Fabrication of polymeric micelles with core–shell–corona structure for applications in controlled drug release

Thermo-responsive polymeric micelles of poly (ethylene glycol)-b-poly(2-hydroxyethyl methacrylate-g-lactide)-b-poly(N-isopropylacrylamide) (PEG-P(HEMA-PLA)-PNIPAM) with core–shell–corona structure were fabricated for applications in controlled drug release. The graft copolymer of PEG-P(HEMA-PLA)-PNIPAM was self-assembled into core–shell micelles with a densely PLA core and mixed PEG/PNIPAM shells at 25 °C in aqueous media. By increasing the temperature above the lower critical solution temperature of PNIPAM, these core–shell micelles could be converted into core–shell–corona micelles because of the collapse of PNIPAM block on the PLA core as the inner shell and the soluble PEG block stretching outside as the outer corona. Anticancer drug doxorubicin (DOX) was loaded in the polymeric micelles as a model drug. Compared with polymeric micelles formed by liner PEG-b-PLA-b-PNIPAM triblock copolymer, these polymeric micelles exhibited higher loading capacity, and release of DOX from the polymeric micelles with core–shell–corona structure was well-controlled.     

Preparation and stabilization of silver nanoparticles by a thermo-responsive pentablock terpolymer

Thermo-reversible silver nanoparticles (Ag-NPs) were prepared by the sodium borohydride reduction of silver nitrate (AgNO₃) in the presence of a pentablock terpolymer, poly(N-isopropylacrylamide)-b-poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-b-poly(N-isopropylacrylamide) (PNIPAM₁₅₀-PEO₁₃₆-PPO₄₅-PEO₁₃₆-PNIPAM₁₅₀). The pentablock terpolymer-stabilized silver nanoparticles (Pentablock-S-Ag) were characterized by UV-VIS spectroscopy, X-ray diffraction (XRD), thermal gravimetric analysis (TGA) and transmission electron microscopy (TEM). At temperatures below lower critical solution temperature (LCST) of Pentablock-S-Ag solutions, the obtained Ag-NPs are well-dispersed with spherical shape, and their sizes mainly depend upon the molar ratios of pentablock terpolymer to AgNO₃; at temperatures above LCST, the size of Ag-NPs decreases and their aggregates are observed due to the collapse and shrinkage of the thermo-responsive PNIPAM and PPO segments. A reversible dispersion-aggregation process upon recyclically changing temperature is also observed.     

The doubly thermo-responsive triblock copolymer nanoparticles prepared through seeded RAFT polymerization

The doubly thermo-responsive triblock copolymer nanoparticles of polystyrene-block-poly(N-isopropylacrylamide)-block-poly[N,N-(dimethylamino) ethyl methacrylate] (PS-b-PNIPAM-b-PDMAEMA) are successfully prepared through the seeded RAFT polymerization in situ by using the PS-b-PNIPAM-TTC diblock copolymer nanoparticles as the seed. The seeded RAFT polymerization undergoes a pseudo-first-order kinetics procedure, and the molecular weight increases with the monomer conversion linearly. The hydrodynamic diameter (D _h) of the triblock copolymer nanoparticles increases with the extension of the PDMAEMA block. In addition, the double thermo-response behavior of the PS-b-PNIPAM-b-PDMAEMA nanoparticles is detected by turbidity analysis, temperature-dependent 1H-NMR analysis, and DLS analysis. The seeded RAFT polymerization is believed as a valid method to prepare triblock copolymer nanoparticles containing two thermo-responsive blocks.     

