RSC Advances
·
2016
·Vol. 6
·期 11
·9082-9089
·
IF 3.289
Yongchao Yao,He Xu,Chang Liu,Yayuan Guan,Deqiu Xu,Jiya Zhang,Yuling Su,Lili Zhao,Jianbin Luo
Biodegradable multi-blocked polyurethane (PU) based micelles with redox responsive properties have been widely used as anticancer drug delivery systems due to their customizable molecular structures. Disulfide bonds can be easily introduced into the hard segment of polyurethanes by conventional two-step polymerization processes, which result in a random distribution of the reduction responsive disulfide linkages on polyurethanes. We speculated that the disassembly and drug release profiles of polyurethane micelles were related to the location of the disulfide linkages on the polymer main chain. To this end, two kinds of redox responsive polyurethane micelles with the same quantity of disulfide bonds but at different locations were prepared: (i) most of the disulfide bonds located at the hydrophobic core of the polyurethane micelles (PU-SS-C) and (ii) disulfide bonds located primarily at the interface between the hydrophobic core and the hydrophilic shell (PU-SS-I). Paclitaxel (PTX) was chosen as the model hydrophobic drug to evaluate the loading and redox-triggered release of the PU micelles. It was demonstrated that the PU-SS-I micelles disassembled simultaneously in response to a 10 mM glutathione (GSH) stimulus and the payloads released more rapidly than that of PU-SS-C nanocarriers. The results show that the release profiles of PU based nanocarriers can be optimized by the location of the disulfide on the polyurethane main chain. The rapid redox-stimulated release properties of the PU-SS-I nanocarriers will be a promising anticancer drug delivery system to ensure sufficient drug concentration to kill the cancer cell and to prevent the emergence of multidrug resistance (MDR). In addition, confocal laser scanning microscopy (CLSM) demonstrated the cellular uptake of doxorubicin-loaded (DOX-loaded) micelles and the GSH-responsive intracellular release of DOX. The in vitro cytotoxicity and cell uptake of the PTX-loaded micelles was also assessed in H460 cells.
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Journal of Materials Chemistry B
·
2015
·Vol. 4
·期 6
·1122-1133
·
IF 4.726
Zhihui Su,Yanchao Liang,Yao Yao,Tianqi Wang,Na Zhang
Stimuli-triggered drug release and improved drug loading are two key prerequisites in the preparation of nano-drug delivery systems. Herein, we constructed the first pluronic P123-double (d)–hydrazone bond (hyd)–docetaxel (DTX)/DTX complex micelles (P123-d–hyd–DTX/DTX) which integrated the highly pH-sensitive strategy and the dual drug-loading pattern in one platform. We synthesized pluronic P123-double (d)–hydrazone bond (hyd)–docetaxel (DTX) conjugates (P123-d–hyd–DTX) by conjugating DTX to the PEO chains of P123 via two hydrazone linkages in the backbone for the first time. An increase in the number of hydrazone linkages within the unimolecular conjugate was conducive to improve the pH sensitivity of conjugated-based micelles. Besides, aiming at improving drug loading, the dual drug-loading strategy (chemical conjugation and physical encapsulation) was adopted. Namely, pH-sensitive P123-d–hyd–DTX was used as a vehicle to further encapsulate DTX for preparing P123-d–hyd–DTX/DTX complex micelles. The resulting P123-d–hyd–DTX/DTX micelles exhibited intact spherical shape, uniform particle size distribution (110.37 nm) and higher drug loading (12.64%). The release study in vitro confirmed that P123-d–hyd–DTX/DTX micelles and P123-d–hyd–DTX micelles (as a control) showed highly pH-responsive release properties. In particular at pH 6.5, almost 90.9% and 75% of DTX was released within 48 h, respectively. Compared to P123-d–hyd–DTX micelles, P123-d–hyd–DTX/DTX complex micelles exhibited higher proliferation inhibition effects on B16F10 cells (p < 0.01), while the cytotoxicity of P123-d–hyd–DTX/DTX complex micelles was slightly inferior to that of free DTX (p < 0.05). In the xenograft B16F10 melanoma model, P123-d–hyd–DTX/DTX complex micelles suppressed tumor growth more effectively than Duopafei® (p < 0.01) and P123-d–hyd–DTX micelles (p < 0.05), without causing obvious adverse effects. Overall, the novel polymeric complex micelle based on double-hydrazone bond and dual drug-loading strategies was a promising delivery platform to improve therapeutic efficiency and decrease side effects in cancer treatments.
