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A series of water damage phenomena of asphalt pavement during service show that water is very important. To comprehensively analyze the influence of water vapor factors on the response of pavement structure, this article first tests the water vapor diffusion coefficient of asphalt pavement materials at different temperatures establishes the water vapor concentration field model of the pavement structure, and analyzes the actual water vapor distribution of the pavement structure; then, the relationship between viscoelastic parameters of the mixture and water vapor concentration is established. Based on this, the finite element model of the pavement structure considering the water vapor factor is established, and the influence of the water vapor factor on the pavement structure response and fatigue life is quantified. It is found that water vapor has an important influence on the mechanical response. On the hottest days in summer, the attenuation of surface modulus caused by water vapor has the greatest impact on the upper layer of the pavement structure. Under the influence of water vapor, the position just below the wheel of the upper layer at the bottom of the horizontal tension strain increases by 108.26%, and the horizontal tension strain of the other layers increases by about 5%, increasing the risk of upper layer cracking. At the same time, water vapor reduces the stress that can be borne by the surface layer, while the rest of the stress is borne by the base. Compared with the fatigue life calculation method in the specification, the actual non-uniform water vapor concentration field reduces the fatigue life of the surface layer by 12.246%. This shows that the current structural calculation does not consider the water vapor factor, which makes the pavement structure more dangerous, and the influence of the water vapor factor should be fully considered.

Capacity of tumor niche chemotaxis and long-term persistency making macrophage as great vehicles for anti-tumor factor delivery. Macrophages-based delivery of chemokines or cytokines have been tested for tissue homeostasis and cancer repression. TRAIL as a promising anti-tumor cytokine, made little clinical progress due to limited stability and off-target toxicity. Here we engineered macrophages with tumor micro-environment (TME)-induced trimerized CP1-TRAIL secretion under the TME specific promoter Arg1 (Tri-TRAIL-iM). The Tri-TRAIL-iM cells displayed high specific inducible activity in both cell-based co-culture assay and in tumor baring mice models. Compared to normal TRAIL over-expressed macrophages under none-inducible promoter, Tri-TRAIL-iM infiltrated to tumor sites and showed superior apoptosis induction of cancer cells and tumor growth repression as well as less systemic side effect. This inducible delivery TRAIL strategy can be effectively further applied in clinical studies and can be coupled with other engineered methods to maximize the therapeutic outcomes for solid tumors.

Mast cell activation and inflammatory mediators play central roles in the pathogenesis of chronic spontaneous urticaria (CSU). The factors that induce mast cell activation in CSU are still largely unknown. Exosomes (EXs) are extracellular vesicles that activate mast cells. In this study, we enriched the EXs derived from the plasma of healthy volunteers and that of patients with CSU without antihistamine sensitivity (i.e., CSU-derived EXs with antihistamine sensitivity) or resistance (i.e., CSU-derived EXs with antihistamine resistance) using ultracentrifugation. We then incubated these EXs with HMC-1 human mast cells. Notably, CSU-derived EXs with antihistamine sensitivity and CSU-derived EXs with antihistamine resistance increased tryptase-1 expression; histamine production; inflammatory mediator production; and toll-like receptor (TLR) 2, TLR4, and phosphorylated MAPK levels in HMC-1 cells. These effects were more significant in the group with CSU-derived EXs with antihistamine resistance than in the group with CSU-derived EXs with antihistamine sensitivity. TLR2, TLR4, and MAPK inhibitors (CC-401, TAK-715, and SCH772984, respectively) reduced CSU-derived EXs-Stimulated production of inflammatory mediators in HMC-1 cells. Overall, EXs in the plasma of patients with CSU were found to activate mast cells and elicit the production of multiple inflammatory mediators, partly through the TLR2, TLR4, and MAPK pathways. In addition, CSU-derived EXs with antihistamine resistance had more powerful mast cell‒activating and histamine-release abilities. Thus, these EXs may be involved in the pathogenesis of CSU with antihistamine resistance.

