Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Mass transfer process of peanut protein extracted by bis(2-ethylhexyl)sodium sulfosuccinate reverse micelles

The liquid-liquid extraction method using reverse micelles can simultaneously extract lipid and protein of oilseeds,which have become increasingly popular in recent years.However,there are few studies on mass transfer processes and models,which are helpful to better control the extraction process of oils and proteins.In this paper,mass transfer process of peanut protein extracted by bis(2-ethylhexyl)sodium sulfosuccinate(AOT)/isooctane reverse micelles was investigated.The effects of stirring speed(0,70,140,and 210 r/min),temperature of extraction(30,35,40,45,and 50℃),peanut flour particle size(0.355,0.450,0.600,and 0.900 mm)and solidliquid ratio(0.010,0.0125,0.015,0.0175,and 0.020 g/mL)on extraction rate were examined.The results showed that extraction rate increased with temperature rising,particle size reduction as well as solid-liquid ratio increase respectively,while little effect of stirring speed(P>0.05)was observed.The apparent activation energy of extraction process was calculated as 10.02 kJ/mol and Arrhenius constant(A)was 1.91 by Arrhenius equation.There was a linear relationship between reaction rate constant and the square of the inverse of initial particle radius(1/r_(0)^(2))(P<0.05).This phenomenon and this shrinking core model were anastomosed.In brief,the extraction process was controlled by the diffusion of protein from the virgin zone interface of particle through the reacted zone and it was in line with the first order reaction.Mass transfer kinetics of peanut protein extracted by reverse micelles was established and it was verified by experimental results.The results provide an important theoretical guidance for industrial production of peanut protein separation and purification.

Linear-like polypeptide-based micelle with pH-sensitive detachable PEG to deliver dimeric camptothecin for cancer therapy

Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin(CPT).However,many challenges for CPT delivery remain,including low drug loading efficiency,premature drug leakage,and poor cellular internalization.Herein,we report a novel dual-sensitive polypeptide-based micelle with remarkably high drug loading of CPT for cancer therapy.This self-assembled micelle possesses the following essential components for CPT:(1)pH-sensitive PEG(OHC-PEG-CHO)for prolonging blood circulation and allowing biocompatibility by shielding the cationic micelles,which can be detached under the tumor acidic microenvironment and facilitates the cellular uptake;(2)polypeptide polylysine-polyphenylalanine(PKF)synthesized via ring-opening polymerization for micelle formation and CPT analogue loading;(3)dimeric CPT(DCPT)with redox-sensitive linker for increasing CPT loading and ensuring drug release at tumor sites.Interestingly,the linear-like morphology of PEG-PKF/DCPT micelles was able to enhance their cellular internalization when compared with the spherical blank PKF micelles.Also,the anticancer efficacy of DCPT against lung cancer cells was significantly improved by the micelle formation.In conclusion,this work provides a promising strategy facilitating the safety and effective application of CPT in cancer therapy.

Physico-chemical parameters for the assembly of moxifloxacin hydrochloride and cetyltrimethylammonium chloride mixture in aqueous and alcoholic media

The aggregation behavior of the mixture of cetyltrimethylammonium chloride(CTAC), a cationic surfactant, and moxifloxacin hydrochloride(MFH), a fourth-generation fluoroquinolone antibiotic drug, has been studied using the conductivity technique in aqueous and alcoholic(EtOH, 1-PrOH, and 2-BuOH)media. The study was performed at several temperatures between 298.15 and 323.15 K at 5 K intervals.The assembly has been characterized by evaluating the micellar parameters, such as the critical micelle concentration(CMC) and the counter ion binding(β), of the CTAC + MFH mixture. The values of the CMC for the assembly of the CTAC + MFH mixture were reliant on the composition of alcohols in the mixed solvents and the temperature. The CMC values of the CTAC + MFH mixture increased with increasing temperature;that is, assembly was delayed by increased temperature. The micellization of the CTAC + MFH mixed system was delayed in alcoholic media. The observed-ΔG0mvalues for the association of the CTAC + MFH mixed system demonstrated a spontaneous aggregation process under all study conditions.Based on the-ΔH^(0)_(m) and +ΔS^(0)_(m) values, the association of the CTAC + MFH mixture is exothermic and the interaction forces acting between the CTAC and MFH species are hydrophobic, ion–dipole, and electrostatic interactions. The transfer properties and enthalpy–entropy compensation were also assessed and described comprehensively.

