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Thermo-responsive amphiphilic poly(methyl methacrylate)-b-poly(N-isopropylacrylamide-co-N-acryloxysuccinimide) (PMMA-b-P(NIPAAm-co-NAS)) block copolymer was synthesized by successive RAFT polymerizations. The uncross-linked micelles were facilely prepared by directly dissolving the block copolymer in an aqueous medium, and the shell cross-linked (SCL) micelles were further fabricated by the addition of ethylenediamine as a di-functional cross-linker into the micellar solution. Optical absorption measurements showed that the LCST of uncross-linked and cross-linked micelles was 31.0°C and 40.8°C, respectively. Transmission electron microscopy (TEM) showed that both uncross-linked and cross-linked micelles exhibited well-defined spherical shape in aqueous phase at room temperature, while the SCL micelles were able to retain the spherical shape with relatively smaller dimension even at 40°C due to the cross-linked structure. In vitro drug release study demonstrated a slower and more sustained drug release behavior from the SCL micelles at high temperature as compared with the release profile of uncross-linked micelles, indicating the great potential of SCL micelles developed herein as novel smart carriers for controlled drug release., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Galactosylated and fluorescein isothiocyanate (FITC) labeled polycaprolactone-g-dextran (Gal-PCL-g-Dex-FITC) polymers were synthesized. The grafted polymers can self-assemble into stable micelles in aqueous medium and in serum. Transmission electron microscopy (TEM) images showed that the self-assembled micelles were regularly spherical in shape. Micelle size determined by size analysis was around 120 nm. The anti-inflammation drug prednisone acetate as a model drug was loaded in the polymeric micelles, and the in vitro drug release was investigated. The galactosylated micelles could be selectively recognized by HepG2 cells and subsequently accumulate in HepG2 cells. The in vivo study demonstrated the relative uptake of the micelles by liver is much higher than the other tissues, indicating that the galactosylated micelles have great potential as a liver targeting drug carrier.

Thermosensitive and biotinylated biotin-poly (N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-block-poly(methyl methacrylate) (biotin-P(NIPAAm-co-HMAAm)-b-PMMA) block copolymers were designed and synthesized. The conjugation of biotin molecule with the copolymer as well as the capability of easily functionalizing with ligands for pretargeting approach of the biotinylated multifunctional drug carrier was confirmed by a novel method called capillary electrophoresis immunoassay (CEIA) based on enhanced chemiluminescence (CL) detection. The biotin-P(NIPAAm-co-HMAAm)-b-PMMA copolymer was capable of self-assembling into nanometer-sized micelle. The anticancer drug methotrexate (MTX), used as a model drug, was loaded in the self-assembled micelles and the thermo-triggered release behavior of MTX was investigated., ((c) 2008 Wiley Periodicals, Inc.)

An interesting transition from spherical micelles to vesicles, which was time and temperature dependent, was observed for the first time; it is tentatively attributed to the thermal hysteresis of temperature-responsive poly(N-isopropylacrylamide).

Novel micelles, comprising hydrophilic PEG shells, hydrophobic PMMA cores, and thermosensitive P(NIPAAm-co-HMAAm) segments were self-assembled from the biotin-PEG-b-P(NIPAAm-co-HMAAm)-b-PMMA triblock copolymer. The thermosensitive micelles exhibited superior stability and showed thermotriggered drug release behavior upon temperature alterations. The fluorescence spectroscopy and confocal microscopy studies confirmed that the self-assembled biotinylated micelles can be specifically and efficiently bonded to cancer cells with the administration of biotin-transferrin, suggesting that the multifunctional micelles have great potential as drug carriers for tumor targeting chemotherapy.

Shell cross-linked (SCL) thermoresponsive hybrid micelles consisting of a cross-linked thermoresponsive hybrid hydrophilic shell and a hydrophobic core domain were synthesized from poly(N-isopropylacrylamide-co-3- (trimethoxysilyl)propyl methacrylate)-b-polymethyl methacrylate (P(NIPAAm-co-MPMA)-b-PMMA) amphiphilic block copolymers. Transmission electron microscopy (TEM) images showed that the SCL micelles formed regularly globular nanoparticles. The SCL micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 degrees C, observed by turbidity measurements and dynamic light scattering (DLS). The drug loading and in vitro drug release properties of the SCL micelles bearing a silica-reinforced PNIPAAm shell were further studied, which showed that the SCL micelles exhibited a much improved entrapment efficiency (EE) as well as a slower release rate which allowed the entrapped molecules to be slowly released over a much longer period of time as compared with pure PNIPAAm-b-PMMA micelles.

