Delivery of radioiodinated antisense oligonucleotides in long circulating liposomes in vivo

The anionic long circulating liposomes (ALCLs) prepared in previous studies enabled high loading efficiency, small particle size, and good stability. In addition, the uptake by tumor cells and delivery of radioiodinated antisense oligonucleotides (ASON) to MCF‐7 breast cancer cell line was improved. The liposomes also displayed valuable pharmacologic properties characterized by a long half‐life, slow clearance, and a significant area under the concentration–time curve (AUC) in vivo. This study emphasizes the contribution of ALCLs to the anti‐tumor effect of ASON and radiation therapy. Our results show that ALCLs improve biodistribution and delivery of radioiodinated ASON in tumor bearing rats, which is characterized by the suppression of tumor growth, decreased bcl‐2 expression, and increased tumor cell necrosis in the mammary tumor.     

Smart polyion complex micelles for targeted intracellular delivery of PEGylated antisense oligonucleotides containing acid-labile linkages

A novel pH-sensitive and targetable antisense ODN delivery system based on multimolecular assembly into polyion complex (PIC) micelles of poly(L-lysine) (PLL) and a lactosylated poly(ethylene glycol)-antisense ODN conjugate (Lac-PEG-ODN) containing an acid-labile linkage (beta-propionate) between the PEG and ODN segments has been developed. The PIC micelles thus prepared had clustered lactose moieties on their peripheries and achieved a significant antisense effect against luciferase gene expression in HuH-7 cells (hepatoma cells), far more efficiently than that produced by the nonmicelle systems (ODN and Lac-PEG-ODN) alone, as well as by the lactose-free PIC micelle. In line with this pronounced antisense effect, the lactosylated PIC micelles showed better uptake than the lactose-free PIC micelles into HuH-7 cells; this suggested the involvement of an asialoglycoprotein (ASGP) receptor-mediated endocytosis process. Furthermore, a significant decrease in the antisense effect (27 % inhibition) was observed for a lactosylated PIC micelle without an acid-labile linkage (thiomaleimide linkage); this suggested the release of the active (free) antisense ODN molecules into the cellular interior in response to the pH decrease in the endosomal compartment is a key process in the antisense effect. Use of branched poly(ethylenimine) (B-PEI) instead of the PLL for PIC micellization led to a substantial decrease in the antisense effect, probably due to the buffer effect of the B-PEI in the endosome compartment, preventing the cleavage of the acid-labile linkage in the conjugate. The approach reported here is expected to be useful for the construction of smart intracellular delivery systems for antisense ODNs with therapeutic value.     

Recovery and Recycling of CO2/N2‐Switchable Anionic Surfactants in Emulsions

To develop a mild, effective, and clean strategy for recovery and recycling of anionic surfactants in CO₂/N₂‐switchable emulsions, a CO₂/N₂‐switchable anionic surfactant, which is a combination of dodecyl seleninic acid (DSA) and N,N,N′,N′‐tetramethyl‐1,2‐ethylenediamine (TMEDA), here referred to as DSA–TMEDA, was used to stabilize an oil‐in‐water (O/W) emulsion. Upon stimulation with CO₂, DSA–TMEDA was switched off to form insoluble DSA and the water‐soluble TMEDA bicarbonate. Upon N₂ bubbling and heating, the OFF state of DSA–TMEDA was restored to the surfactant of DSA–TMEDA. In this manner, O/W emulsions stabilized by DSA–TMEDA can be switched reversibly between demulsification (phase separation) and re‐emulsification (recovered emulsion) by triggering with CO₂/N₂ over ten times. After breakage of the emulsion, nearly all of the OFF state surfactant could be separated conveniently away from the oil phase, thus facilitating recovery and recycling of the surfactant afterward in emulsifying oil. No obvious adverse changes in the dispersed oil particles size and the relative stability of the regenerated emulsions were observed over five cycles, and the surfactant loss can be neglected during the recycling.     

On robust tail index estimation for linear long‐memory processes

We consider robust estimation of the tail index α for linear long‐memory processes with i.i.d. innovations ε_j following a symmetric α‐stable law (1 < α < 2) and coefficients a_j ～ c·j^?β. Estimates based on the left and right tail respectively are obtained together with a combined statistic with improved efficiency, and a test statistic comparing both tails. Asymptotic results are derived. Simulations illustrate the finite sample performance.     