Thrombin-induced mast cell activation represents cross-talk between coagulation and inflammation. However, there is still controversy concerning the pro- or anti-inflammatory effects mast cells have in response to thrombin signaling. Human mast cell HMC-1 was incubated with 0.2 U/mL thrombin. Cells and supernatants were collected. Production of pro- and anti-inflammatory mediators was determined by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). Expression of proteinase-activated receptor-1 (PAR1) and -4 (PAR4) mRNA in HMC-1 cells was analyzed by qPCR. Activation of mitogen-activated protein kinases (MAPKs) was measured by immunoblotting. Furthermore, the impact of PAR1 inhibitor (SCH79797) and agonist (TFLLR-NH2), PAR4 inhibitor (BMS986120) and agonist (AYPGKF-NH2), and MAPK inhibitors (SB203580, PD98059, and SP600125) on the production of mediators was evaluated using qPCR and ELISA. Thrombin exposure increased pro- and anti-inflammatory mediators, expression of PAR1 and PAR4 mRNA, and phosphorylation of JNK, p38, and ERK1/2 MAPKs in HMC-1 cells. SCH79797, BMS986120, and MAPK inhibitors (SB203580, PD98059, and SP600125) were inhibited, while TFLLR-NH2 and AYPGKF-NH2 promoted pro- and anti-inflammatory cytokines in this process. HMC-1 produces pro- and anti-inflammatory cytokines after thrombin incubation, namely PAR1 and PAR4. Alongside HMC-1, MAPK signaling pathways are involved in the production of these mediators. The mast cells showed dual activation after thrombin stimulation.

Background. Thrombin could elicit degranulation of mast cells involved in numerous physiologic and pathologic processes; however, the detailed scrutiny of this procedure and further research of possible cell signaling pathways are lacking. Methods. P815 mouse mast cells were exposed to various concentrations of thrombin for 16 h. Expression of protease-activated receptor (PAR)1, PAR2, PAR3, and PAR4 mRNA in P815 was analyzed by quantitative real-time PCR (qRT-PCR) and the fittest concentration of thrombin was decided. Then, secretions of mediators from P815 stimulated by thrombin 0.2 U/ml were determined using enzyme-linked immunosorbent assay (ELISA) and Luminex liquichip; the possible cell signaling pathways were measured by immunoblotting. Furthermore, inhibition of thrombin inhibitor (hirudin), PAR1 inhibitor (SCH79797), and MAPK inhibitors (SB203580, PD98059, and SP600125) on the mediator section was evaluated by ELISA and Luminex liquichip. Results. Thrombin 0.2 U/ml induced the elevated expression of PAR1, PAR2, PAR3, and PAR4, as well as the increasing level of phospho-IκBα, phospho-SAPK/JNK MAPK, phospho-P38 MAPK (Thr180/Tyr182), and phospho-ERK1/2 MAPK (p44/42) in P815. Secretion of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), interleukin- (IL-) 2, IL-6, chemokine ligand- (CCL-) 2, chemokine (C-X-C motif) ligand- (CXCL-) 1, and CXCL-5 from P815 increased apparently; this effect could be diminished by hirudin, whereas SCH79797 and MAPK inhibitors (SB203580, PD98059, and SP600125) diminish the secretions with weaker effect. Conclusion. We found the expression of PAR mRNA in P815, activation of signaling pathways of nuclear factor-kappaB (NF-κB), and mitogen-activated protein kinases (MAPKs) including C-Jun NH2-terminal kinase (JNK), P38, and extracellular signal-regulated kinase 1/2 (ERK1/2), and the release of multiple inflammatory mediators stimulated by thrombin, as well as the inhibition of the inflammatory releases by hirudin, SCH79797, and MAPK inhibitors including SB203580, PD98059, and SP600125.

In vitro antioxidant activity of an exopolysaccharide from Lactobacillus plantarum SKT109 (L-EPS) and potential application of this strain for Cheddar cheese production were evaluated. Cheddar cheese was manufactured using a cheese starter culture consisting of lactococci combined with L. plantarum SKT109 as an adjunct culture. The chemical composition, microbial changes, proteolysis, textural profiles and volatile compounds of the cheeses were studied during 12 weeks of ripening. The experimental cheese made with L. plantarum SKT109 as an adjunct had greater moisture contents than those of the control cheese made with starter alone. L. plantarum SKT109 survived well in Cheddar cheese, with counts of 7.89 log cfu/g at the end of the ripening period. Inclusion of the adjunct strain had no detectable negative effects on cheeses in terms of proteolysis and texture. L. plantarum SKT109 improved the Cheddar cheese flavor profile by increasing the levels of low threshold value compounds including ethyl acetate, 3-methyl-1-butanol, 3-hydroxy-2-butanone and butanone. L-EPS had the strongest scavenging activity toward hydroxyl (68.52%) radicals at a dose of 5 mg/mL. These results indicated that EPS-producing L. plantarum SKT109 or its EPS may be promising ingredients, with favorable effects on cheese texture and flavor as well as potential health benefits.

