Thermal modulation of intracellular drug distribution using thermoresponsive polymeric micelles

Intracellular distribution of free doxorubicin (DOX) or DOX-loaded in polymeric micelles with thermoresponsive outer shells of poly(N-isopropylacrylamide) or its copolymers in cultured human breast cancer cells (MCF-7) were investigated by fluorescence and confocal laser scanning microscopy. Free DOX accumulated rapidly and selectively in cell nuclei, independent of temperature changes. In contrast to free drugs, the intracellular distribution of DOX-loaded in the thermoresponsive polymeric micelles was significantly affected by temperature changes across lower critical solution temperature (LCST) of the micelles. Above the micelle LCST, DOX delivered by the micelles was localized uniformly inside of MCF-7 cells. By contrast, the amount of DOX delivered to MCF-7 cells drastically decreased below the micelle LCST due to minimal interaction of the micelles with cell membrane surfaces. These results clearly showed that the mechanism of the intracellular drug localization was different between free drugs and DOX-loaded in the micelles. The thermoresponsive micelles aggressively interacted with the cells and carried DOX into the cells via triggered phase transition of the outer shells. In addition, much lower accumulation of free DOX was observed in the resistant cells compared to its parent sensitive MCF-7 due to the resistant mechanism. Of interest, DOX accumulation in the resistant cells was almost in the same level as with MCF-7 (sensitive) cells for the micelle system above the LCST.     

Enhanced loading of doxorubicin into polymeric micelles by a combination of ionic bonding and hydrophobic effect,and the pH-sensitive and ligand-mediated delivery of loaded drug

Folate-conjugated micelles were fabricated from amphiphilic diblock copolymers with poly(ethylene glycol) as the hydrophilic block and a random copolymer of n-butyl methacrylate and methacrylic acid as the hydrophobic block. Doxorubicin (DOX), a model drug that contains an amine group and hydrophobic moiety, was loaded with a high loading capacity into micelles by a combination of ionic bonding and hydrophobic effect. The combined interactions imparted a pH-sensitive delivery property to the system. The release rate of loaded DOX was slow at pH 7.4 (i.e., mimicking the plasma environment) but increased significantly at acidic pH (i.e., mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the carboxylate protonation of poly(methacrylic acid), which dissociated the ionic bonding between the micelles and DOX. Cellular uptake by folate receptor-overexpressing HeLa cells of the DOX-loaded folate-conjugated micelles was higher than that of micelles without folate conjugation. Thus, the DOX-loaded folate-conjugated micelles displayed higher cytotoxicity to HeLa cells.     

PEGylated nanodiamond for chemotherapeutic drug delivery

Nanodiamond (ND) has the excellent biocompatibility, similarly to other sp³-carbon based materials, and is a potential drug carrier for cancer therapy. In our work, firstly, to increase the dispersity and stability of ND (size ~ 140 nm) in vitro under the physiological environment or in cell culture medium and be suitable for biomedicine applications, ND was covalently conjugated with biocompatible polymers, such as hydroxy-polyethylene glycol-4000 (PEG-4000). Secondly, doxorubicin hydrochloride (DOX), a chemotherapy drug, was physically adsorbed onto the PEGylated nanodiamond (ND-PEG-OH). These results revealed that ND-PEG-OH nanoparticle associated DOX (ND-PEG-DOX) could efficiently deliver the drug into the human liver cancer cells (HepG2) via a clathrin-dependent endocytosis pathway, and especially enhance the DOX uptake as compared to DOX alone. The uptake half-life of ND-PEG-DOX (t_1/2 = 3.31 h) was approximately two times that of free DOX uptake (t_1/2 = 1.67 h), which was related to the uptake pathway. The results from the confocal fluorescence microscopy study showed that DOX detached from ND-PEG-DOX composites inside the cytoplasm could migrate and enter the nucleolus to inhibit the cellular growth. Thirdly, in vitro dialysis determination and imaging experiments using the confocal fluorescence microscopy indicated that DOX released from ND-PEG-DOX composites had a slow and sustained drug release capability. In summary, our study has shown that ND-PEG-OH nanoparticles can act as effective drug carriers for cancer therapy.     