Encapsulation of docosahexaenoic acid (DHA) using self-assembling food-derived proteins for efficient biological functions

Docosahexaenoic acid(DHA;22n-6)possesses multiple biological functions, including antioxidant activity and ameliorating hypertriglyceridemia. However, the application of DHA has been limited due to poor aqueous solubility and susceptible to oxidation. Here, ovalbumin(O), myosin(M), 7S soy globulin(S), and β-lactoglobulin(β), hydrolyzed by chymotrypsin, self-assembled into micelles, respectively. Adding incremental DHA to micelles caused endogenous fluorescence quenching of O, M, S, and β micelles, implying successful incorporation of DHA into hydrophobic cores of micelles(O(DHA), M(DHA), S(DHA), and β(DHA)). The results showed that micelles provided spatial stability and improved solubility, and stability against thermal and ultraviolet(UV)light for DHA. The uptake of DHA from M(DHA), β(DHA), O(DHA), and S(DHA)was 3.27-, 3.91-, 2.7-, and 3.95-fold higher, respectively, than that of DHA by Caco-2 cells. Encapsulation in micelles increased DHA aqueous solubility and uptake, which enhanced cellular endogenous antioxidant defense. Meanwhile, increased uptake of DHA was verified by HepG2 cells, and O, M, S, and β micelles were proven to increase DHA uptake to reduce lipid deposition. Our findings strongly support the possibility that O, M, S, and β micelles can be regarded as a carrier for loading DHA.

Antibiotic-based small molecular micelles combined with photodynamic therapy for bacterial infections

The appearance of multidrug-resistant bacteria and the formation of bacterial biofilms have necessitated the development of alternative antimicrobial therapeutics.Antibiotics conjugated with or embedded in nano-drug carriers show a great potential and advantage over free drugs,but the mass proportion of carriers generally exceeds 90%of the nano-drug,resulting in low drug loading and limited therapeutic output.Herein,we fabricated a nanocarrier using antibiotics as the building blocks,minimizing the use of carriermaterials,significantly increasing the drug loading content and treatment effect.Firstly,we conjugated betaine carboxylate with ciprofloxacin(CIP)through an ester bond to form the amphiphilic conjugate(CIP-CB),which self-assembled into micelles(CIP-CBMs)in aqueous solutions,with a CIP loading content as high as 65.4%and pH-induced surface charge reversal properties.Secondly,a model photosensitizer(5,10,15,20-tetraphenylporphyrin(TPP))was encapsulated in CIP-CBMs,generating infection-targeted photodynamic/antibiotic combined nanomedicines(denoted as TPP@CIP-CBMs).Upon accumulation at infection sites or in deep bacterial biofilms,the ester bond between the betaine carboxylate and CIP is cleaved to release free TPP and CIP,leading to a synergetic antibacterial and antibiofilm activity in vitro and in vivo.

Construction of curcumin-loaded micelles and evaluation of the anti-tumor effect based on angiogenesis

