RSC Advances
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2019
·Vol. 9
·期 27
·15196-15204
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IF 3.049
Yun Hong,Dongsen Mao,Rui Wu,Zhe Gao,Tingting Meng,Rongrong Wang,Lin Liu,Jing Miao
DNAzymes have the potential to suppress gene expression through sequence-specific mRNA cleavage and can therefore play an important role in various gene therapies. Hepatitis B virus (HBV) is still one of the most serious liver infections in people around the world and is difficult to treat. We previously designed a 10-23 DNAzyme called DrzBS, which targets HBV S gene expression, but this enzyme depends on exogenous delivery, and so its application has been limited. To overcome this limitation, we have now developed a chitosan-based nanocarrier (chitosan-g-stearic acid, CSO–SA) for intracellular delivery of DrzBS, then compared the inhibition effect of our CSO–SA/DrzBS complex to a common transfection reagent, Lipofectamine™ 2000/DrzBS, on hepatitis B surface antigen expression. The synthesized CSO–SA assembles into micelles in an aqueous solution and exhibits excellent cytoplasmic targeting, and could protect DrzBS from degradation by ribonuclease. CSO–SA/DrzBS showed a higher inhibition rate (IR) than Lipofectamine™ 2000/DrzBS. Moreover, at the same DrzBS concentration (1.2 μmol L−1), the maximum IR of CSO–SA/DrzBS micelles was 2.4-fold that of the Lipofectamine™ 2000/DrzBS complex, and held on for 96 hours. Compared with Lipofectamine™ 2000/DrzBS, CSO–SA/DrzBS achieved a higher HBV inhibition effect. This study demonstrates that CSO–SA micelles can serve as a potential vector for DrzBS and that CSO–SA/DrzBS micelles are a promising application for anti-HBV gene therapy.
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JOURNAL OF APPLIED POLYMER SCIENCE
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2019
·Vol. 136
·期 37
·47946
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IF 2.188
Xiao Ma,Jiangtao Liu,Lei Lei,Hong Yang,Zhongli Lei
Stimulus-responsive polymeric nanoparticles have great potential as nanocarriers. Here, triple-stimuli-responsive core-crosslinked (CCL) micelles were developed that were convenient for drug delivery by taking advantage of dual-redox and UV light synergistic triggers. Amphiphilic block copolymers methoxy poly(ethylene glycol)- b -poly(3-azido-2-hydroxy-propyl methacrylate- co - ο -nitrobenzyl methacrylate) [mPEG- b -P(GMA-N 3 - co -NBM)] were synthesized via atom transfer radical polymerization and ring-opening reaction of ethylene oxide; these block copolymers can spontaneously self-assemble into noncrosslinked (NCL) micelles. Afterward, CCL micelles were prepared using an alkyne-functionalized crosslinking agent. Furthermore, the CCL micelles showed an excellent Nile Red dye molecule encapsulation, light and dual-redox-responsive performance, and increasing release rate of the dye as the concentration of glutathione and light irradiation increased. The triple-stimuli-responsive CCL micelles showed excellent stability and controllable release compared to NCL micelles. Therefore, we have developed a new smart nanocarrier, and the triple-stimuli-responsive CCL micelles could also be a potential delivery system in cancer therapy. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136 , 47946.
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ACS Applied Materials & Interfaces
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2019
·
IF 8.456
Yuxin Xing,Tao Ding,Zhenqiang Wang,Liucan Wang,Haidi Guan,Jia Tang,Dong Mo,Jixi Zhang
Currently, the simple integration of multiple therapeutic agents within a single nanostructure for combating multidrug resistance (MDR) tumors yet remains a challenge. Herein, we report a photoresponsive nanocluster (NC) system prepared by installing polydopamine (PDA) nanoparticle clusters on the surface of d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) (a drug efflux inhibitor) micelles solubilized with IR780 (a photosensitizer) to achieve a combined chemotherapy (CT)/photothermal therapy (PTT)/photodynamic therapy (PDT) for drug-resistant breast cancer. Mediated by the fluorescence resonance energy transfer and radical scavenging properties of PDA, NC shows prominently quenched fluorescence emission (∼78%) and inhibited singlet oxygen generation (∼67%) upon exposure to near-infrared (NIR) light (808 nm, 0.5 W cm–2), favoring a highly efficient PTT module. Meanwhile, the photothermal heat can also boost the release of doxorubicin hydrochloride whose intracellular accumulation can be greatly enhanced by TPGS. Interestingly, the first NIR irradiation and subsequent incubation (∼24 h) can induce the gradual relocation and disintegration of PDA nanoparticles, thereby leading to activated PDT therapy under the second irradiation. Upon the temporally controlled sequential application of PTT/PDT, the developed NC exhibited a great potential to treat MDR cancer both in vitro and in vivo. These findings suggest that complementary interactions among PTT/PDT/CT modalities can enhance the efficiency of the combined therapy for MDR tumor.