A multifunctional micellar drug carrier formed by the thermosensitive and biotinylated double-hydrophilic block copolymer (DHBC), biotin-poly(ethylene glycol)-block-poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide) (biotin-PEG-b-P(NIPAAm-co-HMAAm)), was designed and prepared. The P(NIPAAm-co-HMAAm) block with an molar feed ratio of NIPAAm and HMAAm (10:1) was identified to exhibit the reversible phase transition at the lower critical solution temperature (LCST) of 36.7 degrees C. Cytotoxicity study indicated that the biotin-PEG-b-P(NIPAAm-co-HMAAm) copolymer did not exhibit obvious cytotoxicity. The block copolymer was capable of self-assembling into micelle in water. Transmission electron microscopy showed that the self-assembled micelles were regularly spherical in shape. The anticancer drug methotrexate (MTX) was loaded in the micelles and the in vitro release behaviors of MTX at different temperatures were investigated. The association of biotin molecule with the copolymer was confirmed by a unique capillary electrophoresis immunoassay (CEIA) method based on enhanced chemiluminescence (CL) detection. The fluorescence spectroscopy analysis as well as confocal microscopy studies confirmed the DHBC drug carriers could specifically and efficiently bind to cancer cells with pretreatment of biotin-transferrin, suggesting that the multifunctionalized DHBC micelle may be a useful drug carrier for tumor targeting.

An amphiphilic tris(dibenzoylmethanato)europium(III) (Eu(DBM)(3)) coordinated P(MMA-co-EIPPMMA)-co-P(NIPAAm-co-NDAPM) copolymer was synthesized, which exhibited good biocompatibility and emitted strong red luminescence (MMA, methyl methacrylate; EIPPMMA, 4-(1-ethyl-1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenyl methacrylate; NIPAAm, N-isopropylacrylamide; NDAPM, (N-(3-dimethylamino)propyl)methacrylamide). The copolymer could self-assemble into micelles of size around 260 nm, and the micelles were thermosensitive at around body temperature. The drug-loaded micelles showed thermosensitive controlled drug release, and the paclitaxel loaded micelles were capable of being internalized into the tumor cells (A549) and exhibited obvious inhibition to the growth of A549 cells. Importantly, in vivo study showed the self-assembled micelles of Eu(DBM)(3) coordinated P(MMA-co-EIPPMMA)-co-P(NIPAAm-co-NDAPM) copolymer uptaken by the larvae of zebrafish could be easily tracked and be eliminated from the body within several days.

A novel seven-arm star block copolymer poly(L-lactide-star block-N-isopropylacrylamide) (PLLA-sb-PNIPAAm), comprised of a hydrophobic poly(L-lactide) (PLLA) arm and an average of six hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) arms, was designed and synthesized. The amphiphilic PLLA-sb-PNIPAAm copolymer was capable of self-assembling into nano-sized micelle in water, which was confirmed by FT-IR, 1H NMR and fluorescence spectroscopy. Transmission electron microscopy images showed that these nano-sized micelles were regularly spherical in shape. Micelle size determined by size analysis was around 100 nm in diameter. The micelles showed reversible dispersion/aggregation in response to temperature changes through an outer polymer shell of PNIPAAm at around 31 degrees C, observed by optical absorbance measurements. The anticancer drug methotrexate (MTX) as model drug was loaded in the polymeric nano-sized micelles. In vitro release behavior of MTX was investigated, which showed a drastic thermoresponsive fast/slow switching behavior according to the temperature-responsive structural changes of a micellar shell structure. The reversible and sensitive thermoresponse of this micelle might provide opportunities to construct a novel drug delivery system in conjunction with localized hyperthermia., ((c) 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2007.)

A novel class of functional poly(N-isopropylacrylamide) (PNIPAAm) hydrogels with pendent micellar structure resulting from the pending amphiphilic polymers was designed and prepared. The influence of the pendent micellar structure on the properties of the resulted PNIPAAm hydrogels was examined in terms of morphology observed by scanning electron microscopy, thermal response through differential scanning calorimetry, and deswelling/reswelling kinetics upon external temperature changes. In comparison with the conventional ones, the novel PNIPAAm hydrogels with pendent micellar structure presented improved temperature-sensitive properties, i.e., enlarged water containing capability at room temperature, as well as improved deswelling rate upon heating.

