Nanomaterials
·
2022
·Vol. 12
·期 4
·696
·
IF 5.719
Chao Zhang,Shuangqing Fu,Fanghua Zhang,Mengnan Han,Xuming Wang,Jie Du,Honglei Zhang,Wei Li
Combination chemotherapy is emerging as an important strategy for cancer treatment with decreased side effects. However, chemotherapeutic drugs with different solubility are not easy to realize co-delivery in traditional nanocarriers. Herein, an affibody modified G-quadruplex DNA micellar prodrug (affi-F/GQs) of hydrophilic 5-fluorodeoxyuridine (FUdR) by integrating polymeric FUdRs into DNA strands is developed for the first time. To achieve synergistic efficacy with hydrophobic drugs, curcumin (Cur) is co-loaded into affi-F/GQs micelles to prepare the dual drug-loaded DNA micelles ([email protected]/GQs), in which affibody is employed as a targeting moiety to facilitate HER2 receptor-mediated uptake.[email protected]/GQs have a small size of approximately 130 nm and exhibit excellent stability. The system co-delivers FUdR and Cur in a ratiometric manner, and the drug loading rates are 21.1% and 5.6%, respectively. Compared with the physical combination of FUdR and Cur,[email protected]/GQs show higher cytotoxicity and greater synergistic effect on HER2 positive gastric cancer N87 cells. Surprisingly,[email protected]/GQs significantly enhance the expression and activity of apoptosis-associated proteins in Bcl-2/Bax-caspase 8, 9-caspase 3 apoptotic pathway, which is the main factor in the death of tumor cells induced by FUdR. Overall, this nanoencapsulation is a promising candidate for the targeted co-delivery of drugs with significant differences in solubility.Keywords:G-quadruplex;DNA micelles;affibody;5-fluorodeoxyuridine;curcumin;synergetic therapy
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INSTRUMENTATION SCIENCE & TECHNOLOGY
·
2021
·
IF 1.584
Zhao-chan Liu,Li Yang,Rong-rong Xing,Xuan Chen,Xiao-hong Bai,Shuang Hu
This work describes three phase dispersive liquid-liquid microextraction based on reverse micelles for the determination of Q-markers of cinnamic acids (caffeic acid, p-hydroxycinnamic acid, ferulic acid, and cinnamic acid) in traditional Chinese medicine followed by high performance liquid chromatography (HPLC) analysis. The variables influencing the procedure were optimized separately. Enrichment factors from 110 to 189, linearities from 1.2 to 960 ng mL−1 with r2 exceeding 0.9943, detection limits from 0.1 to 0.6 ng mL−1, excellent precision with relative standard deviations below 5.6%, and good relative recoveries from 80.0% to 113.3% were achieved. In addition, the mechanism of the procedure was explored by comparison with conventional dispersive liquid-liquid microextraction at the optimum conditions. The results showed that the developed microextraction procedure improved the sensitivity and consumed less organic solvent and is a greener approach.