pH-Sensitive hydrogels formed by self-assembled amphiphilic triblock copolyelectrolytes

Results are reviewed of a recent extensive investigation of the behavior of self-assembled pH-sensitive triblock copolymers in aqueous solution. The hydrophilic central block was polyacrylic acid and the two hydrophobic end-blocks were statistical copolymers of n-butyl acrylate and acrylic acid containing 50 mol% acrylic acid units. The hydrophobicity of the end blocks could be modified by changing the degree of ionization of the acrylic acid units (α). The relationship between the pH and α was determined. Scattering techniques showed that flower-like micelles are formed that upon increasing concentration connect via bridging into larger aggregates and above a critical concentration into a percolating network. The rheology of the system is controlled by the exchange rate of the end-blocks between micelles and can be fine-tuned by varying the pH. The exchange rate increases exponentially with increasing α. As a consequence the system changes from a quasi-permanent hydrogel at pH < 4.5 to a free flowing liquid at pH > 5.5. The effect of the ionic strength on the structure and the rheology was found to be important only above 0.5 M.     

Synthesis,structure and fluorescence properties of a uranyl-2,5-pyridinedicarboxylic acid coordination polymer: The missing member of the UO22+-2,n-pyridinedicarboxylic series

A 3D uranium-pyridinedicarboxylate, compound (1) [UO₂(C₇H₃NO₄)], represents the final member of a series of materials incorporating a series of 2,n-pyridinedicarboxylic (pydc) acids (n = 3,4,5,6). The resulting crystal structure [FW = 419.13, monoclinic, P2₁/n, a = 9.0096(3) Å, b = 8.1371(2) Å, c = 11.6954(4) Å, V = 852.45 ų, Z = 4] was determined by single crystal X-ray diffraction and fluorescent properties were investigated. Additionally, the complete series of uranium-2,n-pydc materials was examined on a basis of fluorescent behaviors and architectural similarities.     

pH-responsive micelles based on (PCL)2(PDEA-b-PPEGMA)2 miktoarm polymer: controlled synthesis,characterization, and application as anticancer drug carrier

Amphiphilic A₂(BC)₂ miktoarm star polymers [poly(ϵ-caprolactone)]₂-[poly(2-(diethylamino)ethyl methacrylate)-b- poly(poly(ethylene glycol) methyl ether methacrylate)]₂ [(PCL)₂(PDEA-b-PPEGMA)₂] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC₅₀ of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)₂(PDEA-b-PPEGMA)₂ micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.     

Hydrothermal synthesis,crystal structure and properties of a thermally stable dysprosium porphyrin with a three-dimensional porous open framework

A thermally stable dysprosium porphyrin with a three-dimensional (3D) porous open framework, [Dy(H₂TPPS)]_n∙ nH₃O∙2nH₂O (1) (H₂TPPS = tetra(4-sulfonatophenyl)porphyrin), has been synthesized via hydrothermal reactions and structurally analyzed by an X-ray single-crystal diffraction method. The 24-membered macrocyclic ring of H₂TPPS is exactly coplanar and the center is free from metal. The dysprosium ion is coordinated by eight O_sulfonic atoms from eight H₂TPPS moieties, forming a distorted square anti-prism geometry. Complex 1 shows a void space of 210 Å³, occupying 9.06% of the unit-cell volume. The 3D porous open framework of 1 is thermally stable up to 380 °C. Complex 1 exhibits a red fluorescence emission with a quantum yield and lifetime of 2.7% and 136 μs, respectively. CV result reveals one reductive peak at − 0.33 V and one quasi-reversible wave with E_1/2 = − 0.81 V.     