In comparison to elective cesarean delivery, emergency cesarean delivery under endotracheal intubation is associated with higher risk of life-threatening airway problems. In this retrospective study, we evaluate the efficacy and feasibility of using SUPREME laryngeal mask airway (SLMA) in emergency cesarean delivery under general anesthesia (GA). The study included a total of 1039 paturients undergoing emergency cesarean delivery under GA with SLMA from January 2015 to December 2015 at Quanzhou Children’s and Women’s Hospital. Outcome measures included incidence of the adverse events related to using SLMA, maternal mortality, and neonatal outcomes. Briefly, no aspiration or regurgitation was noticed; the first attempt was successful in all but 2 subjects, both because of incorrect location, one was detected by decreasing oxygenation and the other by high airway pressure, the second attempt was successful in both cases. No subject was switched to endotracheal intubation. No laryngospasm or bronchospasm was detected. No maternal death occurred. There were 1139 neonates (including 944 single birth, 92 twins, 3 triplets) in this study, 5-min Apgar score was 7–10 in 1092 (96.72%) neonates. Thirty-seven (3.28%) neonates received endotracheal intubation. In conclusion, this retrospective study showed that the SLMA was used successfully in 1039 patients undergoing emergent cesarean delivery without any major complications. Vigilant attention by attending anesthesiologists is warranted.

A purified neutral exopolysaccharide (EPS) designated as EPS0142 was obtained from Lactobacillus plantarum JLK0142. EPS0142 consisted of glucose and galactose in an approximate molar ratio of 2.13:1.06 and had a molecular weight of 1.34 × 105 Da. The FT-IR spectrum showed that EPS0142 had a typical polysaccharide absorption pattern. 1H NMR and 13C NMR spectra analysis showed the presence of N-acetylated sugar residues. EPS0142 had no toxic effects on RAW 264.7 cells and significantly improved their phagocytic activity and NO secretion in vitro. Further in vivo studies revealed that the spleen index and splenic lymphocyte proliferation activities of the cyclophosphamide-induced immunosuppression mice treated with a middle-dose (50 mg/kg body weight) or a high-dose (100 mg/kg body weight) of EPS0142 were significantly increased (P

Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer death worldwide. Most current therapeutic agents lack the tumor-targeting efficiency and result in a nonselective biodistribution in the body. In our previous study, we identified a peptide Ala-Pro-Asp-Thr-Lys-Thr-Gln (APDTKTQ) that can selectively bind to the receptor of advanced glycation end-products (RAGE), an immunoglobulin superfamily cell surface molecule overexpressed during HCC malignant progression. Here, we report the design of a mixed micelles system modified with this peptide to target HCC cells. Specifically, we modified Pluronic F68 (F68) with APDTKTQ (F68-APDTKTQ), and we conjugated d-α-tocopheryl polyethylene glycol succinate (TPGS) with poly(lactic-co-glycolic acid) (PLGA) by a disulfide linker (TPGS-S-S-PLGA). We mixed TPGS-S-S-PLGA and F68-APDTKTQ (TSP/FP) to form a micelle, followed by the loading of oridonin (ORI). The prepared micelles showed a homogeneously spherical shape without aggregation, triggered an increased cellular uptake, and induced apoptosis in more cells than did the free ORI. Taken together, these results demonstrate the potential of this APDTKTQ-modified ORI-loaded TSP/FP mixed micelle system as a promising strategy for HCC-targeting therapy.

Ultrasonic-assisted extraction technology was employed to prepare Ligusticum chuanxiong Hort polysaccharide. Single factor test and orthogonal experimental design were used to optimize the extraction conditions. The results showed that the optimal extraction conditions consisted of ultrasonic temperature of 80°C, ultrasonic time of 40 min and water to raw material ratio of 30 mL/g. Three novel polysaccharides fractions, LCX0, LCX1 and LCX2, were isolated and purified from the crude polysaccharides using DEAE-52 cellulose and Sephadex G-100 column chromatography. The molecular weight and monosaccharide composition of three LCX polysaccharides fractions were analyzed with gel permeation chromatography (GPC) and HPLC analysis, respectively. Furthermore, the antioxidant and in vitro anticancer activities of the polysaccharides were investigated. Compared with LCX0, LCX2 and LCX1 showed relative higher antioxidant activity and inhibitory activity to the growth of HepG2, SMMC7721, A549 and HCT-116 cells. It is suggested that the novel polysaccharides from rhizome of L. chuanxiong could be promising bioactive macromolecules for biomedical use.