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CARBOHYDRATE POLYMERS
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2018
·
IF 5.158
Zhaojie Wang,Hu Bai,Chunbo Lu,Chunyan Hou,Yuanhao Qiu,Peng Zhang,Jinyou Duan,Haibo Mu
Bacterial biofilms are widely associated with persistent infections and food contamination. High resistance to conventional antimicrobial agents resulted in an urgent need for novel formulation to eliminate these bacterial communities. Herein we fabricated light controllable chitosan micelles loading with thymol (T-TCP) for elimination of biofilm. Due to the exterior chitosan, T-TCP micelles easily bind to negative biofilm through electrostatic interaction and efficiently deliver the essential oil payloads. Under irradiation, T-TCP micelles generated ROS , which triggered simultaneous thymol release and also resulted in additional ROS-inducing bactericidal effects, both effectively eradicating biofilms of Listeria monocytogenes and Staphylococcus aureus . This formulation provided a platform for other water-insoluble antimicrobials and might be used as a potent and controllable solution to biofilm fighting.
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2018
·
IF 3.466
Wenli Zhang,Zhiyu Wang,Chenchen Wu,Ya Jin,Xinyue Liu,Zimei Wu,Jianping Liu
In cholesterol/DSPE-PEG 2000 /DPPC systems, nano-disks could evolve between liposomes and spherical micelles in a certain range of PEG-lipids. How cholesterol or drug influences this evolution and what about the properties of discoidal micelles as drug carrier are still not clear. Aiming at this, nanocarriers with different contents of cholesterol and DSPE-PEG 2000 were prepared by thin-film-hydration method. Firstly, the bilayer fluidity of nanocarriers was investigated and proved to decrease with the increase of cholesterol, and the cooperative degree between phospholipids was also related to cholesterol content in an order of 30 > 40 > 15 > 0 mol%. Then three different levels of cholesterol were chosen to study its effect on DSPE-PEG 2000 limit used to form discoidal micelles. For transition from liposomes to disks, the limit of DSPE-PEG 2000 employed is above 0.5 mol% at 0 mol% cholesterol, above 15 mol% at 30 mol% cholesterol and above 5 mol% at 40 mol% cholesterol observed from TEM images, indicating that nanocarriers with 30 mol% cholesterol formed discoidal micelles most difficultly due to the strongest interaction between phospholipids. However, membrane fluidity seems to have little responsibility for the different morphologies. And imatinib (IM) could promote the formation of discoidal micelles, resulting from the interaction between IM and polar headgroups of phospholipid demonstrated by DSC . The relative reduction of entrapment efficiency for three agents with different dissolving properties showed that lipophilic drugs were the most suitable drug that could be loaded into discoidal micelles. In addition, the discoidal micelle formulations tested could readily change to other morphologies after 80 days' storage. In conclusion, both the cholesterol content and IM could affect the formation of discoidal micelles by probably influencing the interaction between phospholipids, also the discoidal structure was not stable enough and only suitable for lipophilic drug loading. We hope this study could help to design the formula and choose the proper drugs that may retain the discoidal morphology.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2018
·Vol. 19
·期 10
·3132
·
IF 3.687
Liang Li,Na Liang,Danfeng Wang,Pengfei Yan,Yoshiaki Kawashima,Fude Cui,Shaoping Sun
The present investigation aimed to develop a tumor-targeting drug delivery system for paclitaxel (PTX). The hydrophobic deoxycholic acid (DA) and active targeting ligand folic acid (FA) were used to modify water-soluble chitosan (CS). As an amphiphilic polymer, the conjugate FA-CS-DA was synthesized and characterized by Proton nuclear magnetic resonance (1H-NMR) and Fourier-transform infrared spectroscopy (FTIR) analysis. The degree of substitutions of DA and FA were calculated as 15.8% and 8.0%, respectively. In aqueous medium, the conjugate could self-assemble into micelles with the critical micelle concentration of 6.6 × 10−3mg/mL. Under a transmission electron microscope (TEM), the PTX-loaded micelles exhibited a spherical shape. The particle size determined by dynamic light scattering was 126 nm, and the zeta potential was +19.3 mV. The drug loading efficiency and entrapment efficiency were 9.1% and 81.2%, respectively. X-Ray Diffraction (XRD) analysis showed that the PTX was encapsulated in the micelles in a molecular or amorphous state. In vitro and in vivo antitumor evaluations demonstrated the excellent antitumor activity of PTX-loaded micelles. It was suggested that FA-CS-DA was a safe and effective carrier for the intravenous delivery of paclitaxel.Keywords:chitosan;deoxycholic acid;folic acid;amphiphilic polymer;micelles;paclitaxel