Objective:Inhibition of tumor angiogenesis has become a new targeted tumor therapy.In this study,we established a micellar carrier with a tumor neovascularization-targeting effect modified by the neovascularization-targeting peptide NGR.Methods:The targeted polymer poly(ethylene glycol)-b-poly(lactide-co-glycolide)(PEG-PLGA)modified with Asn–Gly–Arg(NGR)peptide was prepared and characterized by 1H nuclear magnetic resonance and Fourier-transform infrared spectrometry.NGR-PEG-PLGA was used to construct curcumin(Cur)-loaded micelles by the solvent evaporation method.The physicochemical properties of the micelles were also investigated.Additionally,we evaluated the antitumor efficacy of the polymer micelles(PM)using in vitro cytology experiments and in vivo animal studies.Results:The particle size of Cur-NGR-PM was 139.70±2.51 nm,and the drug-loading capacity was 14.37±0.06%.In vitro cytological evaluation showed that NGR-modified micelles showed higher cellular uptake through receptor-mediated endocytosis pathways than did unmodified micelles,leading to the apoptosis of tumor cells.Then,in vivo antitumor experiments showed that the modified micelles significantly inhibited tumor growth and were safe.Conclusions:NGR-modified micelles significantly optimized the therapeutic efficacy of Cur.This strategy offers a viable avenue for cancer treatment.

Preparation of adhesive resveratrol micelles and determination of drug content

Objective:Resveratrol polymer micelles with tissue adhesion were prepared and the content of resveratrol in the micelles was determined by HPLC.Method:The micelle adhesion experiment was carried out by polylysine orifice plate experiment and small animal fluorescence imaging method,and the micelle prescription was optimized to obtain resveratrol micelles with good adhesion.The separation was performed on a Shiseido SPOLAR C18 column(150 mm×4.6 mm,5μm)with methanol-water(42:58)as the mobile phase.The flow rate was 1.0 mL·min^(-1),the detection wavelength was 305 nm,the column temperature was 35℃,and the injection volume was 10μL.Results:Resveratrol micelles prepared with F127 alone had the best adhesion.The peak area and concentration of resveratrol had a good linear relationship in the concentration range of 10~200μg/mL(r=0.9996).The specificity,precision,recovery and stability all met the methodological requirements.Conclusion:In this experiment,resveratrol micelles with tissue adhesion were successfully prepared,and a method for the determination of resveratrol content in micelles was established.The method is accurate,rapid and simple.

Development of therapeutic cancer vaccines using nanomicellar preparations

Cancer treatment is a multifaceted challenge,and therapeutic vaccines have emerged as a promising approach.The micellar preparation efficiently encapsulates antigen polypeptides and enhances antigen presentation through the major histocompatibility class I pathway,promoting cytotoxic T lymphocyte immune responses.Moreover,it enables codelivery of both antigen and adjuvant to the same target antigen-presenting cells.Combining themicellar vaccine with traditional cancer treatments(such as chemotherapy,radiotherapy,and surgery)has demonstrated improved efficacy in murine tumor models.Overall,the polyethylene glycol-phosphatidylethanolamine micelle-based vaccine presents a promising platformfor cancer therapeutic vaccines.By leveraging the strengths of various treatmentmodalities,this innovative vaccine approach holds the potential to revolutionize cancer therapy and bring new possibilities for cancer patients.

Adsorption of Natural Surfactant on Sandstone in Enhanced Oil Recovery: Isotherms and Kinetics Studies

In chemical enhanced oil recovery, surfactants are injected into the reservoir with the intention to lower interfacial tension (IFT) between the water and oil phases, and thereby bring about efficient displacement of oil. However, the adsorption of the surfactants to reservoir rock surfaces leads to the loss and reduction in concentration of the surfactants, which in turn reduces the overall efficiency of the oil recovery process, with attendant financial losses. In this work, the adsorption of Quillaja Saponaria (QS), a novel, natural, non-ionic surfactant, on crushed sandstone reservoir rock is investigated. X-ray diffraction (XRD) study of clean sandstone particles has been undertaken to determine the main components present in the sand particles. The conductivity method was used to measure CMC and the surfactant concentrations in aqueous solutions. Batch adsorption experiments were used to determine the amount of QS adsorbed on rock surface. Equilibrium conditions were reached after almost 5 days. From the results of the study, the Langmuir isotherm model is more suited for predicting the adsorption behaviour of QS on sandstone. The kinetic adsorption of QS obeys the pseudo-second order model. This study is particularly relevant in surfactant selection for chemical EOR processes.