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Nanoscale
·
2020
·Vol. 12
·期 9
·5380-5396
·
IF 6.895
Yalin Sun,Yan Liang,Na Hao,Xiaoheng Fu,Bin He,Shangcong Han,Jie Cao,Qingming Ma,Wen Xu,Yong Sun
9-Nitro-20(S)-camptothecin (9-NC) is a broad-spectrum antitumor drug used in tumor treatments, but its clinical applications and antitumor efficacy are limited by its structural instability, poor solubility, and extremely low drug utilization in tumor tissues. In this study, enzyme-sensitive nuclear-targeted dual-functional polymeric micelles were developed for 9-NC delivery with a high drug loading content (12.93 ± 0.88%), steady-state circulation, and a rapid attack at the “heart” of tumor cells. Briefly, chrysin (CHR) as a π-conjugated moiety was immobilized on the PCL terminal in the TAT–PCL amphiphiles and combined with the ALAL peptide as a linker on HA chains to yield the ultimate CHR–PCL–TAT–ALAL–HA (HATPC) amphiphiles. Spherical 9-NC-loaded micelles were obtained from the self-assembly of the dual-functional amphiphiles comprising HATPC and 9-NC with uniform nanosize (121.6 ± 5.79 nm), well-distributed morphology (PDI: 0.256), and negative surface charge (−23.2 ± 0.5 mV), yielding high stability during blood circulation. In this drug delivery system, HA acts as an active tumor-targeting instrument via CD44-receptor-mediated endocytosis; further, the ALAL peptide could be cutoff in the lysosomes of the tumor cells due to the high expression of cathepsin B, leading to lysosomal escape, while the secondary polymeric micelles targeted the tumor cell nucleus via the exposed TAT peptide. The enzyme sensitivity and nuclei targetability of the 9-NC/HATPC micelles were confirmed by dynamic light scattering and confocal laser scanning microscopy analyses. As compared to free 9-NC and traditional mPEG2k–PCL2k polymeric micelles, 9-NC/HATPC micelles were the most concentrated in the tumor cell nucleus; therefore, they exhibited the highest cytotoxicity against SKOV3 tumor cells both in vitro (IC50 = 0.03 μg mL−1) and in vivo. This enzyme-sensitive nuclear-targeted dual-functional drug delivery system involving HATPC provided a new and promising strategy for enhanced 9-NC delivery and antitumor efficacy.
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ACS Sustainable Chemistry & Engineering
·
2019
·
IF 6.97
Jing Chen,Yuzhi Wang,Xiaoxiao Wei,Wei Xu,Panli Xu,Rui Ni,Jiaojiao Meng
A novel aqueous micellar two-phase system (AMTPS) formed by two new types of PEG-based hydrophobic (acted as “cationic surfactant” or “nonionic surfactant”) and hydrophilic deep eutectic solvents (DESs) was first established. Three typical representative pigments, methylene blue (MB), Sudan III (Su), and sunset yellow FCF (SY) with diverse charge and hydrophobicity, were selected as the target to evaluate the possibility of the novel DES/DES-based AMTPS as a green extraction technology for partitioning various substances. The constitutions of AMTPS were systematically studied, including the effects of hydrophobic and hydrophilic DES types, molar ratio of choline chloride/glycerol, and molecular weights of PEG. After investigation, the DES/DES-based AMTPS was prepared with [N8881]Cl/PEG400 as hydrophobic DES and Ch/G (molar ratio 1:1) as hydrophilic DES. The concentration of pigments, ionic strength, pH value, and temperature were comprehensively evaluated in the influence factor experiments. Also, the results showed that more than 95.00% of Su/SY distributed in the micellar-rich phase, and nearly all of MB could be transferred from micellar-poor phase to micellar-rich phase with the increase of the pH value. Response surface methodology was utilized to further optimize the extraction conditions for Su. It was found that almost 99.75% Su was separated into the micellar-rich phase. Method validation illustrated that the proposed method had the priority to get precise experimental data for pigments’ separation. Mechanism studies through the conductivity, dynamic light scattering (DLS), and transmission electron microscope (TEM) proved that the formation of micelles between pigments and DESs by hydrophobic and electrostatic interaction was the dominant force in the separation. In addition, [N8881]Cl/PEG400 could efficiently be recovered and reused in the regeneration studies. The novel DES/DES-based AMTPS proposed in this work provided an eco-friendly extraction way in the separation of various charges or hydrophobicity substances.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Cihui Tian,Sajid Asghar,Ziyi Hu,Yue Qiu,Jingwei Zhang,Feng Shao,Yanyu Xiao
The gliomas treatment is challenging due to the limits imposed by blood-brain barrier to the distribution of the drugs in the brain. Therefore, we designed a brain glioma targeting redox-sensitive hyaluronic acid (HA)-ss-curcumin (CUR) micelles . HA was conjugated to CUR through a disulfide bond , which could form micelles independently in aqueous solution. And we further increased the drug loading by loading free CUR. Brain penetration was achieved with Tween 80, whereas glioma-targeting was inclined by CD44-mediated endocytosis . Compared to the disulfide-free group, the redox-sensitive micelles exhibited rapid in vitro drug release under high glutathione conditions, significantly enhanced cell apoptosis and cellular uptake in G422 glioma cells. Redox-sensitive micelles displayed about 4.70-fold higher area under the curve in rats after intravenous injection in comparison to the free CUR and effectively accumulated in the brain. These findings suggest that redox-sensitive micelles could be a promising candidate to achieve brain targeted CUR delivery.