Enzymatic synthesis of poly(ɛ-caprolactone) in supercritical carbon dioxide medium by means of a variable-volume view reactor

Poly (ɛ-caprolactone) (PCL) is a biodegradable polyester approved for applications in the human body such as drug delivery devices and sutures. Conventional synthesis of PCL involves metal catalysts and organic solvents that may leave toxic residues in the products and contribute to environmental pollution. Polymerization processes catalyzed by enzymes are becoming more attractive due to the importance of clean processes, which produces substances free of residues, ideal for pharmaceutical and food applications. The aim of this work was to investigate the enzymatic ring-opening polymerization (e-ROP) of PCL in supercritical carbon dioxide (scCO₂) solvent medium through a set of experiments assessing the influence of pressure (120–280 bar), solvent/monomer ratio (2:1–1:2 mass ratio) and enzyme percentage related to monomer (5–15 wt%) on the reaction yield, number-average molecular weight (M_n), weight-average molecular weight (M_w) and polydispersity index (P.I.). The results of these first experiments were used in the selection of the conditions for the kinetic experiments evaluating the influence of catalyst content and temperature on reaction yield, M_n, M_w, P.I. and on the characteristics of the polymer produced. This study also evaluates the enzyme reuse in order to reduce the impact of the enzyme cost on the process. Results for ANOVA statistical analysis for the first set of experiments show that the pressure or the solvent density has no significant influence over the parameters evaluated, while the solvent/monomer mass ratio presented significant effect on M_n and on M_w, with the best results obtained for the solvent/monomer mass ratio of 1:2. As expected, the enzyme content affects significantly all parameters evaluated. Polymerization results for the kinetic experiments indicate reaction yields up to 90 wt%, M_n up to 13,700 Da and M_w up to 22,200 Da, with P.I. ranging from 1.2 to 1.7. Taking into account the reaction productivity, the conditions for the reuse assays were chosen: 120 bar, 1:2 solvent/monomer ratio, 3 wt% of enzyme, 65 °C and 12 h of reaction. The enzyme recycling experiments suggested viability up to the second cycle as an alternative to improve the enzyme use. The variable-volume view reactor was adequate to provide simultaneous control of the process variables.     

Preparation of π-conjugated polymers consisting of 1-aminopyrrole and 4-amino-1,2,4-triazole units

π-Conjugated polymers based on 1-aminopyrrole and 4-amino-1,2,4-triazole were prepared. Pd-catalyzed organometallic polycondensation gave poly(arylene-ethynylene) (PAE)-type π-conjugated polymers consisting of BOC-protected 4-amino-1,2,4-triazole (Taz(BOC)) units (BOC = t-butoxycarbonyl). The number average molecular weights (M_n) were determined to be 5200–19,200 using GPC. An alternating copolymer of Taz(BOC) and bithiophene (Th–Th) units, P(Taz(BOC)-Th-Th)_n-Pd, with an M_n of 10,800 was also prepared by Pd-catalyzed organometallic polycondensation. (Taz(BOC)-Th-Th)_n-Pd showed a UV–Vis absorption peak at λ_max = 425 nm, which is reasonable for a π-conjugated five-membered ring polymer with a coplanar structure. The deprotection of the BOC group of the polymers proceeded at 200 °C; this BOC-deprotection was investigated using a model compound. The optical and electrochemical properties of the π-conjugated polymers are reported.     

Low-temperature microwave and THz dielectric response in novel microwave ceramics

Low-temperature dielectric properties of BaZn_1/3Nb_2/3O₃-based ceramics, CeO₂-based ceramics and Ruddlesden–Popper Sr_n+1Ti_nO_3n+1 (n = 1–4) ceramics has been studied in microwave, THz and infrared frequency range down to 10 K. Extrinsic dielectric losses originating probably from diffusion of charged defects are observed in two families of compounds by a minimum in the temperature dependence of microwave quality Q. The rise of microwave permittivity and dielectric losses at low temperatures in Sr_n+1Ti_nO_3n+1 (n = 2–4) ceramics was explained by softening of an optical polar mode in SrTiO₃, which is in the Sr_n+1Ti_nO_3n+1 (n = 3, 4) ceramics contained as a second phase.     