Efficient Removal of Anionic Organic Dyes from Aqueous Solution with Cu‐Organic Frameworks

Cu‐metal‐organic frameworks (Cu‐MOFs) were synthesized in one step using copper acetate, glutamic acid, and small‐molecular organic amines at room temperature. Organic amines served as modulators to modify the structure of Cu‐MOFs. Characterization results proved that the addition of modulators changes the surface morphology. Batch adsorption data indicated high adsorption capacities for anionic organic dyes with glutamic‐Cu‐triethylamine (Glu‐Cu‐TA), higher than that of most MOFs reported. An acid pH was the optimum adsorption parameter. The easy regeneration of recycled Cu‐MOFs suggested there were weak intermolecular interactions between Cu‐MOFs and dyes. The main adsorption forces included electrostatic interaction, ion exchange, π‐π complexation, and hydrogen bonds.     

Broadband semi‐parametric estimation of long‐memory time series by fractional exponential models

This article proposes broadband semi‐parametric estimation of a long‐memory parameter by fractional exponential (FEXP) models. We construct the truncated Whittle likelihood based on FEXP models in a semi‐parametric setting to estimate the parameter and show that the proposed estimator is more efficient than the FEXP estimator by Moulines and Soulier (1999) in linear processes. A Monte Carlo simulation suggests that the proposed estimation is more preferable than the existing broadband semi‐parametric estimation.     

Preparation and efficacy of tumor vasculature‐targeted doxorubicin cationic liposomes coated by N‐trimethyl chitosan

Cationic liposomes (CLs) can accumulate in tumor vascular endothelial cells (VECs) to show high selective targeting ability. Therefore, chemotherapeutic agent‐loaded CLs are considered as new therapeutic vehicles to enhance the treatment efficacy. This study investigated the effect of N‐trimethyl chitosan (TMC), one of derivatives of chitosan with positive charge determined by its degree of quaternization (DQ), on preparing doxorubicin (DOX)‐loaded CLs. TMCs with various DQ, i.e., 20% (TMC20), 40% (TMC40), and 60% (TMC60) were synthesized and characterized by ¹HNMR. DOX‐loaded liposomes (DOXL) were prepared by ammonium sulfate gradients followed by TMC‐coating to obtain TMC‐coated DOXL with various positive surface charges. The morphology, size, ζ‐potential and drug release in vitro of TMC‐coated DOXL were studied compared with those of DOXL. Human umbilical vein endothelial cells (HUVECs) as cell model, the vascular targeting ability of TMC‐coated DOXL was evaluated in vitro. A solid tumor, formed by implantationmurine hepatoma cells (H₂₂) into mice, as tumor model, the tumor inhibition rate and tumor histological sections stained by HE of TMC‐coated DOXL group were researched compared with those of free DOX and DOXL group. It was found that with the increase of TMC's DQ, the positive surface charge of TMC‐coated DOXL was enhanced accordingly, which had little effect on DOX release in vitro while led to the significant increase of DOX uptake by HUVECs in vitro and the treatment effect on solid tumor in vivo. Especially, TMC‐coated DOXL showed better targeting ability to the nuclei compared with free DOX and DOXL, which could further enhance the efficacy of DOX in vivo. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Multizone circulating reactor modeling for gas‐phase polymerization. I. Reactor modeling

A new gas‐phase technology for polyolefin production is being developed to be commercially available for large‐scale production between 2004 and 2005. This new technology uses a multilane circulating reactor, which consists of two interrelated zones where two distinct and different fluodynamic regimes are realized, between which the polymer particles are kept in continuous circulation. This article presents a mathematical model for the multilane circulating reactor presenting the typical behavior of the reactor operation and a parameter sensibility analysis. Simulations were conducted for polyethylene production. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1042–1052, 2004     

Amino‐terminated polylactide micelles with an external poly(ethylene oxide) corona as carriers of drug‐loaded anionic liposomes

Micelles were prepared from a mixture of NH₂‐terminated poly(l ‐lactide) and poly(d ,l ‐lactide)‐block‐poly(ethylene oxide) (molar ratio of 3:7). The micelles were complexed with bilayer lipid vesicles (liposomes) composed of anionic palmitoyloleoylphosphatidylserine and zwitterionic dioleoylphosphatidylcholine in a molar ratio of 3:7. The micelles and micelle–liposome complexes were characterized using dynamic light scattering, laser electrophoresis, fluorimetry, transmission electron microscopy, enzymatic hydrolysis and cell viability with the following main findings. (i) Average diameter of micelle cores was found to be 70 ± 10 nm. (ii) Each micelle carried ca 20 000 amino groups. (iii) In a pH 7 solution the impact of the protonated NH₂ groups in the total surface of micelles was negligible owing to their screening by bulky poly(ethylene oxide) blocks. (iv) The micelles were stable in slightly acidic and neutral aqueous solutions, but aggregated in slightly alkaline solutions. (v) The micelles showed no cytotoxicity up to 0.04 mg mL^?1 concentration (the maximum concentration in the experiment). (vi) Each micelle adsorbed ca 30 anionic liposomes loaded with the antitumor antibiotic doxorubicin; the liposomes retained their integrity upon binding with micelles. (vii) The initial micelles and the micelle–liposome complexes showed two‐week stability to enzymatic hydrolysis. © 2018 Society of Chemical Industry     

