ACS Applied Materials & Interfaces
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2020
·
IF 8.758
Shengyu Zhang,Ye Gan,Lanlan Shao,Tianqing Liu,Danyi Wei,Yanyan Yu,Hongwei Guo,Hongyan Zhu
Targeting vascular endothelial growth factor (VEGF) using small interfering RNA (siVEGF) has shown great potential in inhibiting the growth, proliferation, and migration of tumors by reducing the proliferation of blood vessels. On the basis of bionic principles, a novel pH-responsive and virus mimetic shell-sheddable chitosan (CS) micelles (CMs) as siRNA delivery system was introduced in this study. The cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) modified poly(enthylene glycol) (PEG) was conjugated to the HA2 modified chitosan via a hydrazone linkage (cRGD-PEG-Hz-CS-HA2). The cRGD-PEG-Hz-CS-HA2 conjugate could form micelles by interacting with the complex of octanal, Boc-l-lysine, and 9-d-arginine (9R) (octyl-Lys-9R) as a hydrophodic core forming agent, termed as cRGD-PEG-Hz-CS-HA2/octyl-Lys-9R (abbreviated as cRGD/HA2/Hz-CMs).The CMs modified with cRGD can accurately target glioma cells (U87MG cells) with high expression of αvβ3. The payloads of siVEGF were packed into the core of cRGD/HA2/Hz-CMs via electrostatic interaction and hydrophobic interaction. The intracellular cargo release was achieved by the pH-responsive lysis of the hydrazone bond in acidic environment of endosome. Moreover, the exposed HA2, as a pH-sensitive membrane-disruptive peptide, assists the escape of the carriers from endosome into cytosol. In addition, cRGD/HA2/Hz-CMs can effectively deliver siVEGF and silence VEGF gene expression in U87MG cells, leading to the significant tumor growth inhibition. This study demonstrates that cRGD/HA2/Hz-CMs can deliver and release siVEGF in a controlled manner, which was traced by the fluorescence resonance energy transfer (FRET) system in order to achieve RNAi-based anti-angiogenic treatment of cancer in vivo.
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JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2020
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IF 2.69
Qianqian Qi,Xianwu Zeng,Licong Peng,Hailiang Zhang,Miao Zhou,Jingping Fu,Jianchao Yuan
Herein, we construct a charge - switchable polymer nano micelles poly (2-(hexamethyl eneimino) ethyl methacrylate) - b - poly (ethylene glycol) monomethyl ether methacrylate) - b - poly (diethyl enetriaminepentaacetic acid methacrylate) - b - poly (1-vinyl imidazole) - b - poly (4-vinyl phenylboronic acid) (PC7A-PEG-DTPA-VI-PBA) in different pH solutions. DOX released faster from micelles in a weakly acidic environment (pH 5.0) than at pH 7.4. In order to enhance the anti-tumor effect, the imidazole functional groups in the polymer were used to coordinate CdSeTe quantum dots (QDs) for photodynamic treatment (PDT). In addition, the surfaces of the micelles were further decorated with phenylboronic acidas a targeting group, using DTPA chelating 99mTc for SPECT imaging.It has been successfully demonstrated that the nanoparticles have a good cumulative effect on the tumor site.The structure of the polymer was characterized by 1HNMR. The morphology and particle size of the micelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The drug loading capacity (DLC) and drug loading efficiency (DLE) of the micelles were analyzed by ultraviolet visible spectroscopy. And the pH-sensitive drug release and cytotoxicity of the micelles were verified in vitro. In vitro experiments showed that the nano micelles were noncytotoxic to different cell lines, while DOX@CdSeTe@PC7A-PEG-DTPA-VI-PBA inhibited the proliferation and promoted the apoptosis of B16F10 cells. An in vivo study with C57BL tumor-bearing mice indicated that DOX@CdSeTe@PC7A-PEG-DTPA-VI-PBA nano micelles efficiently inhibited tumor growth. Results showed that the nano micelles had good pH responsibility and biocompatibility, and the loaded DOX could be released in the weak acidic environment of tumor cells, and it was expected to be a good drug delivery system.