反相胶团软模板法制备氯化银晶体纳米线研究

The nanosystem has received considerable attention because of its peculiar pheno mena,which is different from macroscopy and microscopy. At present,the upsurge o f researching nanomaterials has shifted from nano particles to one dimensional na nosystem,such as nanowires,nanotubes,and so on.Seen from literatures, the repor ts on carbon nanotubes wer e more,on nanowires were less,and on transition metallic salt nanowires were noth ing .In this paper,AgCl nanocrystalline wires were successfully synthesized by Rever s e Micelle soft Templates, which will open a new way for the synthesis and applic ation of one dimensional nanomaterials.

pH-sensitive polymeric micelles triggered drug release for extracellular and intracellular drug targeting delivery

Most of the conventional chemotherapeutic agents used for cancer chemotherapy suffer from multidrug resistance of tumor cells and poor antitumor efficacy.Based on physiological differences between the normal tissue and the tumor tissue,one effective approach to improve the efficacy of cancer chemotherapy is to develop pH-sensitive polymeric micellar delivery systems.The copolymers with reversible protonationedeprotonation core units or acid-liable bonds between the therapeutic agents and the micelle-forming copolymers can be used to form pH-sensitive polymeric micelles for extracellular and intracellular drug smart release.These systems can be triggered to release drug in response to the slightly acidic extracellular fluids of tumor tissue after accumulation in tumor tissues via the enhanced permeability and retention effect,or they can be triggered to release drug in endosomes or lysosomes by pH-controlled micelle hydrolysis or dissociation after uptake by cells via the endocytic pathway.The pH-sensitive micelles have been proved the specific tumor cell targeting,enhanced cellular internalization,rapid drug release,and multidrug resistance reversal.The multifunctional polymeric micelles combining extracellular pH-sensitivity with receptor-mediated active targeting strategies are of great interest for enhanced tumor targeting.The micelles with receptor-mediated and intracellular pH targeting functions are internalized via receptor-mediated endocytosis followed by endosomal-pH triggered drug release inside the cells,which reverses multidrug resistance.The pH sensitivity strategy of the polymeric micelles facilitates the specific drug delivery with reduced systemic side effects and improved chemotherapeutical efficacy,and is a novel promising platform for tumor-targeting drug delivery.

Synthesis and Surface Activity of Novel Triazole-based Cationic Gemini Surfactants

The synthesis and surfactant activities of two new cationic gemini surfactants containing triazole compound as spacer were described. Their critical micelle concentrations (CMC), which are 1.8×10-4 mol/L and 3.9×10-4 mol/L respectively, are much lower than that of conventional surfactant cetyltrimethyl ammonium chloride (CTAC). In addition, compared with some gemini surfactants containing phenylene, xylylene and stilbenyl as spacer, this new kind of surfactants has good solubility in water at room temperature because of containing more hydrophilic groups or atoms in molecules.

Enhanced oil recovery by nonionic surfactants considering micellization, surface, and foaming properties

Surfactants for enhanced oil recovery are important to study due to their special characteristics like foam generation,lowering interfacial tension between oleic and aqueous phases,and wettability alteration of reservoir rock surfaces.Foam is a good mobility control agent in enhanced oil recovery for improving the mobility ratio.In the present work,the foaming behavior of three nonionic ethoxylated surfactants,namely Tergitol 15-S-7,Tergitol 15-S-9,and Tergitol 15-S-12,was studied experimentally.Among the surfactants,Tergitol 15-S-12 shows the highest foamability.The effect of Na Cl concentration and synthetic seawater on foaming behavior of the surfactants was investigated by the test-tube shaking method.The critical micelle concentrations of aqueous solutions of the different nonionic surfactants were measured at 300 K.It was found that the critical micelle concentrations of all surfactants also increased with increasing ethylene oxide number.Dynamic light scattering experiments were performed to investigate the micelle sizes of the surfactants at their respective critical micelle concentrations.Core flooding experiments were carried out in sand packs using the surfactant solutions.It was found tha t22% additional oil was recovered in the case of all the surfactants over secondary water flooding.Tergitol 15-S-12exhibited the maximum additional oil recovery which is more than 26%after water injection.