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Materials Science & Engineering C-Materials for Biological Applications
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2017
·
IF 4.164
Peizong Deng,Fangfang Teng,Feilong Zhou,Zhimei Song,Ning Meng,Na Liu,Runliang Feng
Ketoconazole is a hydrophobic broad-spectrum antifungal agent for skin infection therapy. In order to develop topical formulation of ketoconazole for improving its selective skin deposition and water-solubility, ketoconazole-loaded Y-shaped monomethoxy poly(ethylene glycol)-block-poly(ɛ-caprolactone) micelles were prepared through thin-film hydration method with high entrapment efficiency (96.1 ± 0.76%) and small particle (about 58.66 nm). The drug-loaded micelles showed comparative in vitro antimicrobial activity with KET cream. In e x in vivo skin deposition and permeation study, ketoconazole-loaded micelles provided skin accumulation higher than marketed ketoconazole cream without obvious permeation in the whole period. Fluorescence microscopy study and histopathological study demonstrated the copolymeric micelles' penetrating into skin in depth due to its capability of weakening the barrier function of stratum corneum. In vivo skin deposition parameters further confirmed high skin deposition of drug-loaded micelles (AUC (0-t) = 396.16 μg·h/cm 2 ) over marketed ketoconazole cream (AUC (0-t) = 250.03 μg·h/cm 2 ). Meanwhile, in vivo pharmacokinetic parameters proved that ketoconazole-loaded micelles reduced ketoconazole's distribution in blood in comparison with the cream (AUC (0-t) = 93,028.00 μg·h/L vs AUC (0-t) = 151,714.00 μg·h/L), meaning lower possibility of its systemic unwanted effects in the skin fungal infection treatment. The results suggested that the copolymeric micelles can be adopted for specific delivering ketoconazole into skin for fungal infection cure.
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DRUG DELIVERY
·
2016
·
IF 4.843
Jiang Ni,Fengchun Tian,Fatima Zohra Dahmani,Hui Yang,Deren Yue,Shuwang He,Jianping Zhou,Jing Yao
The low oral bioavailability of numerous drugs has been mostly attributed to the significant effect of P-gp-mediated efflux on intestinal drug transport. Herein, we developed mixed polymeric micelles (MPMs) comprised of curcumin-carboxymethyl chitosan (CNC) conjugate, as a potential inhibitor of P-gp-mediated efflux and gastrointestinal absorption enhancer, and low-molecular-weight heparin-all-trans-retinoid acid (LHR) conjugate, as loading material, with the aim to improve the oral absorption of P-gp substrate drugs. CNC conjugate was synthesized by chemical bonding of curcumin (Cur) and carboxymethyl chitosan (CMCS) taking advantage of the inhibition of intestinal P-gp-mediated secretion by Cur and the intestinal absorption enhancement by CMCS. The chemical structure of CNC conjugate was characterized by 1H NMR with a degree of substitution of Cur of 4.52–10.20%. More importantly, CNC conjugate markedly improved the stability of Cur in physiological pH. Cyclosporine A-loaded CNC/LHR MPMs (CsA-CNC/LHR MPMs) were prepared by dialysis method, with high drug loading 25.45% and nanoscaled particle size (∼200 nm). In situ single-pass perfusion studies in rats showed that both CsA + CNC mixture and CsA-CNC/LHR MPMs achieved significantly higher Ka and Peff than CsA suspension in the duodenum and jejunum segments (p < 0.01), which was comparable to verapamil coperfusion effect. Similarly, CsA + CNC mixture and CsA-CNC/LHR MPMs significantly increased the oral bioavailability of CsA as compared to CsA suspension. These results suggest that CNC conjugate might be considered as a promising gastrointestinal absorption enhancer, while CNC/LHR MPMs had the potential to improve the oral absorption of P-gp substrate drugs.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2017