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2018
·
IF 3.997
Yanzhuo Zhang,Kai Dong,Fang Wang,Hongtao Wang,Jing Wang,Ziqiu Jiang,Shuai Diao
In the current study, a novel three-dimensional macroporous hydroxyapatite/ chitosan foam (HA/CS)-supported polymer micelle (PM/HA/CS) was developed, and its potential as an oral drug delivery system to enhance the solubility and oral bioavailability of poorly soluble compounds was systemically studied. Candesartan cilexetil (CC) was selected as a poorly soluble model drug. Firstly, HA/CS foam was synthesized using a wet chemical co-precipitation approach and poly-(methyl methacrylate) colloidal crystals as a macropore template. Subsequently, the CC-loaded polymer micelles were efficiently encapsulated into the macropores of the HA/CS foam and freeze-dried to produce powdery CC-loaded PM/HA/CS composites (CC-PM/HA/CS). The resulting CC-PM/HA/CS particles were then characterized in terms of porous structure, morphology, angle of repose, crystallinity, drug loading, dissolution profiles, and physical stability. Differential scanning calorimetry (DSC) analysis confirmed that CC-PM/HA/CS was present in an amorphous form and has an excellent physical stability. Under both simulated gastric and intestinal conditions, the aqueous solubility and dissolution rate of the PM/HA/CS-based CC formulation were significantly increased compared with the pure drug powder. In addition, PM/HA/CS is almost completely non-cytotoxic. The PM/HA/CS-based CC formulation produced approximately 1.9-fold increased bioavailability when compared to the marketed tablets (Blopress ® ) administered to fasted Sprague-Dawley rats. On the whole, PM/HA/CS benefits from the advantages of three dimensional macroporous HA/CS foam and polymer micelles, and exhibits great potential as a drug delivery system for increasing the solubility and oral bioavailability of a poorly soluble compound, like CC.
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ACS Applied Materials & Interfaces
·
2018
·
IF 8.097
Juanjuan Li,Xuan Meng,Jian Deng,Di Lu,Xin Zhang,Yanrui Chen,Jundong Zhu,Aiping Fan,Dan Ding,Deling Kong,Zheng Wang,Yanjun Zhao
Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT’s antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.
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PHARMACEUTICAL RESEARCH
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2018
·Vol. 35
·期 1
·1-15
·
IF 3.335
Jin Ya,Wu Zimei,Li Caibin,Zhou Weisai,Shaw John P.,Baguley Bruce C.,Liu Jianping,Zhang Wenli
Purpose To enhance therapeutic efficacy and prevent phlebitis caused by Asulacrine (ASL) precipitation post intravenous injection, ASL-loaded hybrid micelles with size below 40 nm were developed to improve drug retention and tumor penetration. Methods ASL-micelles were prepared using different weight ratios of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethyleneglycol-2000 (DSPE-PEG 2000 ) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymers. Stability of micelles was optimized in terms of critical micelle concentration (CMC) and drug release properties. The encapsulation efficiency (EE) and drug loading were determined using an established dialysis-mathematic fitting method. Multicellular spheroids (MCTS) penetration and cytotoxicity were investigated on MCF-7 cell line. Pharmacokinetics of ASL-micelles was evaluated in rats with ASL-solution as control. Results The ASL-micelles prepared with DSPE-PEG 2000 and TPGS (1:1, w /w) exhibited small size (~18.5 nm), higher EE (~94.12%), better sustained in vitro drug release with lower CMC which may be ascribed to the interaction between drug and carriers. Compared to free ASL, ASL-micelles showed better MCTS penetration capacity and more potent cytotoxicity. Pharmacokinetic studies demonstrated that the half-life and AUC values of ASL-micelles were approximately 1.37-fold and 3.49-fold greater than that of free ASL. Conclusions The optimized DSPE-PEG 2000 /TPGS micelles could serve as a promising vehicle to improve drug retention and penetration in tumor.