“Smart” carboxymethylchitosan hydrogels crosslinked with poly(N-isopropylacrylamide) and poly(acrylic acid) for controlled drug release

Carboxymethylchitosan (CMC) hydrogels containing thermo-responsive poly(N-isopropylacrylamide) (poly(NIPAAm)) and pH-responsive poly(acrylic acid) (poly(AA)) were prepared via a free radical polymerization in the presence of hexamethylene-1,6-di-(aminocarboxysulfonate) crosslinking agents. A proper ratio of CMC to NIPAAm and AA used in the reaction was investigated such that the thermo- and pH-responsive properties of the hydrogels were obtained. Water swelling of the hydrogels was improved when the solution pH was in basic conditions (pH 10) or the temperature was below its lower critical solution temperature (LCST). Effects of the change in solution temperature and pH on water swelling properties of the hydrogel as well as the releasing rate of an entrapped drug were also investigated. The hydrogels were not toxic and showed antibacterial activity against Straphylococcus aureus (S. aureus). The pH- and thermo-responsive properties of this novel “smart” hydrogel might be efficiently used as dual triggering mechanisms in controlled drug release applications.     

Preparation and characterization of dual stimuli-responsive microcapsules with a superparamagnetic porous membrane and thermo-responsive gates

A novel dual stimuli-responsive microcapsule with a superparamagnetic porous membrane and linear-grafted poly(N-isopropylacrylamide) (PNIPAM) gates in the membrane pores is successfully prepared and characterized. Oleic acid (OA)-modified Fe₃O₄ nanoparticles are embedded into the polyamide microcapsule membrane during interfacial polymerization process, and then plasma-induced grafting polymerization is used to graft PNIPAM into the pores of microcapsule membranes. The prepared microcapsule membranes exhibit time-independent superparamagnetic property with good magnetic-responsive ability, and satisfactory thermo-responsive controlled-release property due to the thermo-responsive swollen/shrunken property of PNIPAM gates grafted on the inner pore surface of the microcapsule membranes.     

Cisplatin-loaded polymer/magnetite composite nanoparticles as multifunctional therapeutic nanomedicine

Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe3O4 nanoparticles with diblock copolymer folate-poly（ethylene glycol）-b-poly（glycerol monomethacrylate） （FA-PEG-b- PGMA）, and triblock copolymer methoxy poly（ethylene glycol）-b-poly（2-（dimethylamino） ethyl methacrylate）-b- poly（glycerol monomethacrylate） （MPEG-b-PDMA-b-PGMA）. The PGMA segment was attached to the surfaces of Fe304 nanoparticles, and the outer PEG shell imparted biocompatibility. In addition, folate was conjugated onto the surfaces of the nanocarriers. Cisplatin was then loaded into the nanocarrier by coordination between the Pt atom in cisplatin and the amine groups in the inner shell of the multilayer architecture. The loaded cisplatin showed pH-responsive release： slower release at pH 7.4 （i.e. mimicking the blood environment） and faster release at more acidic pH （i.e. mimicking endosome/lysosome conditions）. All of the cisplatin-loaded nanoparticles showed concentration-dependent cytotoxicity in HeLa cells. However, the folate-conjugated cisplatin-loaded carriers exhibited higher cytotoxicity in HeLa cells than non-folate conjugated cisplatin-loaded carriers.     

Facile synthesis of thermoresponsive block copolymers of N-isopropylacrylamide using heterogeneous controlled/living nitroxide-mediated polymerizations in supercritical carbon dioxide

A new protocol for preparation of thermoresponsive poly(N-isopropylacrylamide, NIPAM) containing block copolymers is described. It involves two successive heterogeneous controlled/living nitroxide-mediated polymerizations (NMPs) in supercritical carbon dioxide (scCO₂) using N-tert-butyl-N-[1-diethylphosphono-(2,2-dimethylpropyl)]nitroxide (SG1), as the nitroxide. Precipitation NMPs give narrow dispersity macroinitiators (MIs), and a first report of the controlled/living polymerization of N,N-dimethylacrylamide (DMA) in scCO₂ is described. The MI is then used in an inverse suspension NMP of NIPAM in scCO₂ resulting in the efficient preparation of block copolymers containing DMA, tert-butyl acrylate and styrene. Aqueous cloud point temperature analysis for poly(DMA)-b-poly(NIPAM) and poly(acrylic acid)-b-poly(NIPAM) shows a significant dependence on poly(NIPAM) chain length for a given AB block copolymer.     

