COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2020
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IF 3.99
Yunran Zhang,Haiping Zhou,Zhe Zhang,Yijun Zhu,Tao Wang,Liguo Yu,Hongrui Song
Betulinic acid (BA) is a new class of anticancer drug , but its relatively short half-life and poor water solubility limit its therapeutic effect and clinical application. Herein, to tackle the dilemma, BA prodrugs were prepared by conjugating BA onto the polyethylene glycol (PEG) polymer via cleavable disulfide bonds. The prodrugs exhibited high water solubility (270-fold of free BA) and a relatively high drug-loading efficiency of 14.2 %. To further endow the BA prodrugs with a photothermal therapeutic effect, the near-infrared (NIR) agent Cypate was grafted on the Pluronic triblock copolymer . The different PEG polymers and different Pluronic polymers were chosen to obtain the optimal drug loading efficiency and the photothermal generation effect. The P-SS-BA/F68-Cy prodrug micelles integrate the redox-responsive BA prodrugs and the NIR-responsive amphiphilic triblock polymer into one single nanocomposite . The release of BA was less than 20 % in pH 7.4 PBS in the absence of glutathione (GSH), whereas the release of BA was obviously accelerated in pH 5.0 PBS with 10 mM GSH. In addition, the release of BA was further accelerated under the NIR irradiation. The P-SS-BA/F68-Cy micelles showed an excellent photothermal heating effect under NIR irradiation. The prepared P-SS-BA/F68-Cy micelles showed the synergistic thermochemotherapeutic effect on tumors both in vitro and in vivo . Therefore, the present study shows the great potential of dual-triggered drug delivery and thermochemotherapy for combination therapy.
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Polymers
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2020
·Vol. 12
·期 10
·2268
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IF 3.426
Song Feng,Junqin Wang,Lihua Zhang,Qin Chen,Wang Yue,Ni Ke,Haibo Xie
Currently, controlled release formulations (CRFs) of pesticides in response to biotic and/or abiotic stimuli have shown great potential for providing “on-demand” smart release of loaded active ingredients. In this study, amphiphilic biopolymers were prepared by introducing hydrophobic (7-diethylaminocoumarin-4-yl)methyl succinate (DEACMS) onto the main chain of hydrophilic carboxymethylchitosan (CMCS) via the formation of amide bonds which were able to self-assemble into spherical micelles in aqueous media and were utilized as light-responsive nanocarriers for the controlled release of pesticides. FTIR and NMR characterizations confirmed the successful synthesis of the CMCS-DEACMS conjugate. The critical micelle concentration (CMC) decreased with the increase in the substitution of DEACMS on CMCS, which ranged from 0.013 to 0.042 mg/mL. Upon irradiation under simulated sunlight, the hydrodynamic diameter, morphology, photophysical properties and photolysis were researched by means of dynamic light scattering (DLS), transmission electron microscopy (TEM), UV-vis absorption spectroscopy and fluorescence spectroscopy. Moreover, 2,4-dichlorophenoxyacetic acid (2,4-D) was used as a model pesticide and encapsulated into the CMCS-DEACMS micelles. In these micelle formulations, the release of 2,4-D was promoted upon simulated sunlight irradiation, during which the coumarin moieties were cleaved from the CMCS backbone, resulting in a shift of the hydrophilic–hydrophobic balance and destabilization of the micelles. Additionally, bioassay studies suggested that this 2,4-D contained which micelles showed good bioactivity on the target plant without harming the nontarget plant. Thereby, the light-responsive CMCS-DEACMS micelles bearing photocleavable coumarin moieties provide a smart delivery platform for agrochemicals.Keywords:carboxymethyl chitosan micelles;light-responsive;coumarin;2,4-D;controlled release;pesticide
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2020
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IF 2.734
Miaomiao Long,Shenhuan Liu,Xiaotian Shan,Jing Mao,Fuwei Yang,Xiaoyu Wu,Lipeng Qiu,Jinghua Chen
Polymeric micelles have attracted much attention in the field of anticancer drug delivery system because of their special properties. However, the slow drug release rate of micelles after reaching tumor cells is still considered to be a major problem. Therefore, we constructed a new orthoester-based pH-sensitive polyethylene glycol–hydroxydodecanoic acid (PAE) polymer to form doxorubicin-loaded micelles (DOX/PAE). DOX/PAE micelles with uniform particle size showed pH-sensitive drug release behavior in vitro . And the in vitro cytotoxicity studies showed that blank PAE micelles were nontoxic to cells while DOX/PAE micelles could inhibit the growth of tumor cells in a concentration-dependent manner. Furthermore, cellular uptake studies showed that DOX/PAE micelles were uptaken by tumor cells and transported into the nucleus to achieve the effect of killing tumor cells. The results of the uptake mechanism showed that clathrin and macrophage mediated endocytic pathways played important roles in internalization of DOX/PAE micelles. Altogether, the above results show that pH-sensitive PAE micelles have potential in anticancer drug delivery.