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JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2016
·
IF 1.733
Liyan Shi,Kaikai Ding,Xin Sun,Ling Zhang,Tian Zeng,Yihua Yin,Hua Zheng
In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH)-sensitive strategy is based on a Michael addition–elimination reaction, that is the amphiphilic polymeric prodrug which contains α, β-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile – glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 ± 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days. In vitro drug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV–vis spectrophotometer. In vitro macrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs.
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ANALYST
·
2016
·Vol. 141
·期 7
·2303-2307
·
IF 4.033
Lina Yao,Fei Yan,Bin Su
Halonitrobenzenes (HNBs) are a class of molecules that are highly toxic to human health and the ecological environment. Thus, effective and efficient approaches capable of monitoring and detecting HNBs are greatly desired. We report herein a simple and sensitive method for the detection of HNBs. The detection was based on the indium tin oxide (ITO) electrodes modified with a binary assembly of highly ordered surfactant micelles (OSMs) and silica mesochannels (SMs). The SMs have a diameter of 2–3 nm and a vertical orientation, which provide a hard support to stabilize soft OSMs. Moreover, each OSM consists of a hydrophobic core due to the organized assembly of surfactant hydrocarbon chains, which can selectively extract and concentrate lipophilic HNBs from aqueous media, allow their transport to the underlying ITO electrode surface and therein their detection by voltammetry. As a proof-of-concept experiment, 1-chloro-3-nitrobenzene, 1-chloro-4-nitrobenzene, 1-bromo-4-nitrobenzene and 2,4-dinitrobromobenzene were analyzed in aqueous solutions. A simple and fast detection was achieved in all cases, with a wide linear dynamic range, a high sensitivity and a low limit of detection at the ppb level. Apart from the extraction ability, the OSMs also prohibited the access of and surface contamination by unwanted substances, showing excellent anti-fouling and anti-interference power. Indeed, as we demonstrated, the sensor could be employed for direct electrochemical detection of HNBs in complex samples, such as lake water and soil dispersion, without any pre-treatment, indicating its potential usefulness in practical analysis.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2017
·
IF 4.233
Fangfang Teng,Peizong Deng,Zhimei Song,Feilong Zhou,Runliang Feng,Na Liu
In order to improve azithromycin’s antibacterial activity in acidic medium, monomethoxy poly (ethylene glycol)-block-poly (aspartic acid-graft-imidazole) copolymer was synthesized through allylation , free radical addition, ring-opening polymerization and amidation reactions with methoxy poly (ethylene glycol) as raw material. Drug loading capacity and encapsulation efficiency of azithromycin-loaded micelles prepared via thin film hydration method were 11.58 ± 0.86% and 96.06 ± 1.93%, respectively. The drug-loaded micelles showed pH-dependent property in the respects of particle size, zeta potential at the range of pH 5.5–7.8. It could control drug in vitro release and demonstrate higher release rate at pH 6.0 than that at pH 7.4. In vitro antibacterial experiment indicated that the activity of azithromycin-loaded micelles against S. aureus was superior to free azithromycin in medium at both pH 6.0 and pH 7.4. Using fluorescein as substitute with pH-dependent fluorescence decrease property, laser confocal fluorescence microscopy analysis confirmed that cellular uptake of micelles was improved due to protonation of copolymer’s imidazole groups at pH 6.0. The enhanced cellular uptake and release of drug caused its activity enhancement in acidic medium when compared with free drug. The micellar drug delivery system should be potential application in the field of bacterial infection treatment.