Preparation and drug release property of CO2 stimulus-sensitive poly(N, N-dimethylaminoethyl methacrylate)-b-polystyrene nanoparticles

The CO₂ stimulus-sensitive nanoparticles based on poly(N, N-dimethylaminoethyl methacrylate)-b-poly styrene (PDMAEMA-b-PS) were prepared via surfactant-free miniemulsion reversible addition–fragmentation chain transfer (RAFT) polymerization. The as-prepared nanoparticles exhibited core–shell structure with about 120 nm in diameter. Their dispersion/aggregation in water can be adjusted by alternatively bubbling of CO₂ and N₂. Drug release from these nanoparticles can be accelerated (or delayed) by bubbling (or removing) of CO₂.     

Thermosensitive polyion complex micelles prepared by self-assembly of two oppositely charged diblock copolymers

Polyion complex (PIC) micelles were spontaneously formed in aqueous solutions through electrostatic interaction between two oppositely charged block copolymers, poly(N-isopropylacrylamide)-b-poly(L-glutamic acid) and poly(N-isopropylacrylamide)-b-poly(L-lysine). Their controlled synthesis was achieved via the ring opening polymerization of N-carboxyanhydrides (NCA), ε-benzyloxycarbonyl-L-lysine (Lys(Z)-NCA) or γ-benzyl-L-glutamate (BLG-NCA) with amino-terminated poly(N-isopropylacrylamide) macroinitiator and the subsequent deprotection reaction. The formation of PIC micelles was confirmed by dynamic light scattering and transmission electron microscopy. Turbidimetric characterization suggested that the formed PIC micelles had a concentration-dependent thermosensitivity and their phase transition behaviors could be easily adjusted either by the block length of coplymers or the concentration of micelles.     

Synthesis and self-assembly of pH-responsive amphiphilic dendritic star-block terpolymer by the combination of ROP, ATRP and click chemistry

Novel pH-responsive amphiphilic dendritic star-block poly(l-lactide)-b-poly(2-(N, N-diethylamino)ethyl methacrylate)-b-poly(ethylene oxide) (DPLLA-b-PDEAEMA-b-PEO) terpolymers were synthesized by the combination of ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP), and click chemistry. DPLLAOH was synthesized by ROP of l-lactide (LLA) and then reacted with propargyl 3-carboxylic-propanoate to obtain alkynyl-DPLLA. PEO-b-PDEAEMA-Br was prepared by ATRP of DEAEMA and then reacted with NaN₃ to obtain PEO-b-PDEAEMA-N₃. DPLLA-b-PDEAEMA-b-PEO was easily prepared by click chemistry of alkynyl-DPLLA and PEO-b-PDEAEMA-N₃. DPLLA-b-PDEAEMA-b-PEO can assemble into micelles in water with PLLA segments as core and PEO segments as corona. The hydrophilicity/hydrophobicity of PDEAEMA can be adjusted with the alteration of pH values. Therefore, PDEAEMA segments form core or corona of micelles at pH ? 7 or pH < 7. Due to the pH-responsive property of PDEAEMA and unique structure of terpolymer, the size and conformation of the micelles can be changed to some extent by altering the pH values of solutions.     

Synthesis and Characterization of Thermo-responsive Poly(N-vinyl-2-pyrrolidinone)-block-poly(N-isopropylacrylamide) Micelles

A novel thermo-responsive diblock copolymer of poly(N-vinyl-2-pyrrolidinone)-block-poly(N-isopropylacrylamide) (PNVP-b-PNIPAM) was synthesized. FT-IR, ¹H-NMR and SEC results confirmed the successful synthesis of PNVP-b-PNIPAM diblock copolymer via anionic polymerization. The polymeric micelles formed from PNVP-b-PNIPAM copolymer in aqueous solution were developed and characterized as a potential thermo-responsive and biocompatible drug delivery system. Micellization of the diblock copolymer in aqueous solution was characterized by dynamic laser scattering (DLS), turbidity measurement, tension measurement and transmission electron microscopy (TEM). The thermo-responsive polymeric micelles with the size ranges of 200 to 260 nm and thickness of 30 nm are localized, selected and targeted for drug release, having a great potential in response to external-stimulus such as temperatures from 35 to 39°C. The critical micellization concentration (cmc) of PNVP-b-PNIPAM in aqueous solution is 0.0026 wt% determined by turbidity measurement. The size of micelles determined by DLS increased from 163 to 329 nm with increasing concentration of PNVP-b-PNIPAM from 0.25 to 0.5 wt% in aqueous solution at 40°C, which is determined by DLS.     