Discovery of a Small‐Molecule pBcl‐2 Inhibitor that Overcomes pBcl‐2‐Mediated Resistance to Apoptosis

Although the role of Bcl‐2 phosphorylation is still under debate, it has been identified in a resistance mechanism to BH3 mimetics, for example ABT‐737 and S1 . We identified an S1 analogue, S1‐16 , as a small‐molecule inhibitor of pBcl‐2. S1‐16 efficiently kills EEE‐Bcl‐2 (a T69E, S70E, and S87E mutant mimicking phosphorylation)‐expressing HL‐60 cells and high endogenously expressing pBcl‐2 cells, by disrupting EEE‐Bcl‐2 or native pBcl‐2 interactions with Bax and Bak, followed by apoptosis. In vitro binding assays showed that S1‐16 binds to the BH3 binding groove of EEE‐Bcl‐2 (K_d=0.38 μM by ITC; IC₅₀=0.16 μM by ELISA), as well as nonphosphorylated Bcl‐2 (npBcl‐2; K_d=0.38 μM ; IC₅₀=0.12 μM ). However, ABT‐737 and S1 had much weaker affinities to EEE‐Bcl‐2 (IC₅₀=1.43 and >10 μM , respectively), compared with npBcl‐2 (IC₅₀=0.011 and 0.74 μM , respectively). The allosteric effect on BH3 binding groove by Bcl‐2 phosphorylation in the loop region was illustrated for the first time.     

A hydrodynamic model of a circulating fluidised bed with low‐density particles

In this study, a two‐dimensional mathematical model was developed considering the hydrodynamic behaviour of a circulating fluidised bed biomass gasifier (CFBBG), which is also applicable for other low‐density particles. In the modelling, the CFB riser was divided into two regions: a dense region at the bottom and a dilute region at the top of the riser. Kunii and Levenspiel's [Kunii and Levenspiel, Powder Technol. 61, 193‐206 (1990)] model was adopted to express the vertical solids distribution with some other assumptions. Radial distributions of bed voidage were taken into account in the upper zone by using Zhang et al.'s [Zhang et al., Chem. Eng. Sci. 46(12), 3045‐3052 (1991)] correlation. For model validation purposes, a cold model CFB was employed, in which sawdust was transported with air as the fluidising agent. The column is 10 m in height and 280 mm in diameter, and is equipped with pressure transducers to measure axial pressure profile and with a reflective optical fibre probe to measure local solids holdup. A satisfactory agreement between the model predictions and experimental data was found. © 2011 Canadian Society for Chemical Engineering     

Retention of Eucalyptol,a Natural Volatile Insecticide,in Delivery Systems Based on Hydroxypropyl‐β‐Cyclodextrin and Liposomes

Eucalyptol (Euc) is a natural monoterpene with insecticide effects. Being highly volatile and sensitive to ambient conditions, its encapsulation would enlarge its application. Euc‐loaded conventional liposomes (CL), cyclodextrin/drug inclusion complex, and drug‐in‐cyclodextrin‐in‐liposomes (DCL) are prepared to protect Euc from degradation, reduce its evaporation, and provide its controlled release. The liposomal suspension is freeze‐dried using hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) as cryoprotectant. The liposomes are characterized before and after freeze‐drying. The effect of Euc on the fluidity of liposomal membrane is also examined. A release study of Euc from delivery systems, in powder and reconstituted forms, is performed by multiple head extraction at 60 °C after 6 months of storage at 4 °C. CL and DCL suspensions are homogeneous, show nanometric vesicles size, spherical shape, and negative surface charge before and after freeze‐drying. Moreover, HP‐β‐CD does not affect the fluidity of liposomes. CL formulations present a weak encapsulation for Euc. The loading capacity of eucalyptol in DCL is 38 times higher than that in CL formulation. In addition, freeze‐dried DCL and HP‐β‐CD/Euc inclusion complex show a higher retention of eucalyptol than CL delivery system. Both carrier systems HP‐β‐CD/Euc and Euc‐loaded DCL decrease Euc evaporation and improve its retention. Practical Applications: Eucalyptol is a natural insecticide. It is highly volatile and poorly soluble in water. To enlarge its application, its encapsulation in three delivery systems (conventional liposomes, cyclodextrin/drug inclusion complex, combined system composed of cyclodextrin inclusion complex and liposome) is studied. In this paper it is proved that cyclodextrin/eucalyptol inclusion complex and eucalyptol‐in‐cyclodextrin‐in‐liposome are effective delivery systems for encalyptol encapsulation, retention, and release.     