Electrochemical syntheses and structures of lead(II) and bismuth(III) complexes of 4-(trimethylammonio)benzenethiolate

Two main-group metal complexes of the zwitterionic ammonium thiolate complexes, [M(Tab)₃](ClO₄)_n (Tab = 4-(trimethylammonio)benzenethiolate) (1: M = Pb, n = 2; 2: M = Bi, n = 3), were prepared by electrochemical oxidation of Pb or Bi electrode in MeCN containing Tab and Et₄NClO₄. Each M atom in 1 and 2 is coordinated by three S atoms of three Tab ligands, forming a trigonal pyramidal coordination geometry. The resulting [M(Tab)₃]ⁿ⁺ cations are interconnected by secondary M⋯S interactions to form two different 1D cationic chains. The electrochemical properties of 1 and 2 were also investigated by cyclic voltammetry.     

The influence of crosslinking and fumed silica nanoparticles on mixed gas transport properties of poly[1-(trimethylsilyl)-1-propyne]

Crosslinking poly[1-(trimethylsilyl)-1-propyne] (PTMSP) films with 3,3′-diazidodiphenylsulfone, a bis(azide) crosslinker, rendered the films insoluble in common solvents for PTMSP such as toluene. At all temperatures, mixed gas CH₄ and n-C₄H₁₀ permeabilities of crosslinked PTMSP were less than those of uncrosslinked PTMSP, which correlates with lower free volume in the crosslinked material. The presence of fumed silica (FS) nanoparticles in both uncrosslinked PTMSP and crosslinked PTMSP increased mixed gas CH₄ and n-C₄H₁₀ permeabilities, consistent with the disruption of polymer chain packing by such nanoparticles. Mixed gas CH₄ permeabilities of all films were significantly less than their corresponding pure gas CH₄ permeabilities. For example, at 35 °C, the mixed gas CH₄ permeabilities were approximately 60–80% less than their pure gas values. The greatest decrease was observed for uncrosslinked PTMSP, while nanocomposite PTMSP films showed the least decrease. The mixed gas n-C₄H₁₀/CH₄ selectivities of crosslinked PTMSP and nanocomposite PTMSP films were less than those of uncrosslinked PTMSP at all temperatures. For example, at 35 °C, the mixed gas n-C₄H₁₀/CH₄ selectivities of uncrosslinked PTMSP, crosslinked PTMSP containing 10 wt% crosslinker, and uncrosslinked PTMSP containing 30 wt% FS were 33, 27, and 17, respectively, when the feed gas contained 2 mol% n-C₄H₁₀ and the total upstream mixture fugacity was 11 atm. For all films, as temperature decreased, mixed gas n-C₄H₁₀ permeabilities increased, and mixed gas CH₄ permeabilities decreased. Consequently, the mixed gas n-C₄H₁₀/CH₄ selectivities increased substantially as temperature decreased and the mixed gas selectivity of uncrosslinked PTMSP increased from 33 to 170 as temperature decreased from 35 °C to ?20 °C when the feed gas contained 2 mol% n-C₄H₁₀ and the total upstream mixture fugacity was 11 atm.     

Controlled radical copolymerization of β-pinene and n-butyl acrylate

The feasibility of the radical copolymerization of β-pinene and n-butyl acrylate (n-BA) was clarified for the first time. β-pinene was found to undergo degradative chain transfer during the copolymerization. This degradative chain transfer became less competitive with the copolymerization by the addition of EtAlCl₂, and the copolymer yield, β-pinene incorporation and molecular weight of the copolymer increased remarkably compared with the case in the absence of EtAlCl₂. The monomer reactivity ratios evaluated by the nonlinear least-squares method were r_β-pinene ∼ 0 and r_n-BA ∼ 2.2 in the absence of EtAlCl₂, r_β-pinene ∼ 0 and r_n-BA ∼ 0.86 in the presence of EtAlCl₂ in bulk at 70 ˚C. Furthermore, the possible controlled copolymerization of β-pinene and n-butyl acrylate was then attempted via the reversible addition-fragmentation transfer (RAFT) technique. The copolymerization (f_β-pinene = 0.20) using 2-cyanopropyl-2-yl dithiobenzoate as the RAFT agent displayed the typical features of a controlled system, such as the first-order kinetics and the linear increase in molecular weight with the overall conversion. The livingness of the copolymer chains was further proved by using them as the macroinitiator for the chain extension with styrene by RAFT process.     