Fabrication of multifunctional shell cross-linked micelles for targeting drug release

Thermosensitive amphiphilic poly(N-acroyloxysuccinimide)-b-poly(N-isopropylacrylamide)-b-poly(??-caprolactone) triblock copolymer was synthesized via the combination of reversible addition fragmentation chain transfer and ring-opening polymerization techniques. Shell cross-linked micelle (SCL) was further developed by the addition of cystamine as a di-functional cross-linker into the micellar solution. The persistence of regularly spherical shape against media change demonstrated locked micellar structure resulting from sufficient shell cross-linking. The lower critical solution temperature of the resulting SCL micelles was around 38?°C. The in vitro drug release study was carried out to illustrate the temperature-responsive drug release behaviors. To enhance the internalization to tumor cells, transferring (Tf) was further conjugated to the SCL micelles, and endocytosis experiments further confirmed the efficient uptake of Tf-SCL micelles by tumor cells, indicating that the Tf-SCL micelles would be a promising candidate for tumor-targeted drug delivery.     

In vivo imaging of the morphology and changes in pH along the gastrointestinal tract of Japanese medaka by photonic band-gap hydrogel microspheres

Colloidal crystalline microspheres with photonic band-gap properties responsive to media pH have been developed for in vivo imaging purposes. These colloidal crystalline microspheres were constructed from monodispersed core–shell nano-size particles with poly(styrene-co-acrylic acid) (PS-co-PAA) cores and poly(acrylic acid-co-N-isopropylacrylamide) (PAA-co-PNIPAM) hydrogel shells cross-linked by N,N′-methylenebisacrylamide. A significant shift in the photonic band-gap properties of these colloidal crystalline microspheres was observed in the pH range of 4–5. This was caused by the discontinuous volume phase transition of the hydrogel coating, due to the protonation/deprotonation of its acrylic acid moieties, on the core–shell nano-sized particles within the microspheres. The in vivo imaging capability of these pH-responsive photonic microspheres was demonstrated on a test organism – Japanese medaka, Oryzia latipes – in which the morphology and change in pH along their gastrointestinal (GI) tracts were revealed under an ordinary optical microscope. This work illustrates the potential of stimuli-responsive photonic band-gap materials in tissue-/organ-level in vivo bio-imaging.     

Synthesis of bifunctional core–shell particles with a porous zeolite core and a responsive polymeric shell

The aim of our work is the synthesis and characterization of colloidal core–shell particles with a zeolite core and an environmentally responsive shell. We have synthesized colloidal ZSM-5 zeolite and modified the surface with 3-(trimethoxysilyl)propyl methacrylate in order to introduce double bonds at the surface. The cross-linked polymeric shell was prepared by precipitation polymerization using the functionalized zeolite particles as seeds. We employed thermoresponsive poly(N-isopropylacrylamide) and pH-responsive poly(vinylpyridine) as the polymeric shell, respectively. The temperature- and pH-depending swelling and deswelling of the core–shell particles were characterized with dynamic light scattering techniques. Transmission electron microscopy pictures show the morphology of the synthesized particles. It is proposed that these types of bifunctional core–shell particles could be of use for controlled uptake and release applications and separation of molecules.     