Effect of scale‐up on wall shear rates in circulating bubble columns

Effective wall shear rates were investigated experimentally in an external loop circulating bubble column made from transparent acrylic resin. The riser (D_R) and downcomer (D_D) diameters were 0.19 m and 0.14 m, respectively. The column working volume (V_R) was 170 dm³, with a scale‐up factor (A_D/A_R) of 0.54, and a dispersion height (H_D) of 2.25 m. Polymer solutions of xanthan gum and carboxymethyl cellulose were used to simulate non‐Newtonian behavior of biological systems. Effective wall shear rates for the non‐Newtonian solutions were found by analogy with Newtonian glycerol solutions, employing downcomer liquid velocity as the measurable and comparable parameter. The experimental shear rate results were found to fit between those of the literature data. A new single correlation taking into account all the relevant data in the literature and the results of this work is proposed. The new correlation is an improvement over the other correlations because it includes two important design constants: scale‐up factor and dispersion height. Copyright © 2005 Society of Chemical Industry     

Modeling of circulating fluidized beds systems for post‐combustion CO2 capture via temperature swing adsorption

The technology of circulating fluidized beds (CFBs) is applied to temperature swing adsorption (TSA) processes for post‐combustion CO₂ capture employing a commercial zeolite sorbent. Steady state operation is simulated through a one‐dimensional model, which combines binary adsorption with the CFB dynamics. Both single step and multi‐step arrangements are investigated. Extensive sensitivity analyses are performed varying the operating conditions, in order to assess the influence of the main operational parameters. The results reveal a neat superiority of multi‐step configurations over the standard one, in terms of both separation performance and efficiency. Compared to fixed‐bed TSA systems, CFB TSA features a high compactness degree. However, product purity levels are limited compared to the best performing fixed‐bed processes, and heat management within the system appears to be a major issue. As regards energy efficiency, CFB systems place themselves in between the most established absorption‐based technologies and the fixed‐bed TSA. © 2017 The Authors AIChE Journal published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers AIChE J, 64: 1744–1759, 2018     

Multizone circulating reactor modeling for gas‐phase polymerization. II. Reactor operating with gas barrier in the downer section

A new gas‐phase technology for polyolefin production is being developed to be commercially available for large‐scale production between 2004 and 2005. This new technology uses a multizone circulating reactor, which consists of two interrelated zones where two distinct and different fluodynamic regimes are realized, between which the polymer particles are kept in continuous circulation. In the first part, we presented a mathematical model for the reactor, and this second part of the article we present simulations when a gas barrier is introduced in the top of the downer section and its implications in the polymer characteristics. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1053–1059, 2004     

Cytotoxicity of cationic liposomes coated by N‐trimethyl chitosan and their in vivo tumor angiogenesis targeting containing doxorubicin

Doxorubicin (DOX)‐loaded cationic liposomes (DOXL) coated by N‐trimethyl chitosan (TMCs) has been previously shown to enhance DOX uptake by human umbilical vein endothelial cells (HUVECs) in vitro and the tumor inhibition on solid tumor in vivo, and the effects were both enhanced with the degree of quaternization (DQ) increase of TMCs. The aim of the present work is to study the cytotoxicity of the blank cationic liposomes (CLs) coated by TMCs with various DQ on L‐929 mouse fibroblasts, by MTT assay, using the relative proliferation rate as the indicator, and the toxicity extent was classified according to the evaluation criteria of United States Pharmacopoeia. Furthermore, the in vivo tumor angiogenesis targeting of DOXL coated by TMC60 was studied. It was found that with the increase of TMCs concentration and DQ, cytotoxicity was increased accordingly. However, the cell proliferation rates of TMCs‐coated CLs with TMCs concentrations of 0.02% and 0.05%(w/w) were all above 80%, even the concentration of TMC20 was increased to 0.2%(w/w), the cell proliferation rate was still above 80%, showing noncytotoxicity. The mouse H₂₂ tumor model was established by transplanted tumor experiment. In vivo fluorescence in tumor tissue was investigated through the tail vein injection of fluorescein isothiocyanate conjugated dextran at the 7th day after the administration of different DOX preparations. Compared with DOX solution and uncoated DOXL, the mice given TMC60‐coated DOXL showed tumor angiogenesis with good shape, uniform arrangement, and small vascular branches, and the vascular density was decreased, suggesting promising tumor angiogenesis targeting of TMC60‐coated DOXL. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013