Reduction-sensitive micelles with crosslinked cores were developed to load the lipophilic chemotherapeutic drug docetaxel (DTX) in order to overcome the issues of toxicity, water insolubility, and rapid metabolism of DTX. These DTX-loaded micelles (MM(DTX/Crosslink)) provide efficient incorporation and sustained release of DTX. Using independently synthesized LA–PLGA–TPGS and DSPE–PEG polymers as vehicles, MM(DTX/Crosslink) was found to be reduction-responsive, and possessed desirable drug entrapment efficiency (84.17 ± 1.15%) and drug loading efficiency (6.21 ± 0.07%). The MM(DTX/Crosslink) quickly dissociated under reduction conditions that mimicked the reductive intracellular environment, suggesting that it can rapidly release the encapsulated DTX in vitro. Furthermore, to target MM(DTX/Crosslink) to tumors for cancer therapy, iRGD was conjugated to the surface of MM(DTX/Crosslink). The iRGD-MM(DTX/Crosslink) micelles significantly increased the cellular uptake of DTX and inhibited cell proliferation, compared to the micelles without iRGD modification. Moreover, the iRGD-MM(DTX/Crosslink) micelles presented enhanced antitumor effects based on the analyses of apoptosis and cell cycle arrest. The micelles developed in this work may constitute a stable, efficient, and powerful system to deliver DTX into cancer cells.

An acidic exopolysaccharide (EPS) designated as EPS103 was isolated, purified and characterized from Lactobacillus plantarum JLAU103. EPS103 had a relatively lower molecular weight of 12.4 KDa and was consisted of arabinose, rhamnose, fucose, xylose, mannose, fructose, galactose, and glucose in an approximate molar ratio of 4.05: 6.04: 6.29: 5.22: 1.47: 5.21: 2.24: 1.83. A specific spectrogram of acidic polysaccharide was obtained by FT-IR analysis, and both α- and β-type configurations were presented in EPS103 based on the nuclear magnetic resonance spectroscopy. Microstructural analysis of EPS103 demonstrated a smooth and glittering cube structure, and presence of many homogeneous rod-shaped lumps. Comprehensive study of in vitro antioxidant activity indicated that EPS103 possess strong scavenging abilities against hydroxyl, ABTS, and DPPH radicals with the maximum of 80.4%, 65.5%, and 60.5%, respectively, at 10 mg/mL concentration. Furthermore, EPS103 also showed strong ferrous ions chelating activity and oxygen radical absorbance capacity. These results together indicated that the EPS103 isolated from L. plantarum JLAU103 has great potential for use as a natural antioxidant or functional additive in foods industry.

This study aimed to evaluate the effect of exopolysaccharide (EPS)-producing Lactobacillus plantarum JLK0142 on the ripening characteristics and in vitro health-promoting benefits of low-fat Cheddar cheese. Three batches of cheese were made by employing a non-EPS-producing cheese starter (control), in combination with Lb. plantarum JLK0142 as an adjunct and the purified EPS as an ingredient. Lactobacillus plantarum JLK0142 survived well in cheese, with counts of 7.99 log cfu/g after 90 d of ripening. All experimental cheeses (with adjunct culture or EPS ingredient) had higher moisture, proteolysis, and sensory scores, and lower hardness and cohesiveness compared with the control cheese. Water-soluble extracts from the experimental cheeses outperformed that of the control in scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), and hydroxyl radicals, and inhibiting α-amylase, angiotensin-converting enzyme, and HT-29 tumor cell growth. Therefore, incorporation of the EPS-producing culture of Lb. plantarum JLK0142 is promising for improvement of low-fat cheese quality and bioactivities.