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DRUG DELIVERY
·
2020
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IF 4.902
Xiaojing Xia,Jin Tao,Zhuwa Ji,Chencheng Long,Ying Hu,Zhiying Zhao
The aim of this work is to apply Solutol® HS15 and TPGS to prepare self-assembled micelles loading with ginsenoside Rh2 to increase the solubility of ginsenoside Rh2, hence, improving the antitumor efficacy. Ginsenoside Rh2-mixed micelles (Rh2-M) were prepared by thin film dispersion method. The optimal Rh2-M was characterized by particle size, morphology, and drug encapsulation efficiency. The enhancement of in vivo anti-tumor efficacy of Rh2-M was evaluated by nude mice bearing tumor model. The solubility of Rh2 in self-assembled micelles was increased approximately 150-folds compared to free Rh2. In vitro results demonstrated that the particle size of Rh2-M is 74.72 ± 2.63 nm(PDI = 0.147 ± 0.15), and the morphology of Rh2-M is spherical or spheroid, and the EE% and LE% are 95.27 ± 1.26% and 7.68 ± 1.34%, respectively. The results of in vitro cell uptake and in vivo imaging showed that Rh2-M could not only increase the cell uptake of drugs, but also transport drug to tumor sites, prolonging the retention time. In vitro cytotoxicity and in vivo antitumor results showed that the anti-tumor effect of Rh2 can be effectively improved by Rh2-M. Therefore, Solutol® HS15 and TPGS could be used to entrapping Rh2 into micelles, enhancing solubility and antitumor efficacy.
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Drug Delivery and Translational Research
·
2020
·Vol. 11
·期 3
·1133-1143
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IF 2.664
Li Ruirui,Shan Linwei,Yao Yanan,Peng Feifei,Jiang Shanshan,Yang Dandan,Ling Guixia,Zhang Peng
The platform of the combination chemo-photodynamic therapy has received widespread attention for enhancing anticancer efficacy and inhibiting tumor growth, which supports thermosensitive and controlled drug release. Here, an injectable thermoreversible hydrogel (BPNSs/DTX-M-hydrogel) co-encapsulating black phosphorus nanosheets (BPNSs) and docetaxel (DTX) micelles was prepared to increase drug accumulation in tumor tissue and improve anticancer efficacy. BPNSs were prepared by liquid exfoliation method with a simple and rapid preparation, and DTX micelles were prepared by the thin film dispersion method. Hydrogel was prepared with F127 as hydrogel matrix for intratumoral injection. BPNSs, DTX micelles, and BPNSs/DTX-M-hydrogel were characterized by particle size, morphology, stability and degradation, phase transition feature, and photodynamic performance. And the in vivo anticancer efficacy was evaluated in 4T1 tumor-bearing Balb/c mice. The results showed that the particle size of DTX micelles and BPNSs were about 16 and 180 nm, respectively. The hydrogel with the transformation temperature at near body exhibited great photodynamic efficacy and good biodegradability. Moreover, BPNSs/DTX-M-hydrogel with the combination of chemotherapy and photodynamic therapy exhibited unique anticancer efficacy with low toxicity. In conclusion, the combination platform of chemo-photodynamic therapy based on BPNSs could be a prospective strategy in antitumor research.
Graphical abstract
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JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2020
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IF 2.69
Min Wang,Jianghao Zhan,Laijun Xu,Yanjun Wang,Dan Lu,Zhen Li,Jiehua Li,Feng Luo,Hong Tan
Polyurethane nanomicelle is a promising functional drug delivery system. In this work, the polyurethane (P3-PU) was synthesized from PLGA1200-PEG1450-PLGA1200 (P3, a thermosensitive and biodegradable triblock copolymer) and L-lysine ester diisocyanate (LDI). Then, reactive benzaldehyde was further imported to terminate P3-PU to obtain benzaldehyde modified polyurethane (P3-PUDA). The micelles, temperature-sensitive P3-PU nanomicelle and P3-PUDA nanomicelle, were systematically investigated, including the size, stability, temperature sensitivity, drug loading and release behavior, cytotoxic on human hepatocytes (L02), and inhibitory effect on human hepatocellular carcinoma cells (HepG2). The results show the thermosensitive behavior of the micelles can be adjusted by the terminal group. The polyurethane micelles with a uniform size between 20 nm and 30 nm showed excellent stability and good biocompatibility to L02 cells. Besides, in vitro experiments showed that Dox-loaded P3-PUDA micelles exhibited faster and higher release rate at 37 °C and better inhibitory effect on HepG2 than the Dox-loaded P3-PU micelles. Moreover, the achieved benzaldehyde modified polyurethanes also provides various possibilities to adjust further to enlarge its applications. Therefore, the polyurethane micelles will have great potential in the field of drug carriers.