A four-arm star block copolymer, comprised of a hydrophobic PMMA arm and an average of three hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) arms were designed and synthesized from the molecular level. The amphiphilic star block copolymer is capable of self-assembling into micelles in water, which was confirmed by FT-IR, (1)H NMR and fluorescence spectroscopy. Transmission electron microscopy images showed that these nanoparticles were regularly spherical in shape. The micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 34 degrees C, observed by optical absorbance measurements. Resulted polymeric micelles loaded with prednisone acetate showed a much improved drug release behavior due to the special micellar structure.

An amphiphilic AB block copolymer composed of poly(N-isopropylacrylamide) as a hydrophilic segment and poly(10-undecenoic acid) as a hydrophobic segment was synthesized. Cytotoxicity study of this copolymer exhibited no significant cytotoxicity. The lower critical solution temperature (LCST) of the copolymer was 30.8 degrees C, as determined by the turbidity method. The block copolymer forms micelles in an aqueous medium at the temperature lower than the LCST. Transmission electron microscopy images showed that these micelles were regularly spherical in shape. The micelle size determined by size analysis was around 160 nm. The anti-inflammation drug prednisone acetate was incorporated into the micelles and the release profiles of prednisone acetate showed a dramatic thermoresponsive switching behavior and a unique pH responsive behavior. Moreover, the pH responsive behavior was in relation to the thermoresponsive behavior. That is, the micelles were not pH sensitive at the temperature below the LCST, but the aggregates were pH sensitive at the temperature above the LCST. Based on these results, the thermo- and pH responsive micelles have great potential to be a novel carrier for drug delivery.

A new amphiphilic Y-shaped copolymer, comprised of hydrophobic poly(undecylenic acid) (PUA) and hydrophilic poly(N-isopropylacrylamide) (PNIPAAm), was designed and synthesized. A cytotoxicity study revealed that P(UA-Y-NIPAAm) copolymers did not exhibit apparent inhibition impact on the proliferation of cells when the concentration of the copolymer was below 1000 mg/L. Characterization demonstrated that the P(UA-Y-NIPAAm) copolymer is thermosensitive with a lower critical solution temperature (LCST) of 31 degrees C. In water, the P(UA-Y-NIPAAm) copolymer would self-assemble into micelles with a critical micelle concentration (CMC) of 20 mg/L. Self-assembled P(UA-Y-NIPAAm) micelles exhibited a nanospherical morphology of 40 to approximately 80 nm in size. The controlled drug release behavior of the P(UA-Y-NIPAAm) micelles was further investigated, and self-assembled micelles exhibited improved properties in controlled drug release.

A novel thermosensitive amphiphilic copolymer comprised of two hydrophobic poly(oleic acid) (POA) segments and one hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) segment was designed and synthesized. The structure of the copolymer was confirmed as Y-shaped by FTIR, 1H NMR, and SEC-MALLS analysis. A cytotoxicity study shows that the P(OA-Y-NIPAAm) copolymer exhibits good biocompatibility. The copolymer may self-assemble into micelles in water, with the hydrophobic POA segments at the cores of micelles and the hydrophilic PNIPAAm segments as the outer shells. The resulting micelles demonstrate temperature sensitivity with a lower critical solution temperature (LCST) of 31.5 degrees C and a critical micelle concentration (CMC) of 12.6 mg L(-1). Transmission electron microscopy (TEM) shows that the micelles exhibit a nanospheric morphology within a narrow size range of approximately 10-30 nm. A study of controlled release reveals that the self-assembled micelles have great potential as drug carriers.

To achieve a combination of spatial specificity in a passive manner with a stimuli-response targeting mechanism, a temperature-responsive polymeric micelle was prepared using block copolymers of poly(N-isopropylacrylamide-b-methyl methacrylate) (PNIPAAm-b-PMMA). The critical micelle concentration of amphiphilic block copolymers in aqueous solution was determined by fluorescence spectroscopy using pyrene as a fluorescence probe. Transmission electron microscopy images showed that these nanoparticles were regularly spherical in shape. Micelle size determined by size analysis was around 190 nm. The micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 degrees C, observed by optical absorbance measurements and dynamic light scattering (DLS). The anti-inflammation drug prednisone acetate was loaded as the model drug in the polymeric nanoparticles. In vitro release behavior of prednisone acetate was investigated, which showed a dramatic thermoresponsive fast/slow switching behavior according to the temperature-responsive structural changes of a micellar shell structure. The reversible and sensitive thermoresponse of this micelle might provide opportunities to construct a novel drug delivery system in conjunction with localized hyperthermia.