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Pharmaceutics
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2021
·Vol. 13
·期 9
·1464
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IF 6.321
Yang Yang,Fuwei Yang,Xiaotian Shan,Jiamin Xu,Wenjie Fang,Juan Zhou,Lipeng Qiu,Jinghua Chen
At present, the drug is still difficult to release completely and quickly only with single stimulation. In order to promote the rapid release of polymeric micelles at tumor site, pH/reduction sensitive polymers (PCT) containing disulfide bonds and orthoester groups were synthesized. The PCT polymers can self-assemble in water and entrap doxorubicin to form drug-loaded micelles (DOX/PCT). In an in vitro drug release experiment, the cumulative release of DOX/PCT micelles in the simulated tumor microenvironment (pH 5.0 with GSH) reached (89.7 ± 11.7)% at 72 h, while it was only (16.7 ± 6.1)% in the normal physiological environment (pH 7.4 without GSH). In addition, pH sensitive DOX loaded micellar system (DOX/PAT) was prepared as a control. Furthermore, compared with DOX/PAT micelles, DOX/PCT micelles showed the stronger cytotoxicity against tumor cells to achieve an effective antitumor effect. After being internalized by clathrin/caveolin-mediated endocytosis and macropinocytosis, DOX/PCT micelles were depolymerized in intercellular acidic and a reductive environment to release DOX rapidly to kill tumor cells. Additionally, DOX/PCT micelles had a better inhibitory effect on tumor growth than DOX/PAT micelles in in vivo antitumor activity studies. Therefore, pH/reduction dual sensitive PCT polymers have great potential to be used as repaid release nanocarriers for intercellular delivery of antitumor drugs.Keywords:polymeric micelles;doxorubicin;pH/reduction sensitive release;antitumor effect
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EUROPEAN POLYMER JOURNAL
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2019
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IF 3.621
Yanhai Li,Feng Gao,Jin Guo,Peng Ren,Zhenzhen Tian,Jianan Bai,Jie Hua
Natural polymers have shown special advantages in application as drug delivery carriers. However, microbial ε-polylysine seems to have been snubbed. In this study, we constructed a drug delivery system based on natural ε-polylysine. Amphipathic graft copolymer, methoxypoly(ethylene glycol)- graft -ε-polylysine-tetraphenylethylene (mPEG- g -Plys-TPE), was synthesized based on microbial ε-polylysine which was modified completely with PEG and TPE. MPEG- g -Plys-TPE could self-assemble into nanomicelles with stable shell-core structure. PEG served as the hydrophilic shell to provide long blood circulation and biocompatibility. TPE formed the hydrophobic core with aggregation-induced emission (AIE) effect to load drugs. The physical and chemical properties, including size distribution, morphology, stability and photoluminescent effect, were investigated in detail. In vitro drug release indicated pH-dependent patterns. Furthermore, cytotoxicity of doxorubicin (DOX)-loaded micelles against HT-29, HCT116 and SW480 was significantly higher than that of free DOX, which was explained by the mechanism of cellular uptake against tumor cells. In summary, all results suggested that mPEG- g -Plys-TPE as new type biomaterials exhibited great potential for drug delivery.
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CHEMICAL PHYSICS LETTERS
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2019
·
IF 1.901
Xiaoluan Lu,Wentao Zhu,Tingyu Chen,Qianrong Peng,Changmu Yu,Min Yang
A novel mixed micelles was developed to improve the solubility of Zinc phthalocyanine (ZnPc). Sodium deoxycholate (SDC) and D-alpha tocopheryl polyethylene glycol succinate (TPGS) were utilized as micelles material, mainly based on the design that ZnPc was located inside the hydrophobic core of mixed micelles, which was formed by supramolecular self-assembly of SDC and TPGS. A series of ZnPc loaded mixed micelles containing different quality of SDC were prepared and characterized by means of their physicochemical properties, photodynamic activity, photostability, drug release and cell viability. These mixed micelles appeared spherical, short rod and long rod shape, respectively, with corresponding particle sizes of about 106 nm, 344 nm and 80 nm, respectively. Drug loading efficiencies were higher than 90%. The capacity of ZnPc loaded mixed micelles to produce singlet oxygen ( 1 O 2 ) by irradiation with 650 nm red laser was monitored using 1,3-diphenylisobenzofuran as a probe. The singlet oxygen quantum yields ( Φ Δ ) for ZnPc loaded mixed micelles were high to that of the standard (ZnPc in DMF), and three of mixed micelles displayed excellent ability to generate 1 O 2 (the value of Φ Δ were greater than 0.70). These mixed micelles were photostable in the timescale typically used in photodynamic therapy (PDT), and only a small photobleaching event was observed after 20 min of light irradiation. The in vitro drug release studies of ZnPc loaded mixed micelles demonstrated a sustained release profile. Phototoxicity experiments in A549 cells showed that mixed micelles had higher toxicity than that of free ZnPc with the same concentration. Thus, the mixed micelles developed in this work are a promising strategy to be employed in delivery of ZnPc in PDT.