Organic/inorganic hybrid star-shaped block copolymers of poly(l-lactide) and poly(N-isopropylacrylamide) with a polyhedral oligomeric silsesquioxane core: Synthesis and self-assembly

The star-shaped organic/inorganic hybrid poly(l-lactide) (PLLA) based on polyhedral oligomeric silsesquioxane (POSS) was prepared using octa(3-hydroxypropyl) polyhedral oligomeric silsesquioxane as initiator via ring-opening polymerization (ROP) of l-lactide (LLA). The molecular weight of POSS-containing star-shaped hybrid PLLA (POSSPLLA) can be well controlled by the feed ratio of LLA to initiator. The POSSPLLA was further functionalized into the macromolecular reversible addition-fragmentation transfer (RAFT) agent for the polymerization of N-isopropylacrylamide (NIPAM), leading to the POSS-containing star-shaped organic/inorganic hybrid amphiphilic block copolymers, poly(l-lactide)–block–poly(N-isopropylacrylamide) (POSS(PLLA–b–PNIPAM)). The self-assembly behavior of POSS(PLLA–b–PNIPAM) block copolymers in aqueous solution was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). DLS showed the PNIPAM block in the aggregates is temperature-responsive and its phase-transition is reversible. TEM proved that the star-shaped POSS(PLLA–b–PNIPAM) amphiphilic block copolymers can self-assemble into the vesicles in aqueous solution. The vesicular wall and coronas are composed of the hydrophobic POSS core and PLLA, and hydrophilic PNIPAM blocks, respectively. Therefore, POSSPLLA and POSS(PLLA–b–PNIPAM) block copolymers, as a class of novel organic–inorganic hybrid materials with the advantageous properties, can be potentially used in biological and medical fields.     

Synthesis and self-assembly behaviors of well-defined poly(lauryl methacrylate)-block-poly[N-(2-methacryloylxyethyl)pyrrolidone] copolymers

A series of structurally controllable poly(lauryl methacrylate)-b-poly[N-(2-methacryloylxyethyl)pyrrolidone], PLMA-b-PNMP, diblock copolymers were synthesized by reversible addition–fragmentation chain transfer polymerization. The self-assembly behaviors of PLMA-b-PNMP in a selective solvent, tetrahydrofuran (THF), were studied by employing static light scattering, dynamic light scattering, and transmission electron microscopy in detail. The relationships between the aggregation parameters, such as critical micelle concentration and the aggregation number (N _agg), and the molecular structure were established. It was found that spherical micelles can be formed once the solvophobic block length of poly[N-(2-methacryloylxyethyl)pyrrolidone] is larger than 215. Moreover, extremely small and monodisperse gold nanoparticles (<2 nm) were synthesized by employing PLMA-b-PNMP diblock copolymers in THF.     

Biodegradable and thermoresponsive micelles of triblock copolymers based on 2-(N,N-dimethylamino)ethyl methacrylate and ε-caprolactone for controlled drug delivery

Amphiphilic triblock copolymers, poly(2-(N,N-dimethylamino)ethyl methacrylate)_x-block-poly(caprolactone)-block-poly(2-(N,N-dimethylamino)ethyl methacrylate)_x, PDMAEMA_Co, were synthesized. Polymerization and structural features of the polymers were analyzed by different physicochemical techniques (GPC, ¹H NMR and FTIR). Formation of hydrophobic domains as cores of the micelles was studied by ¹H NMR and further confirmed by fluorescence. Dynamic light scattering measurements showed a monodispersed size distribution only for the copolymer with the lowest degree of polymerization, while increasing the length of PDMAEMA blocks leads to a bimodal size distribution. The micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PDMAEMA at temperatures between 54 and 87 °C. The triblock copolymer micelles were loaded with the sparingly water-soluble anticancer drug, chlorambucil, by a dialysis procedure. The drug release profile monitored by fluorescence showed that the release of chlorambucil from PDMAEMA nanoparticles is controlled by a combined degradation-diffusion mechanism.     