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Asian Journal of Pharmaceutical Sciences
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2018
·
IF 4.56
Lingfei Han,Lejian Hu,Fulei Liu,Xin Wang,Xiaoxian Huang,Bowen Liu,Feng Feng,Wenyuan Liu,Wei Qu
The application of paclitaxel (PTX) in clinic has been restricted due to its poor solubility. Several traditional nano-medicines have been developed to improve this defect, while they are still lack of tumor targeting ability and rapid drug release. In this work, an amphiphilic polymeric micelle of hyaluronic acid (HA) – all-trans-retinoid acid (ATRA) with a disulfide bond, was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with self-assembling to micelles in water, the delivery system displayed satisfying drug loading capacities for both PTX (32.62% ± 1.39%) and ATRA, due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles (HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides, HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16F10 cells. Due to these properties, cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly, HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore, redox-sensitive HA-SS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.
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LANGMUIR
·
2018
·
IF 3.789
Zhitian Liu,Zekun Zhou,Wei Xiong,Qi Zhang
A co-polymerization–carbonization method was employed to synthesize porous carbon nanospheres (PCNSs) using pyrrole–aniline polymers as a carbon source and alkyl phenol non-ionic surfactants as templates. The effect of the hydrophilic length on the carbon nanosphere size was systematically investigated. The so-prepared PCNSs were characterized via high-magnification scanning electron microscopy, dynamic light scattering (DLS) analysis, and N2 adsorption and desorption analysis. The results indicate that the obtained nanosphere diameter can be tuned by changing the length of the hydrophilic groups. The length of the hydrophilic groups mainly affects the size of the vesicles or micelles formed by the assembly of the surfactant in solution, as was verified by the DLS results. After activation by KOH, the typical sample EO(30)–PCNS has a high specific surface area of 2137 m2/g and a large pore volume of 1.76 cm3/g. Electrochemical tests in 6 M KOH demonstrated that the assembled EO(30)–PCNS supercapacitor electrode displays good capacitive properties, such as a high specific capacitance of 221 F/g at 1.0 A/g and a good rate capacity of 68% retention at 10.0 A/g. This finding suggests that the uniform particle shape and high specific surface area are beneficial for the ion transportation, leading to good electrochemical performances. Our work provides a novel synthetic strategy for the fabrication of carbon nanospheres or other nanosphere materials for the construction of high-performance supercapacitors by optimizing few parameters, such as the length of the hydrophilic or hydrophobic groups of the surfactants.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2018
·
IF 3.862
Xiao Du,Shaoping Yin,Fang Zhou,Xu Du,Jianan Xu,Xiaochen Gu,Guangji Wang,Juan Li
Stimuli-responsive nanocarriers have demonstrated their potentials in optimizing chemotherapeutics and anticancer efficacy. In this study, a mixed micelle system (THSP) was prepared by combining reduction-sensitive hyaluronic acid-poly(lactide) (HA-ss-PLA) conjugates and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), with objective to achieve multiple functionalities of selective intracellular rapid release, active targeting capability and multidrug resistance reversal. The mixed micelle possessed desirable particle diameter of 124.32 nm and high entrapment efficiency at 87.97%. Importantly, the THSP mixed micelles demonstrated good stability in systemic circulation and rapidly released PTX in intracellular reductive environment. In vitro cellular uptake study and cytotoxicity assay indicated that the mixed micelles effectively increased drug accumulation in A549 cells and Taxol resistant A549/Taxol cells, and inhibited growth of tumor cells. In addition, the redox-responsive THSP micelles preferentially accumulated to the tumor site and improved anticancer drug activity in vivo, with a TIR of 69.08%. It was concluded that redox-sensitive mixed micelles THSP provided a potential vehicle for efficient anticancer drug delivery and enhancement in treating MDR tumor in the future.
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