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BIOMATERIALS
·
2020
·
IF 10.317
Jinsong Tao,Zhengjie Wei,Yuan He,Xingyang Yan,Simon Ming-Yuen Lee,Xueqing Wang,Wei Ge,Ying Zheng
Understanding the behaviors of nanomedicines in vivo is one of the most important prerequisites for the design and optimization of nanomedicines. However, the in vivo tracking of nanomedicines in rodents is severely limited by the restricted imaging possibilities within these animals. To meet these needs, the FRET (fluorescence or Förster resonance energy transfer) imaging combined with visual zebrafish larvae model (7 dpf) was used to study the behaviors of polymeric micelles in vivo at high spatiotemporal resolution . Firstly, the FRET ordinary Pluronic micelles (OPMs) and disulfide bond crosslinked Pluronic micelles (CPMs) were synthesized to quantify their integrity in vitro and in vivo by FRET ratio. The behaviors and integrity of OPMs and CPMs in vivo were visually investigated in zebrafish larvae across the entire living organism and at cellular molecular level after intravenous microinjection . Results showed that OPMs were rapidly disassociated in circulation, then largely sequestrated by the endothelial cells (ECs) of caudal vein (CV) and liver in zebrafish larvae, which resulted in quick elimination from blood circulation. While the CPMs were more stable and escaped the sequestration by ECs of CV and liver, which prolonged their circulation in blood. Moreover, we pioneered to use the zebrafish model to reveal that polymeric micelles were eliminated through hepatobiliary pathway after disassociation. While the intact micelles were relatively difficult to eliminate. We further verified that the scavenger receptors of ECs but not the macrophages mainly mediated the elimination of polymeric micelles in CV and liver of zebrafish larvae. These finding on behaviors and elimination mechanisms of polymeric micelles in zebrafish model could contribute to the rational design and optimization of nanomedicines, further guide their studies in rodents.
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DRUG DELIVERY
·
2020
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IF 4.902
Tan Yang,Jianfang Feng,Qian Zhang,Wei Wu,Hailan Mo,Lanzhen Huang,Wei Zhang
A delivery system based on l-carnitine (LC) conjugated chitosan (CS)-stearic acid polymeric micelles has been developed for improving the oral bioavailability of paclitaxel (PTX) through targeting intestinal organic cation/carnitine transporter 2 (OCTN2). Stearic acid grafted chitosan (CS-SA), as micelle skeleton material, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The PTX-loaded micelles were prepared by solvent evaporation-hydration method, and the ligand LC was conjugated onto the micelle surface by anchoring its derivative stearoyl group to the lipophilic core of micelle. The modified polymeric micelles showed regular spherical shapes with small particle size of 157.1 ± 5.2 nm and high drug loading capacity of 15.96 ± 0.20 wt%, and the micelle stability in water was supported by low critical micelle concentration of 14.31 ± 0.21 μg/ml. The drug-loaded micelles presented a slow and incomplete in vitro release, and the pharmacokinetic studies indicated the micelle carriers increased the relative bioavailability of PTX to 165.8% against the commercial formulation. The enhancement effect on intestinal absorption was also confirmed by the intracellular uptake of Caco-2 cells. The proposed micelle carrier system manifested a prospective tool for oral drug delivery.