Jinming Zhang,1,* Xiaobin Fang,1,* Zeyong Li,2 Hon Fai Chan,3 Zhixiu Lin,4 Yitao Wang,1 Meiwan Chen1 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; 2Department of Laboratory Medicine, Guangdong No 2 Provincial People’s Hospital, Guangzhou, China; 3Department of Biomedical Engineering, Columbia University, New York, NY, USA; 4Faculty of Science, School of Chinese Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, China *These authors contributed equally to this work Abstract: Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic® F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS-LA), was synthesized. After characterization by 1H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as­apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway. Keywords: poloxamer188, tumor micro-environment, glutathione, Brucea javanica, cancer treatment

To design bundle treatment plan in the early stage for severe human infection by avian influenza H7N9, and explore its clinical efficacy and application value.Fifteen patients with severe human infection by avian influenza H7N9 in Guizhou Province from December 29th, 2016 to June 7th, 2017 were enrolled. Patients admitted from March 6th, 2017 to June 7th, 2017 served as a prospective observation period (bundle treatment group), and those from December 29th, 2016 to March 5th, 2017 were selected as a historical control period (conventional treatment group). Conventional treatment group was given conventional treatment such as isolation, anti-virus, symptomatic treatment, and traditional Chinese medicine and so on. Bundle treatment group was given bundle treatment on the basis of conventional treatment, including isolation, anti-virus, respiratory support, restrictive fluid management, immunotherapy, inhibition of inflammation, antibiotic therapy, nutritional support, prevention of hospital acquired infection (HAP), individual sedation, continuous blood purification (CBP) for acute kidney injury (AKI) and severe acute respiratory distress syndrome (ARDS) patients, and intensive care. A cluster of bundle treatment team was set up to ensure that all measures carried out smoothly. The gender, age, onset to diagnosis time, acute physiology and chronic health evaluation II (APACHE II) score, oxygenation index (PaOThere was no significant difference in gender, age, onset to diagnosis time, APACHE II score, PaOEarly bundle therapy has a significant effect on severe human infection by avian influenza H7N9, which can improve the prognosis and reduce the mortality of patients. It is worthy for clinical application.

Curcumin (CUR), a nontoxic polyphenol derived from the rhizome of turmeric (Curcuma longa), has been recognized as an anti-cancer and chemo-preventative agent. However, its clinical application for cancer treatment has been greatly limited due to its poor water-solubility and low bioavailability. To tackle this problem, Pluronic F68-CUR (F68-CUR) conjugate micelles, which are amphiphilic copolymers, were designed and synthesized in this study. These highly stable micelles with CUR concentrated in the core were formulated using the solvent evaporation method and were confirmed by Fourier transform infrared spectroscopy and nuclear magnetic resonance. Physicochemical characterization of F68-CUR conjugate micelles revealed that high drug loading content (DL%; 0.248 mg CUR/1 mg F68) was achieved, and the average particle size of micelles was 115.2 ± 3.0 nm. Compared with free CUR, a significantly higher cytotoxicity against human breast cancer cell line MDA-MB-231 was observed in F68-CUR conjugate micelles. The IC

A novel amphiphilic derivative of chitosan, namely, a linoleic acid-g-quaternary chitosan (LA-g-QC), was designed and synthesized as low toxic material for biomedical applications in this study. The chemical structure of LA-g-QC was characterized by Fourier transform infrared spectroscopy (FTIR),1H nuclear magnetic resonance (1H-NMR), and elemental analysis. LA-g-QC could form nanosized micelles with self-assembly, which was confirmed by the results of critical micelle concentration (CMC) via fluorescence spectroscopy. The average size of LA-g-QC was 140 nm and its zeta potential was approximately +35.50 mV. CMC value was 31.00 mg/mL. Furthermore, LA-g-QC micelles, at final concentrations between 0.94 μg/mL and 30 μg/mL, did not inhibit the proliferation of HepG2 or SMMC 7721 cell lines. Taken together, LA-g-QC has low cytotoxicity and high potential for the preparation of novel drug-delivery micelles.

Using microwave irradiation as an intercalation method, quaternized chitosan/organo– montmorillonite (QCS/OMMT) nanocomposites were prepared rapidly by intercalating quaternized chitosan into the interlayer of organo–montmorillonite. The structure and morphology of QCS/OMMT nanocomposites were characterized by XRD and TEM, the effects of weight average molecular weight (Mw) of QCS and degree of quaternization (DQ) in QCS on the intercalation, crystallinity and thermal stability of QCS/OMMT nanocomposites were explored. The result showed that the completely exfoliated QCS/OMMT nanocomposites were obtained when the mass ratio of QCS to OMMT was 4:1, in this case, it was found that with the increase of DQ and Mw of QCS, the interlayer distance of clay was enlarged gradually, but the crystallinity of QCS/OMMT nanocomposites was destroyed; the thermal stability of QCS/OMMT nanocomposites was lower with the increasing DQ in QCS and the decreasing Mw of QCS. The study will guide the practical application of chit...