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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2019
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IF 2.367
Yongshun Sun,Yiping Li,Ying Shen,Jian Wang,Jian Tang,Zhiying Zhao
The aim of this study was to improve the solubility, oral bioavailability, and anti-gastroesophageal reflux activity of curcumin (CM) by preparing two CM-loaded, novel, binary mixed micelles (CM-M). The two CM-M were prepared by ethanol thin-film hydration method. One (CM-T) was prepared using D-alpha-tocopheryl polyethylene glycol 1000 succinate and Solutol®HS15, and the other (CM-F) was prepared using Pluronic®F127 and Solutol®HS15. The entrapment efficiency and drug loading of CM-T were 83.61 ± 0.54% and 2.20 ± 0.65%, respectively, which were lower than those of CM-F (88.66 ± 0.12% and 1.47 ± 0.26%, respectively). TEM results demonstrated that CM-T and CM-F were homogeneous and spherical. The permeability of CM delivered via CM-T and CM-F was enhanced across a Caco-2 cell monolayer, and CM-T and CM-F showed a 5.24- and 4.76-fold increase in relative oral bioavailability, respectively compared with free CM. In addition, the in vivo anti-gastroesophageal reflux study showed that CM-T and CM-F achieved higher anti-gastroesophageal reflux efficacy compared with free CM. Collectively, these findings were indicative of an oral micelle formulation of CM with increased solubility, oral bioavailability, and anti-gastroesophageal reflux activity.
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2019
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IF 4.708
Siyu Guan,Qianqian Zhang,Jianwei Bao,Tijie Duan,Rongfeng Hu,Tori Czech,Jihui Tang
In recent decades, targeted drug delivery systems (TDDS) have been widely used as an ideal method of improving therapeutic effects and reducing systemic side effects of chemotherapeutic agents. Historically, a handful of methods have been developed to further improve the targeting ability of delivery systems. Thus, in this study, two methods, taking advantage of tumor characteristics, were used for the creation of a multi-targeted delivery system. The first was the fabrication of pH-sensitive micelles , lending the ability to increase drug release by exploiting the acidic tumor environment. The second method was through utilization of the surface-exposed phosphatidylserine (PS) of tumors, which is normally found in the inner leaflet in healthy cells. Using PS as a target site, PS binding peptide (PSBP-6) was conjugated to pH-sensitive mixed micelles, (consisting of poly (ethylene glycol)-b-poly (D, L-lactide) (PEG-PDLLA) and poly (ethylene glycol)-b-poly (L-histidine) (PEG-PHIS)). After successful preparation of micelles, paclitaxel (PTX), a common chemotherapeutic agent, was selected to measure drug loading capacity and encapsulation efficiency, showing 7.9% and 83.5%, respectively. The in vitro release of PTX from mixed micelles at pH 5.0, 6.5, and 7.4 was 78.1, 56.8, and 51.4%, respectively, indicating acid-triggered drug release. The PSBP-6-modified, mixed micelles exhibited significantly enhanced in vitro cytotoxicity and demonstrated more efficient cellular uptake compared to unmodified mixed micelles in the HeLa cell line. Moreover, pharmacokinetic , in vivo biodistribution , and fluorescence imaging studies showed that PSBP-6-PEG-PDLLA/PEG-PHIS mixed micelles provide prolonged time in blood circulation and enhanced tumor accumulation. These results suggest that the use of PS as a novel targeting site is advantageous, and that these new multi-targeted mixed micelles show great potential for realization of broad prospects in the targeted treatment of tumors for chemotherapeutic delivery.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2019
·Vol. 20
·期 8
·1961
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IF 4.183
Bing Yu,Qingye Meng,Hao Hu,Tao Xu,Youqing Shen,Hailin Cong
Polymeric micelles (PMs) have been applied widely to transport hydrophobic drugs to tumor sites for cancer treatment. However, the low load efficiency of the drug in the PMs significantly reduces the therapeutic efficiency. We report here that disulfide-linked camptothecin (CPT) as a kind of dimeric drug can be effectively embedded in the core of poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) (PCL–PEG–PCL) PMs for improving drug-loading efficiency, and PEG can be used as a hydrophilic shell. Moreover, the dimeric CPT-loaded PCL–PEG–PCL PMs exhibited excellent solubility in phosphate-buffered saline (PBS) media and significant cytotoxicity to cancer cells.Keywords:dimeric drug;camptothecin;micelles;cancer therapy