Physiological and molecular biochemical mechanisms of bile formation

This review considers the physiological and molecular biochemical mechanisms of bile formation.The composition of bile and structure of a bile canaliculus,biosynthesis and conjugation of bile acids,bile phospholipids,formation of bile micellar structures,and enterohepatic circulation of bile acids are described.In general,the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes.Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes,associated with diseases of the liver and biliary tract.

Synthesis and evaluation of cationic polymeric micelles as carriers of lumbrokinase for targeted thrombolysis

To achieve targeted thrombolysis, a targeted delivery system of lumbrokinase(LK) was constructed using RGDfk-conjugated hybrid micelles. Based on the specific affinity of RGDfk to glycoprotein complex of GP Ⅱ b/Ⅲ a expressed on the surface of membrane of activated platelet, LK loaded targeted micelles(LKTM) can be delivered to thrombus. The hybrid micelles were composed of polycaprolactone-block-poly(2-(dimethylamino) ethyl methacrylate)(PCL-PDMAEMA), methoxy polyethylene glycol-block-polycaprolactone(mPEG-PCL)and RGDfk conjugated polycaprolactone-block-polyethylene glycol(PCL-PEG-RGDfk). PCLPDMAEMA was synthesized via ring open polymerization(ROP) and atom transfer radical polymerization(ATRP). PCL-PEG-RGDfk was synthesized via ROP and carbodiimide chemistry. The prepared LKTM was characterized by dynamic light scattering(DLS) and transmission electron microscope(TEM). Colloidal stability assay showed the prepared LKTM was stable. Biocompatibility assay was performed to determine the safe concentration range of polymer. The assay of fluorescent distribution in vivo demonstrated that LKTM can be efficiently delivered to thrombi in vivo. Thrombolysis in vivo indicated the thrombolytic potency of LKTM was optimal in all groups. Notably, the laboratory mice treated with LKTM exhibited a significantly shorter tail bleeding time compared to those treated with LK or LK-loaded micelles without RGDfk, which suggested that the targeted delivery of LK using RGDfk-conjugated hybrid micelles effectively reduced the bleeding risk.

Preparation and evaluation of poly(L-histidine) based pH-sensitive micelles for intracellular delivery of doxorubicin against MCF-7/ADR cells

In this study, a p H-sensitive micelle self-assembled from poly(L-histidine) based triblock copolymers of poly(ethylene glycol)–poly(D,L-lactide)–poly(L-histidine)(mPEG-PLA-PHis) was prepared and used as the intracellular doxorubicin(Dox) delivery for cancer chemotherapy. Dox was loaded into the micelles by thin-film hydration method and a Box–Behnken design for three factors at three levels was used to optimize the preparations. The optimized mPEG-PLA-Phis/Dox micelles exhibited good encapsulation efficiency of 91.12%,a mean diameter of 45 nm and narrow size distribution with polydispersity index of 0.256.In vitro drug release studies demonstrated that Dox was released from the micelles in a p Hdependent manner. Furthermore, the cellular evaluation of Dox loaded micelles displayed that the micelles possessed high antitumor activity in vitro with an IC50 of 35.30 μg/ml against MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments indicated that m PEG-PLA-Phis micelles mediated efficient cytoplasmic delivery of Dox with the aid of poly(Lhistidine) mediated endosomal escape. In addition, blank m PEG-PLA-Phis micelles were shown to be nontoxic to MCF-7/ADR cells even at a high concentration of 200 μg/ml. The pHsensitive mPEG-PLA-PHis micelles have been demonstrated to be a promising nanosystem for the intracellular delivery of Dox for MDR reversal.