Amphiphilic copolymers are well developed as precursors for the preparation of micellar drug carriers. Poly(N-isopropylacrylamide) (PNIPAAm) is one of the most extensively studied thermo-sensitive polymers that exhibits a lower critical solution temperature (LCST) at around 33°C in aqueous solution. Over the past decade, considerable efforts have been devoted to design and preparation of PNIPAAm-based thermo-sensitive polymeric micelles as delivery vehicles for controlled drug release. Present review highlights the recent developments in this field, and focuses on two categories of PNIPAAm-based copolymer micelles as smart drug delivery systems, i.e. micelles with PNIPAAm as hydrophilic shell-forming segments below the LCST and micelles with PNIPAAm as hydrophobic core-forming segments above the LCST. [Copyright &y& Elsevier]

The syntheses of the dinuclear copper(II) complexes 1 and 2 of oxamido-bridge were reported. Reaction kinetics and the mechanism on hydrolysis of p-nitrophenyl picolinate (PNPP) and p-nitrophenyl acetate (PNPA) catalyzed by the metallomicelles formed from the complex (1 or 2) and surfactants (N-lauroyl sarcosinate (LSS), polyoxyethylene (23) lauryl ether (Brij35), cetyl pyridinium bromide (CPB)) were investigated. The kinetic mathematical models for the catalytic hydrolysis of PNPP and PNPA were proposed, respectively. The effects of different micelles and the structure of the ligands on the catalytic hydrolysis of PNPP and PNPA were discussed in detail. The results showed that the rate enhancement of the catalytic hydrolysis of PNPP following the intramolecular reaction is bigger than that of PNPA following the intermolecular reaction in the same experimental conditions, and the metallomicelle containing oxamido-bridged dinuclear copper(II) complex may be a potential catalyst for the hydrolysis of PNPP and PNPA. [Copyright &y& Elsevier]

Comparative reactivities of different metal ions in different micellar solutions (cationic, anionic, nonionic micelle) for the hydrolysis of p-nitrophenyl picolinate (PNPP) were investigated spectrophotometrically at pH 7.0 and 25°C. The kinetics analysis was carried out by invoking a model of micellar catalysis. The results show that compared with metal ions in aqueous solution, cationic micelles inhibit metal ion catalyzed hydrolysis of PNPP, anionic micelles accelerate metal ion catalyzed hydrolysis of PNPP and nonionic micelles show no appreciable effect on metal ion catalyzed hydrolysis of PNPP. The higher the electron charge of metal ions, the greater these effects are, indicating electrostatic interactions are the major reason for metal ion catalyzed hydrolysis of PNPP in micellar solution. [ABSTRACT FROM AUTHOR]

Abstract: In this study, with the aim of designing an ideal anticancer drug carrier, we synthesized novel amphiphilic graft copolymers, P(Glu-alt-PEG)-graft-PCLA, based on poly(ethylene glycol) (PEG) segments and glutamic acid (Glu) units as the hydrophilic main chain, and poly(ɛ-caprolactone-co-lactide) (PCLA) as hydrophobic branches. The chemical structure of the copolymers was characterized by 1H MNR and FT-IR. The self-assembly of the copolymers to form micelles was studied by TEM, DLS and fluorescence spectroscopy. In vitro doxorubicin controlled release studies demonstrated that these graft copolymer micelles had high drug loading capacity and good controlled released properties, demonstrating their potential as a novel anticancer drug carrier. The drug loaded graft copolymer micelles exhibited efficient inhibition of HeLa cells in in vitro studies. [Copyright &y& Elsevier]

Abstract: This paper demonstrated the preparation of temperature-responsive magnetomicelles that consist of a functionalized hexagonal magnetic core, Fe3O4-undecylenic acid (Fe3O4-UA), and an amphiphilic surface layer of temperature-responsive polymer. The functionalized magnetic Fe3O4-UA core was prepared by a suspension-oxidation reaction in an aqueous solution, during which the formation of the Fe3O4 and coordination of UA to the Fe3O4 occurred simultaneously. Amphiphilic poly(undecylenic acid-co-N-isopropylacrylamide) (P(UA-co-NIPAAm)) was grafted to the Fe3O4-UA core as a temperature-responsive micellar surface layer to prepare well dispersed Fe3O4-UA-g-P(UA-co-NIPAAm) magnetomicelles with the size of around 8nm in water. The application of resulted nanosized Fe3O4-UA-g-P(UA-co-NIPAAm) magnetomicelles in controlled drug delivery was further investigated and it was found that resulting magnetomicelles exhibited good potential for temperature triggered controlled drug release. [Copyright &y& Elsevier]