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CARBOHYDRATE POLYMERS
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2020
·
IF 7.182
Feng Shen,Haoquan Zhong,Wenjiao Ge,Junli Ren,Xiaohui Wang
Natural active compounds with antioxidant properties and other potential health benefits, like quercetin (Qu), have aroused wide concern for developing bio-functional products. However, their applications are hindered by their intrinsic poor water solubility and chemical instability. In this paper, a natural antioxidant alpha lipoic acid (ALA) was grafted onto chitosan (CS) to synthesize a novel graft polymer (CS-graft-ALA). In particular, this graft-polymer could self-assemble into spherical nanomicelles in water, with a low critical micelle concentration (CMC) of 0.0076 mg/mL. As a robust and active nanocarrier, the CS-graft-ALA micelles showed high efficiency in encapsulating Qu and dispersing Qu in water. As found, the antioxidant activity of Qu was effectively enhanced when entrapped within CS-graft-ALA micelles. Moreover, CS-graft-ALA micelles could significantly improve the photo-stability and temperature-stability of Qu. The Qu/CS-graft-ALA micelles with excellent water dispersability, stability and improved antioxidant activity hold a great potential for wide applications.
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PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
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2020
·
IF 2.169
Lijun Zhen,Qiuyu Wei,Qilong Wang,Huiyun Zhang,Michael Adu-Frimpong,Caleb Kesse Firempong,Ximing Xu,Jiangnan Yu
6-Gingerol, an active herbal ingredient of ginger has various bioactivities such as anti-neurodegenerative disease, anti-inflammatory and so on. The aim of the present study was to enhance the oral bioavailability and brain distribution of 6-Gingerol via polymeric micelles. A polymeric micelles drug delivery system of 6-Gingerol consisting of D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and Poly (ethylene glycol)-poly (ε-caprolactone) (PEG-PCL) was prepared via solvent injection method. The developed 6-Gingerol-loaded TPGS/PEG-PCL micelles (6-GTPMs) were characterized based on particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), drug loading (DL) and in vitro release profile. The pharmacokinetics and tissue distribution studies were also evaluated. The nanoformulation produced a particle size of 73.24 ± 2.84 nm with acceptable PDI (0.129 ± 0.03), zeta potential (−2.74 ± 0.92 mV), DL (4.64%) and EE (79.68%). The in vitro release profile showed that the 6-GTPMs enhanced the solubility of 6-Gingerol, while the pharmaceutical analysis in rats indicated that 6-GTPMs significantly improved the oral bioavailability of 6-Gingerol (about 3 folds) in circulation. The 6-GTPMs exhibited remarkable brain targetability in the tissue distribution analysis. Collectively, a 6-Gingerol polymeric micelle with enhanced oral bioavailability coupled with excellent brain distribution was successfully developed.
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Polymer Chemistry
·
2019
·Vol. 10
·期 43
·5879-5893
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IF 4.76
Jianhong Liao,Yajing Song,Can Liu,Dan Li,Hua Zheng,Bo Lu
Combination therapy and efficient delivery of two or more drugs into cancer cells to obtain a superior cell-killing performance is one of the major challenges of cancer therapy due to the pathological complexity, multi-drug resistance and inefficient cellular uptake. Herein, we employed reversible addition–fragmentation chain transfer (RAFT) polymerization to prepare poly(AMA-co-IMMA)-b-poly(OEGMA) (PAIPO) copolymers, and paclitaxel (PTX) and cis-platinum (Pt(II)) were then co-conjugated, thus developing a novel approach for prodrug-based combination chemotherapy. In addition, pH-sensitive charge-conversion, dual-redox dual-drug release behavior, cytotoxicity of micelles against two cancer cell lines (HeLa and Skov-3) and the synergistic effects of the dual-drug were evaluated. Accordingly, both free-(PTXn/Pt) and micelle-(PTXn/Pt) showed a synergism (combination index (CI) was always lower than 1), and (PTX0.2/Pt) and (PTX2/Pt) in the micellar form exhibited the strongest synergism against HeLa (CI = 0.37) and Skov-3 (CI = 0.41) cells, respectively. What's more, the cellular uptake and flow cytometric profiles displayed that an enhanced cellular uptake and endo/lysosome escape occurred owing to the charge-conversion of micelles and the proton sponge effect of imidazolyl moieties, respectively, thereby exhibiting a higher cell-killing performance. To the best of our knowledge, this is the first report on prodrug-based systems with charge-conversion for a co-delivery (PTXn/Pt) complex for combination cancer therapy.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2019
