point of the copolymers, the loose aggregates precipitate while the micelles form large spherical structures.     

Thermosensitive poly(N-isopropylacrylamide) nanocapsules with controlled permeability

In this paper, novel thermosensitive poly(N-isopropylacrylamide) (PNIPAM) nanocapsules with temperature-tunable diameter and permeability are reported. Firstly, the core-shell composite microparticles were synthesized by precipitation polymerization with isothiocyanate fluorescein (FITC) entrapped SiO₂ as core and cross-linked PNIPAM as shell. Then, the SiO₂ core was etched by hydrofluoric acid at certain condition and the pre-trapped FITC molecules remained within the inner cavity. The FITC release profile and TEM studies clearly indicate that the release behavior of FITC could be controlled effectively by the external temperature. Above the LCST of PNIPAM (32 °C), the dehydrated PNIPAM shell inhibited the release of FITC from the internal cavity while below its LCST, the fluorophore could permeate the swollen shell easily.     

Synthesis and association properties of thermoresponsive and permanently cationic charged block copolymers

Atom transfer radical polymerization (ATRP) was used to prepare thermosensitive cationic block copolymers of (3-acrylamidopropyl)-trimethylammonium chloride (AMPTMA) and N-isopropylacrylamide (NIPAAM) with different block lengths. By using ethyl-2-chloropropionate (ECP) as initiator and CuCl/CuCl₂/tris(2-dimethylaminoethyl)amine (Me₆TREN) catalytic system in DMF:water 50:50 (v/v) mixtures at 20 °C the polymerization was controlled. The association properties in NaCl aqueous solution were studied as a function of temperature and polymer concentration by dynamic light scattering, NMR spectroscopy, fluorescence spectroscopy and energy filtered-transmission electron microscopy. The block copolymers formed micellar aggregates above the lower critical solution temperature (LCST) of pNIPAAM. The LCST is strongly influenced by the relative length of the two blocks and is significantly higher than that of pure pNIPAAM. The size of core and shell of the micelles is discussed in terms of block copolymer composition.     

Stimuli-induced core-corona inversion of micelles of water-soluble poly(sodium 2-(acrylamido)-2-methyl propanesulfonate-b-N-isopropylacrylamide)

Micelles of poly(sodium 2-(acrylamido)-2-methylpropanesulfonate-b-N-isopropylacrylamide) (PAMPS-b-PNIPAM) have been investigated in aqueous solutions using various techniques including dynamic light scattering, scanning electron microscopy, transmission electron microscopy and ζ-potential measurements. It was found that PAMPS-b-PNIPAM produces two distinct types of micelle structures; one is a PAMPS-core/PNIPAM-corona structure and the other is a PNIPAM-core/PAMPS-corona structure. The PAMPS-core micelle with the PNIPAM-corona was obtained by insolubilizing the PAMPS block with ferric ion (Fe³⁺) at room temperature, and the PNIPAM-core micelle with the PAMPS-corona was obtained by increasing the solution temperature above the lower critical solution temperature (LCST) of the PNIPAM block in the absence of the Fe³⁺ ion. We have also found that the inversion from one type to the other is reversible. The transformation from the PAMPS-core micelle to the PNIPAM-core micelle was induced by removing Fe³⁺ ion using ethylenediaminetetraacetic acid followed by elevating the temperature above the LCST of the PNIPAM block, while the reverse transformation was triggered by adding Fe³⁺ ion at a lower temperature.     

Thermosensitive micelles from PEGylated oligopeptides

New thermosensitive and micelle-forming diblock copolymers were synthesized by amide coupling of carboxylated methoxy-poly(ethylene glycols) with hydrophobic oligopeptides and characterized by means of ¹H NMR spectroscopy, elemental analysis, and dynamic light scattering (DLS) measurements. Stable micelles were formed from copolymers composed of MPEG550 or MPEG750 as a hydrophilic segment and the hexapeptide, GlyPheLeuGlyPheLeuEt, as a hydrophobic segment. All the present diblock copolymers exhibited thermosensitive properties by showing a lower critical solution temperature (LCST) in water. The LCST of the copolymers composed of relatively shorter MPEG350 and GlyPheLeuAspEt₂ was observed at much higher temperature (48 °C) compared with the LCST (29 °C) of the cyclotriphosphazene analogues bearing the same hydrophilic and hydrophobic segments as side groups. The remarkably lower LCST of the cyclotriphosphazene analogue is presumed to be due to the structural effect of the cis-nongeminal conformation of its three hydrophobic oligopeptides, but such a structural effect was found to diminish as the chain lengths of the hydrophilic and hydrophobic blocks of the copolymers increased.     

Thermotropic color changing nanoparticles prepared by encapsulating blue polystyrene particles with a poly‐N‐isopropylacrylamide gel

Water‐dispersed thermotropic nanoparticles with core‐shell structures were synthesized by the in situ polymerization of a lightly crosslinked shell of poly(N‐ isopropylacrylamide) [poly(NIPAM)] onto blue polystyrene cores. At room temperature, the thermal responsive outer shell is hydrophilic and is in a fully swollen gel state; but as the temperature is raised above 31°C, it becomes increasingly hydrophobic and eventually collapses as the temperature reaches the lower critical solution temperature (LCST) of the poly(NIPAM). Passing through the LCST has a drastic effect on the color of the latex solution, which exhibited an intense blue color at room temperature and gradually pales or lightens as the temperature is raised above 31°C. Analysis using spectroscopic and dynamic light scattering techniques showed that it is a reversible process. Microscopy evaluation of samples dried by the evaporation of water at temperatures above and below the LCST revealed that the swollen/collapse state of the polymer shell influenced the morphology of the dry state. Drying at room temperature resulted in thin films in which only particles of sizes corresponding to the polystyrene core are clearly seen in the microscopy images; but for samples prepared above the LCST, the images revealed a morphology made of much larger particles with diameters of 400–500 nm. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007