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Materials Science & Engineering C-Materials for Biological Applications
·
2016
·
IF 3.42
Lili Chen,Fangling Ji,Yongming Bao,Jing Xia,Lianying Guo,Jingyun Wang,Yachen Li
The greatest crux in the combination of chemotherapy and gene therapy is the construction of a feasible and biocompatible carrier for loading the therapeutic drug and gene simultaneously. Here, a new amphiphilic bifunctional pullulan derivative (named as PDP) synthesized by grafting lipophilic desoxycholic acid and low-molecular weight (1 kDa) branched polyethylenimine onto the backbone of pullulan was evaluated as a nano-carrier for the co-delivery of drug and gene for potential cancer therapy. PDP exhibited good blood compatibility and low cytotoxicity in the hemolysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. By self-assembly process, the amphiphilic PDP polymer formed cationic core-shell nanomicelles in aqueous solution with an average diameter of 160.8 nm and a zeta potential of approximate 28 mV. The PDP micelles had relative higher drug encapsulation efficiency (84.05%) and loading capacity (7.64%) for doxorubicin (DOX), an effective anti-tumor drug, demonstrating sustained drug release profile and good DNA-binding ability. The flow cytometry and confocal laser scanning microscopy showed that PDP/DOX micelles could be successfully internalized by MCF-7 cells, and presenting higher cytotoxicity against MCF-7 cells than that of free DOX. Furthermore, PDP micelles could efficiently transport tumor suppressor gene p53 into MCF-7 cells, and the expressed exogenous p53 protein induced MCF-7 cells to die. More excitedly, in comparison with single DOX or p53 delivery, the co-delivery of DOX and gene p53 using PDP micelles displayed higher cytotoxicity, induced higher apoptosis rate of tumor cells and blocked more effectively the migration of cancer cells in vitro . In tumor-bearing mice, co-delivery of DOX and p53 also exhibited enhanced antitumor efficacy as compared with single delivery of DOX or p53 alone. In summary, these results demonstrated that it is highly promising to use cationic PDP micelles for effectively co-delivering functional gene and chemotherapeutic agent, and thus improving antitumor efficacy and systemic toxicity.
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RSC Advances
·
2017
·Vol. 7
·期 18
·11021-11029
·
IF 3.108
Chang Liu,Yayuan Guan,Yuling Su,Lili Zhao,Fancui Meng,Yongchao Yao,Jianbin Luo
The extracellular stability versus intracellular drug release and the long blood stream circulation versus enhanced cell uptake are two dilemmas for micellar drug delivery systems. To resolve the above two problems, a novel core cross-linked polyurethane micelles with redox sensitive and pH-responsive surface charge switchable properties were prepared and investigated as anti-cancer drug carriers. Firstly, amphiphilic multi-blocked polyurethane with pendant carboxyl groups and disulfides in the hard segment (PU-SS-COOH) was synthesized. Afterwards, 1,6-diaminohexane was connected onto some of the pendant carboxyl groups via dicyclohexylcarbodiimide (DCC) condensation, which resulted in polyurethane with pendant amine and carboxyl groups (PU-SS-COOH-NH2). Then the PU-SS-COOH-NH2 was assembled into micelles and the hexamethylene-1,6-diisocyanate (HDI) was added into the micelle solution. The hydrophobic diisocyanate penetrated into the hydrophobic core of PU micelles and reacted with amine groups, which resulted in core crosslinked PU micelles (PU-CCL). PTX and doxorubicin hydrochloride (DOX) were chosen as model hydrophobic drugs to evaluate the loading and redox-triggered release of the PU micelles. The drug release from the cross-linked polyurethane micelles (PU-CCL) demonstrated that the PU-CCL has superior particle stability compared with the