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CERAMICS INTERNATIONAL
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2019
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IF 3.45
Hang Qin,Wenming Guo,Hanning Xiao
Sol-gel process was modified by reverse micelles (RMs) for the preparation of γ-Al 2 O 3 ultrafiltration (UF) membranes and their applications in the efficient rejection of methyl blue and bovine serum albumin were explored. The optimized boehmite sol with a narrower particle size distribution and better sphericity was synthesized by using cetyltrimethyl ammonium bromide RMs as microreactors and was dip-coated on α-Al 2 O 3 microfiltration substrates to prepare γ-Al 2 O 3 UF membranes. It was found that not only the sol particle size, it's distribution and morphology had also an important effect on the pore size, pore size distribution , porosity and pore volume of the membrane. Additionally, the as-prepared membranes with a MWCO of 8 kDa exhibited a narrow pore size distribution (4.8–6.8 nm), relatively high pure-water flux (30.4 L/(h m 2 bar)) and excellent rejection for bovine serum albumin and methyl blue with the maximum rejection rate of 96.2% and 96.8% respectively.
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BIOMATERIALS
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2018
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IF 8.806
Yujie Zhang,Zhongyuan Guo,Zhonglian Cao,Wenxi Zhou,Yu Zhang,Qinjun Chen,Yifei Lu,Xinli Chen,Qin Guo,Chao Li,Donghui Liang,Tao Sun,Chen Jiang
Targeted delivery and accumulation of chemotherapeutics to tumor sites is in high demand and extremely challenging for anticancer therapy. Studies show that albumin is actively recruited into tumor tissue overexpressing albumin-binding proteins including secreted protein acidic and rich in cysteine (SPARC) and gp60. Herein, a novel redox-responsive paclitaxel-loaded micelle system with the modification of ABD035, which specifically and strongly binds to albumin, is designed to combine the strengths of albumin and micelles together for antitumor drug biomimetic delivery. The ABD035-modified micelle has a strong binding response to albumin and co-localization of BODIPY-labeled ABD035-modified micelle and SPARC is observed in tumor tissues. Furthermore, the ABD035-modified micelle significantly improves the therapeutic effect in the animal model bearing triple negative breast cancer by increasing drug accumulation in tumor tissue, enhancing cell uptake efficiency, rapidly releasing prototype drug under intracellular reductive conditions and increasing tumor cell apoptosis. These results together vote the biomimetic delivery of ABD035-modified micelle as a promising strategy for cancer therapy.
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Asian Journal of Pharmaceutical Sciences
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2018
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IF 4.56
Yang Pan,Xiahui Wang,Zongning Yin
To achieve targeted thrombolysis, a targeted delivery system of lumbrokinase (LK) was constructed using RGDfk-conjugated hybrid micelles. Based on the specific affinity of RGDfk to glycoprotein complex of GPⅡb/Ⅲa expressed on the surface of membrane of activated platelet, LK loaded targeted micelles (LKTM) can be delivered to thrombus. The hybrid micelles were composed of polycaprolactone-block-poly (2-(dimethylamino) ethyl methacrylate) (PCL-PDMAEMA), methoxy polyethylene glycol-block- polycaprolactone (mPEG-PCL) and RGDfk conjugated polycaprolactone-block- polyethylene glycol (PCL-PEG-RGDfk). PCL-PDMAEMA was synthesized via ring open polymerization (ROP) and atom transfer radical polymerization (ATRP). PCL-PEG-RGDfk was synthesized via ROP and carbodiimide chemistry. The prepared LKTM was characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). Colloidal stability assay showed the prepared LKTM was stable. Biocompatibility assay was performed to determine the safe concentration range of polymer. The assay of fluorescent distribution in vivo demonstrated that LKTM can be efficiently delivered to thrombi in vivo . Thrombolysis in vivo indicated the thrombolytic potency of LKTM was optimal in all groups. Notably, the laboratory mice treated with LKTM exhibited a significantly shorter tail bleeding time compared to those treated with LK or LK-loaded micelles without RGDfk, which suggested that the targeted delivery of LK using RGDfk-conjugated hybrid micelles effectively reduced the bleeding risk.
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