Supersaturation induced by Itraconazole/Soluplus micelles provided high GI absorption in vivo

To investigate the effect of supersaturation induced by micelle formation during dissolution on the bioavailability of itraconazole(ITZ)/Soluplus~? solid dispersion. Solid dispersions prepared by hot melt extrusion (HME) were compressed into tablets directly with other excipients. Dissolution behavior of ITZ tablets was studied by dissolution testing and the morphology of micelles in dissolution media was studied using transmission electron microscopy (TEM). Drug transferring from stomach into intestine was simulated to obtain a supersaturated drug solution. Bioavailability studies were performed on the ITZ tablets and Sporanox~? in beagle dogs. The morphology of micelles in the dissolution media was observed to be spherical in shape, with an average size smaller than 100 nm. The supersaturated solutions formed by Soluplus~? micelles were stable and no precipitation took place over a period of 180 min. Compared with Sporanox~?, ITZ tablets exhibited a 2.50-fold increase in the AUC (0–96) of ITZ and a 1.95-fold increase in its active metabolite hydroxyitraconazole (OHITZ) in the plasma of beagle dogs. The results obtained provided clear evidence that not only the increase in the dissolution rate in the stomach, but also the supersaturation produced by micelles in the small intestine may be of great assistance in the successful development of poorly water-soluble drugs. The micelles formed by Soluplus~? enwrapped the molecular ITZ inside the core which promoted the amount of free drug in the intestinal cavity and carried ITZ through the aqueous boundary layer(ABL), resulting in high absorption by passive transportation across biological membranes. The uptake of intact micelles through pinocytosis together with the inhibition of P-glycoprotein-mediated drug efflux in intestinal epithelia contributed to the absorption of ITZ in the gastrointestinal tract. These results indicate that HME with Soluplus~?, which can induce supersaturation by micelleformation, may be of great assistance to the successful development of poorly watersoluble drugs.

EPR Effect of Amphiphilic Copolymer Micelles Observed by Fluorescent Imaging

Enhanced permeation and retention（EPR） targeting effect of rhodamine B labeled PEG-b-P（LA-co-DHP） [PEG：poly（ethylene glycol）;LA：L-lactide;DHP：2,2-dihydroxylmethyl-propylene carbonate] micelles（RhB-micelles） was observed in H22 liver cancer bearing mice.The RhB-micelles were prepared by conjugating rhodamine B with the DHP units of amphiphilic block copolymer PEG-b-P（LA-co-DHP） followed by subsequent self-assembling of the conjugate.The parent copolymer PEG-b-P（LA-co-DHP） was synthesized by ring-opening copolymerization of LA and DHP with PEG as macroinitiator and diethyl zinc（ZnEt2） as catalyst.The micelles have a spherical shape and the average diameter is ca.50 nm by TEM（transmission electron microscope） or 80 nm by DLS（dynamic light scattering）.Their in vitro cell uptake experiment by CLSM（confocal laser scanning microscopy） and flow cytometry showed preferential internalization of micelles by MCF-7 human breast cancer cells to free RhB.The in vivo tests by live animal imaging and ex vivo excised organ imaging showed that after vena tail injection,free RhB molecules were distributed in the whole body through the circulation system and then gradually metabolized and excreted and there was no preferential partition in tumor bed from the beginning to the end.But the RhB-micelles were preferentially distributed to the tumor bed so that their concentration（fluorescent intensity） in tumor bed got the level of the liver at a certain time point between 1 and 6 h and reached a maximum relative intensity at around 12 h,indicating an obvious EPR effect of RhB-micelles in H22 liver cancer.

Rheological properties of novel viscoelastic micelle systems containing anionic-nonionic dimeric surfactant

The viscoelastic micelle systems formed by novel anionic-nonionic dimeric surfactant and conventional cationic surfactant cetyltrimethylammonium(1631) were studied.The viscoelasticity,thixotropy,flow curves and constitutive equation for the novel viscoelastic micelle systems were investigated.The results show that the micelle systems possess viscoelasticity,thixotropy,and shear thinning property.Some micelle systems possess hysteresis loops showing both viscoelasticity and thixotropy.It is proved that the flow curves are characterized by the co-rotational Jeffreys constitutive equation correctly.