·
IF 3.973
Hu Lin,Quan Wang,Rui Zhong,Zhen Li,Weifeng Zhao,Yuanwei Chen,Meng Tian,Xianglin Luo
pH-responsive nanocarriers such as polymeric micelles that self-assemble from amphiphilic copolymers containing amino groups have been limited by their significant effects on the blood and thus compromise of their hemocompatibility due to the amino group-induced positive charges. Here we report a biomimetic phosphorylcholine strategy to improve the hemocompatibility of the pH-responsive micelles with positive charges. Amphiphilic copolymers containing different number of tertiary amino groups were synthesized in five steps through ring opening polymerization, azide reaction, thio-bromo “Click” chemistry, and atom transfer radical polymerization to self-assemble biomimetic phosphorylcholine micelles with pH-responsiveness, which shown no significant effects on red blood cells, coagulation, and platelet activation. Moreover, albumin adsorption on the micelles was significantly lower than that of polycaprolactone-methoxypolyethylene glycol (PCL-mPEG) control, and in terms of immune cells, the micelles showed controllable phagocytosis that dependent on the number of tertiary amino groups, in which the one containing four tertiary amino groups in its corresponding copolymer remains had a lower phagocytosis by whole blood leukocyte than that of PCL-mPEG. Based on these results, the hemocompatibility related mechanism of the micelles was discussed and proposed. Our findings demonstrated that this biomimetic phosphorylcholine is a promising strategy to improve the hemocompatibility of the positively charged nanocarriers.
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Journal of Materials Chemistry B
·
2019
·Vol. 7
·期 9
·1415-1426
·
IF 5.047
Zhoujiang Chen,Zhanlin Zhang,Maohua Chen,Songzhi Xie,Tao Wang,Xiaohong Li
The term synergism means that the overall therapeutic benefits should be greater than the sum of the effects of individual agents and that the optimal therapeutic efficacy can be achieved at reduced doses. Micellar systems usually fail to deliver multiple drugs to target sites at synergistic doses and thus are not able to maximize the antitumor efficacy. In the current study, we demonstrate a strategy to coordinate the release of camptothecin (CPT) and α-tocopheryl succinate (TOS) from hybrid micelles for nucleus and mitochondrion interferences. TOS is decorated with cationic triphenylphosphonium (TPP) to promote the targeting capability of TOS-TPP to mitochondria. The combination of CPT and TOS-TPP shows strong synergistism with a combination index of 0.186. Hyaluronic acid (HA) is conjugated with CPT or TOS-TPP via disulfide linkages for tumor cell targeting and intracellular reduction-triggered release. Both conjugates either separately self-assemble into MC and MT micelles, or are blended at different ratios to form MC–T hybrid micelles. In response to elevated intracellular glutathione levels, the coordinated release of CPT and TOS-TPP from MC–T results in a combination index of 0.26 and the dose-reduction indexes of CPT and TOS are 7.7 and 3.4, respectively. Compared with MC and MT, MC–T micelles with 5 fold lower doses exhibit higher intracellular reactive oxygen species (ROS) levels, comparable tumor growth inhibition and animal survival, indicating no hematologic and intestinal toxicities. Moreover, the HA conjugates of MC–T are linked to polylactide via acid-labile linkages and electrospun into short fibers (MC–T@SF) as an injectable depot to release MC–T in response to the acidic tumor microenvironment. At a predetermined synergistic ratio, MC–T@SF with 5 fold lower doses achieves antitumor profiles comparable to those of individual micelle-loaded short fibers. Therefore, the hybrid micelles and micelle-releasing short fibers represent a feasible strategy to synergistically enhance the therapeutic efficacy and enable significant reduction in effective doses of chemotherapeutic agents.
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危险品化学品经营许可证（带存储）