Electrostatic immobilization of substrate and polyoxotungstate catalyst at the surface of micelles for enhanced reaction efficiency in water

Polyoxometalate (POM)-based micellar catalysts were prepared by assembling the Keggin tri-anion [PW₁₂O₄₀]^3 − and (L)-N-acetylmethioninate salts of Gemini surfactants in water. Contrary to conventional catalytic systems, we propose a new approach in which the POM catalyst and the substrate to be oxidized ((L)-N-acetylmethioninate) are both localized at the surface of micelles by electrostatic interaction before the reaction. The high local concentration of reactants due to their confinement at the surface of micelles enhances the reaction kinetics. Catalyst recovery experiments showed that, after two cycles of reactions, the activity of the catalysts  was not changed.     

Preparation of new heteronuclear (NH4)RE[FeII(CN)6]·nH2O complexes (RE = La,Ce, Pr,Nd, Sm,Gd, Dy,Y, Er,Lu) and their low-temperature decomposition for perovskite-type oxide

New heteronuclear (NH₄)RE^III[Fe^II(CN)₆]·nH₂O complexes (RE = La, Ce, Pr, Nd, Sm, Gd, Dy, Y, Er, Lu) were synthesized and their thermal decomposition products were investigated. The crystal structure of (NH₄)RE[Fe^II(CN)₆]·nH₂O would be a hexagonal unit cell (space group: P6₃/m), which was the same as that of La[Fe^III(CN)₆]·5H₂O. The hydration number n = 4 was estimated by TG results for all the RE complexes. The lattice constants depended on the ionic radius of the RE³⁺ ion for the heteronuclear complexes. The single phase of the perovskite type materials was directly obtained by decomposition of the heteronuclear complexes for RE = La, Pr, Nd, Sm, and Gd. A mixture of CeO₂ and Fe₂O₃ was formed for RE = Ce because of its oxidation to Ce⁴⁺. In the case of RE = Dy, Y, Er, and Lu complexes, the perovskite type materials formed at higher temperature via. mixed oxides such as RE₂O₃ and RE₄Fe₅O₁₃ due to the small RE³⁺ ionic radius.     

Promising high temperature thermoelectric properties of dense Ba2Co9O14 ceramics

Layered cobalt oxides have shown high thermoelectric properties. The n = 1 member of the Ba_n+1Co_nO_3n+3(Co₈O₈) family, Ba₂Co₉O₁₄, a new layered cobalt oxides family with Co(II) and Co(III) in the CdI₂ layers, has been synthesized by solid state reaction and sintered as dense ceramics (relative density ∼ 93%) by Spark Plasma Sintering. It presents promising p-type thermoelectric properties at high temperature. The dimensionless figure of merit ZT is 0.032 at 660 K and 0.04 at 1000 K, which is about one quarter to one third of the ZT value of Ca₃Co₄O₉ ceramics.     

Densification mechanisms and microstructural evolution during spark plasma sintering of boron carbide powders

Micron-sized boron carbide (B₄C) powders were subjected to spark plasma sintering (SPS) under temperature ranging from 1700 °C to 2100 °C for a soaking time of 5, 10 and 20 min and their densification kinetics was determined using a creep deformation model. The densification mechanism was interpreted on the basis of the stress exponent n and the apparent activation energy Q_d from Harrenius plots. Results showed that within the temperature range 1700–2000 °C, creep deformation which was controlled by grain-boundary sliding or by interface reaction contributed to the densification mechanism at low effective stress regime (n = 2,Q_d = 459.36 kJ/mol). While at temperature higher than 2000 °C or at high stress regime, the dominant mechanism appears to be the dislocation climb (n = 6.11).     