uncross-linked polyurethane micelles in a phosphate buffer saline (PBS) solution without reducing agents, whereas the drug release rate is markedly accelerated with the addition of a reducing agent, glutathione (GSH). Notably, PU micelles with both amine and carboxyl groups, i.e. PU-SS-COOH-NH2 and PU-CCL micelles, showed pH-responsive charge switchable properties. The in vitro cytotoxicity and cell uptake of the PTX (or DOX used to illustrate the cell uptake) loaded micelles was also assessed in HepG2 cells. It was found that the redox-sensitive polyurethane micelles can rapidly enter tumor cells. In vitro cytotoxicity studies demonstrated that the DOX-loaded PU-CCL display lower cytotoxicity in vitro compared to either free DOX or DOX-loaded uncrosslinked PU micelles. The cross-linked reduction responsive biodegradable micelles, having superior extracellular stability and providing rapid intracellular drug release, may hold great potential as a bio-triggered drug delivery system for cancer therapy.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2016
·
IF 0.62
Jian Sun,Tao Liu,Jianhua Xu
Alfa-hederin (Hed) is regarded as a promising drug in cancer therapy especially in drug-resistant cancers. However, its reduced anticancer activity caused by protein absorption limits its wide clinical applications. The purpose of this study was to develop diblock copolymer-based micelles as an integrated platform for targeted delivery of Hed to overcome its intrinsic drawbacks. Amphiphilic diblock copolymers, poly(epsilon-caprolactone)- b -poly(oligo(ethylene glycol) monomethyl ether methacrylate- co -RGD) (PCL- b -P(OEGMA- co -RGD)) consisting of hydrophobic PCL, hydrophilic POEGMA and targeting peptide (RGD) were fabricated via the combination of ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP), and polymer post-functionalization. Hed-containing targeting micellar nanoparticles , Hed-NP-RGD, were obtained via the co-micellization of PCL- b -P(OEGMA- co -RGD) and Hed, showing hydrodynamic diameter 108 ± 1 nm and zeta potential −4.10 ± 0.15 mV. In vitro experiments demonstrated that Hed-NP-RGD possessed superior anti-proliferative and cellular apoptosis in comparison with that of free Hed possibly due to the assumption that the presence of polymeric micelles protected Hed molecules from absorption by proteins and tumor-targeting effect.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Fang Xie,Nian Liu,Xiaoqing Liu,Xiaofang Feng,Zhaoxing Yang,Zhijun He,Jie Cai
Selenium nanoparticles (SeNPs) exhibit significant potential in antitumor therapy. However, challenges such as aggregation and lack of targeting capability limit their application. Herein, we developed selenium-loaded octenyl succinic anhydride starch (OSAS) micelles functionalized with folic acid (FA) for targeted tumor delivery. The FA-OSAS-SeNPs were synthesized through self-assembly, incorporating SeNPs into FA-conjugated OSAS micelles. Fourier Transform Infrared (FTIR) spectroscopy and UV–visible spectrophotometry confirmed the successful synthesis of FA-OSAS-SeNPs. The nanoparticles exhibited an average size of 131.66 ± 7.88 nm and a zeta potential of −19.54 ± 0.33 mV, with encapsulation efficiency and drug loading capacity of approximately 87.28 % and 8.96 %, respectively. FA-OSAS-SeNPs demonstrated good stability across various conditions, including different dilution ratios, temperatures, pH levels, and ionic strengths. In vitro studies showed that FA-OSAS-SeNPs exhibited significant targeted inhibitory effects on cervical cancer (HeLa) cells and markedly increased intracellular ROS levels, inducing apoptosis. This study presents a novel and effective strategy for targeted SeNPs delivery systems in tumor therapy, offering a valuable reference for future development of nanomaterials for clinical applications in cancer treatment.