Conducting polymer polyparaphenylene (PPP) was synthesized from cis-dihydrocatechol (DHCD) obtained from bacterial transformation of benzene. Results showed that the DHCD to DHCD-DA (diacetate) synthesis process produced some byproducts as impurities includ- ing trace amounts of phenol, quinone, and phenyl acetate derived from phenol. These impurities played a negative role in the polymerization process of DHCD-DA to P(DHCD-DA). In this study, a distillation fractionation method was employed to obtain monomer DHCD-DA with high purity and high yield. Four different polymer- ization methods using the purified DHCD-DA, including bulk polymerization initiated by different catalyst systems, solution polymerization as well as emulsion polymeriza- tion, were compared. A very high P(DHCD-DA) yield of 92% with a molecular weight of 84,500 was obtained under an optimized condition using the bulk polymeriza- tion process initiated by (di)benzoyl peroxide (BPO) and ferrous sulfate. A standard curve was established to evalu- ate the aromatization degree of P(DHCD-DA) to PPP under different temperatures based on the intensity of FTIR absorption and functional groups on the PPP. The glass transition temperature and the crystallinity of PPP increased with the degree of aromatization of the prepoly- mer P(DHCD-DA). Thermal analysis indicated that the PPP possessed high thermal stability both in nitrogen and in air atmospheres. All these results would help the syn- thesis of PPP. V C 2008 Wiley Periodicals, Inc. J Appl Polym Sci 110: 2085-2093, 2008

Curcumin (Cur) is a highly pleiotropic anticancer agent that inhibits cell proliferation and induces apoptosis in cancer cells. A variety of nano-systems constituted by polymer-drug conjugates have been designed to overcome its shortages on water solubility, chemical instability, and poor bioavailability. However, most of them suffer from ineffective release of Cur in cancer cells in vivo. This work developed a novel flexible acid-responsive micelle formulation by covalently conjugating Cur on the hydrophilic terminals of pluronic F68 chains via cis-aconitic anhydride linkers. The synthesized F68-Cis-Cur conjugates can readily precipitate to form homogeneous micelles with average size about 100 nm in aqueous solution. In acid environments, F68-Cis-Cur conjugates would break down and subsequently release Cur rapidly, for the reason of pH-sensitive cleavage of cis-aconitic anhydride linkers. In vitro anticancer activity tests demonstrated that F68-Cis-Cur micelles induced higher cytotoxicity against both A2780 and SMMC 7721 cells than free Cur. It provided a larger decrease of mitochondrion membrane potential and induced cellular apoptosis. F68-Cis-Cur micelles remarkably increased cellular uptake of Cur than free Cur through caveolae-mediated endocytosis in an energy-dependent manner. This study demonstrates F68-Cis-Cur conjugation as a promising tool for improving intracellular drug delivery in cancer therapy.

Gambogic acid (GA), a natural compound from gamboge resin, has been introduced as a promising antitumor drug contributing to its broad spectrum of antitumor activity. However, the poor aqueous solubility and short half-life hinder its clinical application. Pluronic F68 (F68) is a well-known amphiphilic block copolymer consisting of hydrophobic propylene oxide units and hydrophilic ethylene oxide. Although F68 has an amphiphilic structure, its short propylene oxide segment limits its dilution stability and drug-loading capacity. To overcome this limitation, we modified F68 by conjugating linoleic acid, a hydrophobic fatty acid, to increase the hydrophilic-hydrophobic interaction and thus improve the stability of F68 nano-spheres. This F68-linoleic acid (F68-LA) conjugate was synthesized and was used to load GA to improve its anticancer effects. GA-loaded F68-LA nano-spheres were stable for 6 days, with a mean diameter of 159.3 nm and zeta potential of −23.2 mV. The entrapment efficiency of GA in F68-LA nano-spheres was as high as 92.0%. Furthermore, F68-LA/GA nano-spheres exhibited an enhanced cytotoxic activity and proapoptotic effect against human ovarian cancer A2780 cells, compared with free GA. Our results showed that the F68-LA/GA nano-spheres might be a promising cancer-targeted drug delivery system in ovarian cancer therapy.