Degradable micelles based on hydrolytically degradable amphiphilic graft copolymers for doxorubicin delivery

Micelles based on a low-toxic and hydrolytically degradable poly(β-amino ester)-g-octadecyl acrylate (PAE-g-ODA) amphiphilic copolymer were developed for doxorubicin (DOX) delivery. A two-step reaction pathway was used to synthesize PAE-g-ODA copolymers with poly(ethylene glycol) segments in the backbone via Michael-type addition reaction. Copolymers with various grafting degrees were obtained by tuning the feeding molar ratios of acrylate/formed secondary amine and the grafting reaction time. Among this series of copolymers, PAE-g-ODA-2 (PAE-g-ODA with 45% ODA side chains) were found to form spherical micelles with an average size of 72.5 nm, as determined by dynamic light scattering (DLS) and transmission electron microscope (TEM), whereas the other PAE-g-ODA copolymers fail to form stable micelles with a narrow size distribution in an aqueous solution. The titration curve illustrated that PAE-g-ODA-2 has a high buffer capacity in the pH range of 7.5-5. The hydrolytic degradation of PAE-g-ODA-2 copolymer in PBS buffer (pH 7.4, 37 °C) was monitored by ¹H NMR. It was found that up to 70% ester groups in the backbones were hydrolyzed in 48 h. The DOX-loaded micelles release about 70% trapped DOX within 48 h in physiological condition. Cytotoxicity assay showed a low cytotoxicity of PAE-g-ODA-2 micelles as well as a higher inhibition against HepG2 tumor cells of DOX-loaded micelles than free DOX.     

Spark plasma sintering behavior of combustion-synthesized (Y,Ca)-α-SiAlON

This paper describes the sintering behavior of combustion-synthesized (Y, Ca)-α-SiAlON powders when using spark plasma sintering (SPS) technology. The effects of sintering temperature, heating rate, and holding time on the densification behavior, α→β phase transformation, and Vickers hardness were investigated in detail. Fully dense Y-α-Si_12−(m+n)Al_m+nO_nN_16−n (m=1.2, n=0.6, Y-α-SiAlON) and Ca-α-Si_12−(m+n)Al_m+nO_nN_16−n (m=1.0, n=0.5, Ca-α-SiAlON) were obtained during sintering for 10 min at final temperatures as low as 1400 °C and 1500 °C, respectively. X-ray diffraction results showed that more than 50 mass% of α-phase transformed to the β-phase for Y-α-SiAlON after SPS, whereas no obvious α→β phase transformation was observed for Ca-α-SiAlON, even after sintering at a high temperature of 1600 °C. A maximum Vickers hardness of 18.56 GPa and 19.95 GPa was reached for Y-α-SiAlON and Ca-α-SiAlON, respectively.     

Influence of graphite nano-flakes on densification and mechanical properties of hot-pressed ZrB2–SiC composite

Hot pressed monolithic ZrB₂ ceramic (Z), ZrB₂–20 vol% SiC composite (ZS₂₀) and ZrB₂–20 vol% SiC–10 vol% nano-graphite composite (ZS₂₀G_n10) were investigated to determine the influence of graphite nano-flakes on the sintering process, microstructure, and mechanical properties (Vickers hardness and fracture toughness) of ZrB₂–SiC composites. Hot pressing at 1850 °C for 60 min under 20 MPa resulted in a fully dense ZS₂₀G_n10 composite (relative density: 99.6%). The results disclosed that the grain growth of ZrB₂ matrix was efficiently hindered by SiC particles as well as graphite nano-flakes. The fracture toughness of ZS₂₀G_n10 composite (7.1 MPa m^1/2) was essentially improved by incorporating the reinforcements into the ZrB₂ matrix, which was greater than that of Z ceramic (1.8 MPa m^1/2) and ZS₂₀ composite (3.8 MPa m^1/2). The fractographical observations revealed that some graphite nano-flakes were kept in the ZS₂₀G_n10 microstructure, besides SiC grains, which led to toughening of the composite through graphite nano-flakes pull out. Other toughening mechanisms such as crack deflection and branching as well as crack bridging, due to the thermal residual stresses in the interfaces, were also observed in the polished surface.