·
IF 3.887
He-Lin Xu,Zi-Liang Fan,De-Li ZhuGe,Bi-Xin Shen,Bing-Hui Jin,Jian Xiao,Cui-Tao Lu,Ying-Zheng Zhao
Severe toxicity and poor tumour penetration are two intrinsic limited factors to hinder the broad clinical application for most of first-line chemotherapeutics. In this study, a novel vitamin E succinate-grafted ε-polylysine (VES-g-PLL) polymer was synthesized by using ε-polylysine as backbone. By adjusting VES graft ratio, VES-g-PLL (50) with a theoretic VES graft ratio of 50% could self-assemble into a supermolecular micelle with a hydrodynamic diameter (D h ) of ca.20 nm, and Zeta potential of 19.6 mV. VES-g-PLL micelles themselves displayed a strong anti-tumour effect on glioma. The poorly water-soluble curcumin was effectively encapsulated in VES-g-PLL micelles with the drug loading amount and entrapment efficiency reaching 4.32% and 82.27%, respectively. In a physiologic medium, curcumin-loaded VES-g-PLL micelles (Cur-Micelles) not only remained stable without obvious drug leakage but also sustained the release of its encapsulated curcumin for a long time. Because of the ultra-small size and positively-charged surface, Cur-Micelles penetrated the deeper tumour zone than free curcumin, resulting in a significant inhibition of tumour spheroids growth. Moreover, in vivo strong antitumor effect of Cur-Micelles was also exhibited at assistance of ultrasound-targeted microbubble destruction and the real-time MRI imaging demonstrated a nearly complete suppression of glioma after 28 days of treatment. TUNEL staining showed that the therapeutic mechanism of Cur-Micelles was relevant to the apoptosis of tumour cells. Finally, in vivo nontoxicity of Cur-Micelles against normal organs including heart, liver, spleen, lung and kidney tissues was also demonstrated by the HE staining. In conclusion, VES-g-PLL micelles may serve as a potential carrier for curcumin to enhance tumour penetration and improve therapeutic effect on glioma.
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ACS Applied Materials & Interfaces
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2014
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IF 5.9
Xubo Zhao,Peng Liu
A facile and effective approach was established for fabricating core–shell–corona micelles by self-assembly of poly(ethylene glycol)-b-poly(acrylic acid-co-tert-butyl acrylate)-poly(ε-caprolactone) (PEG43-b-P(AA30-co-tBA18)-b-PCL53) triblock copolymer, synthesized via a combination of ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP), click chemistry, and hydrolyzation. The prenanovehicles with three different hydrolysis degrees from PEG43-b-PtBA48-b-PCL53 were developed to evaluate the drug loading capacity (DLC) and drug encapsulation efficiency (DEE). After cross-linking with a disulfide bond to regulate the drug release kinetics, the spherical core–shell–corona micelles with average diameter of 52 ± 4 nm were obtained in aqueous solution. The reduction-responsive cross-linked micelles showed a slow sustained release in normal physiological conditions and a rapid release upon exposure to simulated tumor intracellular conditions. In addition, the cytotoxic analysis and HepG2 cell growth inhibition assays demonstrated their remarkable biocompatibility and similar excellent anticancer activity as the free doxorubicin (DOX), which has also been revealed by the confocal laser scanning microscope (CLSM) analysis. So the reduction-sensitive core–shell–corona micelles are expected to be promising tumor microenvironment-responsive nanovehicles for hydrophobic drugs by glutathione (GSH) triggering.