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COLLOID AND POLYMER SCIENCE
·
2018
·Vol. 296
·期 3
·495-502
·
IF 1.967
Zhang Rongli,Xu Xiaofang,Fan Xiaoxia,Yang Renchun,Wu Tao,Zhang Cuige
A novel kind of biocompatible conducting micelles self-assembled from commercial poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) and chitosan (CS) via electrostatic interaction. The resultant micelles were then used to provide a platform for fabricating high sensitive biosensor. It is expected that the introduction of chitosan in micelles can solve the problem of PEDOT:PSS film easily peeling off from the surface of the electrode. The micelles with nanostructure on the electrode can facilitate the immobilization of enzyme due to the large surface to volume ratio. The good conductivity of the commercial PEDOT:PSS can provide a platform to accelerate the electron transfer and facilitate the signal transduction from the micelles film to the underlying electrode. These advantages endowed the biosensor with high sensitivity for H 2 O 2 detection. Under the optimal conditions, a linear ranged from 1 × 10 −10 to 1 × 10 −5 mol·L −1 with a detection limit of 3 × 10 −11 mol·L −1 were obtained for H 2 O 2 detection. The biosensor can be used to analyze H 2 O 2 in commercial disinfector with satisfactory results.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2012
·
IF 3.456
Xuzhu Zhang,Fang Du,Jin Huang,Wei Lu,Shiyuan Liu,Jiahui Yu
This research is aimed to develop a biodegradable micelle delivery system with sheddable poly (ethylene glycol) shell to achieve the reduction-triggered intracellular sustained release of 6-mercaptopurine (6-MP) and decreased toxicity. Firstly, the amino-disulfide linked poly (ethylene glycol) monomethyl ether (mPEG-SS-NH 2 ) was synthesized by the amidation reaction between cystamine and active ester of mPEG and p-nitrophenyl chloroformate (p-NPC) (mPEG–NPC). And then, the five-member rings in poly ( l -succinimide) (PSI) were successively opened by mPEG-SS-NH 2 and 2-(pyridyldithio)-ethylamine (PDA) to produce the graft copolymer of mPEG-SS-NH- graft -PAsp-PDA. To avoid the drug initial burst, 6-MP was covalently conjugated with mPEG-SS-NH- graft -PAsp-PDA by thoil–disulfide exchange reaction to give the resultant product mPEG-SS-NH- graft -PAsp-MP. The product was found to form spherical micelles in aqueous media because of its amphiphilic nature with average particle size of 160 nm measured by dynamic light scattering (DLS). It was found that the mPEG-SS-NH- graft -PAsp-MP micelles, though stable in phosphate buffer solution (PBS), were prone to aggregation in the presence of dithiothreitol (DTT). The in vitro drug release studies revealed the release of 6-MP were distinct from the conventional micelles whose drugs loaded by physical encapsulation. Sustained release profile of 6-MP over 85 h was found in the presence of DTT (40 mM) simulating the intracellular condition while minimal drug release was observed within 24 h at the level of DTT corresponding to extracellular environment. Remarkably, the cell viability results showed there was essential decrease of cytotoxicity to HL-60 cell line compared to free 6-MP.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2017
·
IF 3.887
Jilian Wu,Huiyuan Zhang,Xu Hu,Ruiling Liu,Wei Jiang,Zhonghao Li,Yuxia Luan
Clinically, codelivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. In this work, we developed a new reduction-sensitive mixed micellar system for self-codelivery of doxorubicin (DOX) and docetaxel (DTX). Biodegradable methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was coupled with DOX and DTX by a reduction-sensitive disulfide bond, resulting in mPEG-PCL-SS-DOX and mPEG-PCL-SS-DTX, respectively. mPEG-PCL-SS-DOX was mixed with mPEG-PCL-SS-DTX at a mole ratio of 1:1 in water, forming a mixed micellar system. The mixed micelles had a diameter of 223.7 nm and a low critical micelle concentration. Reductive-triggered drug release revealed a “smart” characteristic of the mixed micelles. A cellular uptake and cytotoxicity assay in vitro showed that the mixed micelles could efficiently accumulate in MCF-7 cells and suppress the growth of tumour cells. The proposed reduction-sensitive mixed micelles assembled from amphiphilic prodrugs can be used as a promising drug codelivery system for cancer therapy.
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