Synthesis and characterization of pH-responsive diblock copolymers with cadaverine side groups

In this paper, we report the synthesis and characterization of a new pH-responsive diblock copolymer, methoxy poly(ethylene glycol)-b-poly[N¹-(4-vinylbenzyl) pentane-1,5-diamine dihydrochloride] (mPEG-b-PVBPDA). The monomer with cadaverine side group (N¹-(4-vinylbenzyl)pentane-1,5-diamine dihydrochloride, VBPDA) and the macroinitiator (mPEG-ACVA) were synthesized, respectively, and mPEG-b-PVBPDA was then obtained by free radical polymerization. The structure and molecular weight of mPEG-b-PVBPDA was confirmed by FTIR, ¹H NMR, and GPC-MALLS measurements. At low pH, it is hydrophilic due to the protonation of the amine groups. With increasing pH, deprotonation occurs, and the hydrophobicity of PVBPDA block increases. This molecular feature leads to interesting aggregation behavior of mPEG-b-PVBPDA in aqueous solutions at different pH as revealed by DLS measurements, TEM observations, and fluorescence spectrometry. This polymer was further subjected to gene delivery evaluations, and promising DNA transfection capacity has been found.     

Temperature-Responsive Polyoxometalate Catalysts for DBT Desulfurization in One-Pot Oxidation Combined with Extraction

Intelligent thermo-responsive catalysts [C₁₆H₃₃N(CH₃)₃]₃[PO₄{MO(O₂)₂}₄]/poly(N-isopropylacrylamide) (M = Mo and W, abbreviated as C₁₆PM(O₂)₂/PNIPAM) have been prepared using thermo-responsive polymer PNIPAM as a support. The thermo-responsive hybrids exhibit novel switchable property based on the change of temperature, while its solubility in organic solvent is reversibly controllable through an external temperature stimulus linking the gap between heterogeneous catalysis and homogeneous one. Moreover, non-polar organic substrates are accumulated around the catalytic sites by two synergistic effects of amphiphilic POM molecules and the existence of PNIPAM. Therefore, this solid hybrid has been successfully used in catalyzing the oxidation of refractory sulfur-containing compound dibenzothiophene into its corresponding sulfone with high selectivity in the presence of H₂O₂. Application of this catalyst brings about an efficient, useful and green process in desulfurization through extraction and oxidation simultaneously.     

Drug and plasmid DNA co-delivery nanocarriers based on abctype polypeptide hybrid miktoarm star copolymers

We report on the fabrication of self-assembled micelles from ABC-type miktoarm star polypeptide hybrid copolymers consisting of poly(ethylene oxide), poly(L-lysine), and poly(ε-caprolactone) arms, PEO(-b-PLL)-b-PCL, and their functional applications as co-delivery nanocarriers of chemotherapeutic drugs and plasmid DNA. Miktoarm star copolymer precursors, PEO(-b-PZLL)-b-PCL, were synthesized at first via the combination of consecutive "click" reactions and ring-opening polymerizations (ROP), where PZLL is poly(ε-benzyloxycarbonyl-L-lysine). Subsequently, the deprotection of PZLL arm afforded amphiphilic miktoarm star copolymers, PEO(-b-PLL)-b-PCL. In aqueous media at pH 7.4, PEO(-b-PLL)-b-PCL self-assembles into micelles consisting of PCL cores and hydrophilic PEO/PLL hybrid coronas. The hydrophobic micellar cores can effectively encapsulate model hydrophobic anticancer drug, paclitaxel; whereas positively charged PLL arms within mixed micellar corona are capable of forming electrostatic polyplexes with negatively charged plasmid DNA (pDNA) at N/P ratios higher than ca. 2. Thus, PEO(-b-PLL)-b-PCL micelles can act as co-delivery nanovehicles for both chemotherapeutic drugs and genes. Furthermore, polyplexes of pDNA with paclitaxel-loaded PEO(-b-PLL)-b-PCL micelles exhibited improved transfection efficiency compared to that of pDNA/blank micelles. We expect that the reported strategy of varying chain topologies for the fabrication of co-delivery polymeric nanocarriers can be further applied to integrate with other advantageous functions such as targeting, imaging, and diagnostics.