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Journal of Materials Chemistry B
·
2016
·Vol. 4
·期 19
·3377-3386
·
IF 4.872
Li Chen,Bizheng Chen,Xiaodong Liu,Yujie Xu,Lifen Zhang,Zhenping Cheng,Xiulin Zhu
Real-time monitoring of drug delivery systems has attracted growing interest for potential applications in biomedical therapy. Fluorescence imaging is a highly sensitive technique for illuminating the pathways of such systems. In this work, we designed and synthesized a new near infrared (NIR) fluorescent dye monomer (NFM). The NFM monomer was covalently attached to a pH-responsive amphiphilic block copolymer by reversible addition–fragmentation chain transfer (RAFT) copolymerization using hydrophilic poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA) as the macro-RAFT agent and pH-responsive 2-(4-(dodecyloxy)phenyl)-1,3-dioxan-5-yl methacrylate (DBAM) and NFM as the comonomer, to synthesize the multifunctional amphiphilic block copolymer PPEGMA-b-P(DBAM-co-NFM) with NIR moieties and pH-sensitive groups. The PPEGMA-b-P(DBAM-co-NFM) could be self-assembled easily into stable micelles with doxorubicin (DOX) with an average diameter of 66 nm in water. The nano-size of the micelles is suitable for cycling through the body and carrying drugs to tumor sites safely via the enhanced permeability and retention (EPR) effect. Confocal laser scanning microscopy (CLSM) results indicated cells’ uptake and the intracellular distribution. In vivo imaging of the micelles was observed in real time and the fluorescent signals clearly demonstrated the dynamic process of tumor treatment. This versatile and effective strategy is a potential tool for monitoring controlled drug delivery for tumor treatment.
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JOURNAL OF BIOACTIVE AND COMPATIBLE POLYMERS
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2013
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IF 2.207
Feng Xu,Ting-Ting Yan,Yan-Ling Luo
Novel amphiphilic block copolymers consisting of hydrophobic poly(D,L-lactide) segments and hydrophilic poly(N-isopropylacrylamide-co-N, N-dimethylacrylamide) blocks were designed and synthesized through a simple free radical copolymerization route based on a bifunctional initiator, followed by the ring-opening polymerization of D,L-lactide. The copolymers self-assembled into thermosensitive spherical-nanosized core–shell micelles in aqueous solution in the presence or the absence of the model drug prednisone. The chemical and physical characterizations of drug-loaded and unloaded micelles revealed a lower critical solution temperature of 40°C–47°C, and a critical micelle concentration less than 7.20 mg L−1, a transmission electron microscope mean particle size from 50 to 75 nm, and a narrow dynamic light scattering diameter below 180 nm. The prepared blank and drug-loaded micellar nanoparticles were thermodynamically stabile and employed in targeted drug delivery by responding to the higher temperature of the local microenvironment. Based on prednisone release kinetic studies, structural changes of the self-assembled micelles as well as temperature- or environment-induced diffusion controlled drug release and improved bioavailability. The copolymer micelles exhibited good biocompatibility as established by the MTT cytotoxicity assay. Therefore, an effective target therapy against lesion tissues is feasible using these polymeric micelles.
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Nano Research
·
2016
·Vol. 9
·期 12
·3828-3838
·
IF 8.893
Li Zhixiong,Liang Ruizheng,Xu Simin,Liu Wendi,Yan Dongpeng,Wei Min,Evans David G.,Duan Xue
Fluorescence resonance energy transfer (FRET) systems have broad applications in visual detection, intelligent materials, and biological imaging, all of which favor the transmission of light through multiple dimensions and in diverse directions. Herein, we have demonstrated multi-dimensional (0D and 2D) FRET within a multi-layer ultrathin film (UTF) by employing a layer-by-layer (LBL) assembly technique. The anionic block copolymer micelle poly(tert-butyl acrylate-co-ethyl acrylate-co-methacrylic acid) (PTBEM) is chosen as a molecular carrier for the incorporation of bis(8-hydroxyquinolate) zinc (Znq 2 ) and open-ring merocyanine (MC) (denoted as (Znq 2 /MC)@PTBEM). Alternatively, electrostatic assembly is performed with cationic layered double hydroxide (LDH) nanosheets (denoted as [(Znq 2 /MC)@PTBEM/LDH]
n
). This [(Znq 2 /MC)@PTBEM/LDH]
n
system offers a multi-dimensional propagation medium and ensures that the FRET donor and acceptor are located within their Förster radii in each direction. The system demonstrates a FRET process that can be switched via alternating ultraviolet/visible (UV/vis) irradiation, with tunable blue–green/red fluorescence, resulting in a FRET efficiency as high as 81.7%. It is expected that this assembly method, which uses 0D micelles on a 2D layered material, can be extended to other systems for further development of multi-dimensional FRET.
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