Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 16
·2964-2978
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IF 4.543
Mingxing Yin,Yuling Bao,Xueqin Gao,Yupei Wu,Yu Sun,Xinyuan Zhao,Hongzhe Xu,Zhiping Zhang,Songwei Tan
A redox/pH dual-sensitive graft copolymer, poly(β-amino ester)-g-D-α-tocopherol polyethylene glycol succinate (PBAE-g-TPGS), was synthesized through a Michael-type step polymerization using disulfide linkage-containing TPGS macromonomers. Pluronic F127 (F127) and folate-F127 conjugation were introduced to prepare paclitaxel (PTX)-loaded hybrid micelles to improve their biocompatibility and serum stability and also to achieve targeted delivery. The hybrid micelles exhibited in vitro redox/pH-sensitive PTX release, enhanced cellular uptake through receptor-mediated endocytosis, and strengthened anticancer activities in both the drug-sensitive human breast cancer MCF-7 and drug-resistant MCF-7/ADR cells. P-Glycoprotein inhibition by TPGS and folate-mediated targeted delivery helped overcome multidrug resistance (MDR) and increase the therapeutic efficiency of the drug, leading to good anticancer effects in the MCF-7/ADR xenograft model. Overall, the folate-modified redox/pH-sensitive hybrid micelles provided a three-step approach to enhance anticancer activities via targeted delivery, controlled release, and depressed drug efflux; thus, these micelles may be a powerful weapon against MDR cancers in the future.
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Theranostics
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2016
·
IF 8.854
Tangjian Cheng,Jinjian Liu,Jie Ren,Fan Huang,Hanlin Ou,Yuxun Ding,Yumin Zhang,Rujiang Ma,Yingli An,Jianfeng Liu,Linqi Shi
Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)- block -poly(lysine- co -lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.
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CHEMICAL ENGINEERING JOURNAL
·
2017
·
IF 6.216
Na Wen,Shaoyu Lü,Chunmei Gao,Xiubin Xu,Xiao Bai,Can Wu,Piao Ning,Mingzhu Liu
Both blood stability and glucose responsiveness for carriers are the most important issues in insulin controlled release studies. However, few reports focus on reducing macrophage response performance for drug carriers themselves. Zwitterionic self-assembled micelles mitigated recognition by immune cell has evolved to address this limitation. In this work, novel zwitterionic dialdehyde starch-based micelles, sulfobetaine (SB) as the hydrophilic shell, and 3-aminophenylboronic acid (APBA) as glucose-responsive groups to the dialdehyde starch (DAS) backbones (SB-DAS-APBA) with glucose-responsive behavior were developed. Insulin release from the nanocarriers is sensitive to the different concentration of the glucose, rapidly at the condition of 3 mg/mL of glucose at pH 7.4. Methyl thiazolyl tetrazoliumviability (MTT) assay confirmed that zwitterion micelles were cytobiocompatible and low cytotoxic activity with A549 cells. For comparison, PEGylation micelles, monomethyl ether (mPEG) as the hydrophilic shell, and APBA as glucose-responsive groups to the DAS backbones (mPEG-DAS-APBA), were also synthesized. Confocal laser scanning microscopy (CLSM) and flow cytometry results displayed that PEGylation and zwitterion coating micelles have different recognition processes in contact with macrophages. After 4 h, doxorubicin (Dox) fluorescence of the Dox-loaded mPEG-DAS-APBA micelle groups were mostly located in nuclei. However, SB-DAS-APBA micelle groups were slightly detected in both nuclei and cytosol. In addition, the fluorescence signals of mPEG-DAS-APBA micelles showed enhanced trend than that of SB-DAS-APBA micelles in macrophage cells. These results suggest that, as drug carriers, zwitterionic self-assembled micelles SB-DAS-APBA not only possessed glucose-responsive insulin delivery property, but also reduced macrophage response performance.
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EUROPEAN POLYMER JOURNAL
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2016
·
IF 3.485
Can Wu,Jinlong Yang,Xiubin Xu,Chunmei Gao,Shaoyu Lü,Mingzhu Liu
Novel redox-responsive core-cross-linked polymers were prepared by cross-linking mPEGylated starch (mPEG-St) with 3,3′-dithiodipropionic acid (DPA), a cross-linker containing a disulfide bond. The structure of the polymer based on starch (mPEG-St-DPA) was characterized using nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), and Raman spectroscopy. In addition, these polymers could self-assemble into micelles in phosphate-buffered saline (PBS) solution. The size and critical micelle concentration (CMC) of the mPEG-St-DPA micelles decreased with an increase in the degree of cross-linking. Interestingly, the size of the mPEG-St-DPA micelles increased gradually in the presence of 10 mM glutathione (GSH) owing to the cleavage of the disulfide bonds in the micellar core. The mPEG-St-DPA micelles showed good stability, exhibiting slight changes in size after 1000-fold dilution with PBS solution or 10-fold dilution with dimethyl formamide (DMF). The results of a protein adsorption test indicated that the mPEG-St-DPA micelles were hemocompatible. Doxorubicin (DOX), a model anticancer drug, was efficiently loaded into the mPEG-St-DPA micelles. The in vitro release studies revealed that the DOX-loaded mPEG-St-DPA micelles showed enhanced release of DOX in the presence of GSH. An in vitro MTT assay confirmed that the core-cross-linked mPEG-St-DPA micelles were biocompatible with HeLa cells, and the DOX-loaded mPEG-St-DPA micelles displayed higher inhibition of HeLa cell proliferation. These results suggest that the redox-responsive mPEG-St-DPA micelles hold great potential as ideal drug delivery carriers for cancer therapy.
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REACTIVE & FUNCTIONAL POLYMERS
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2016
·
IF 2.725
Rong Ren,Yanhua Wang,Weilin Sun
Metal coordinated micelles based on the diblock copolymer PHEMA 82 -b-HQ 78 were synthesized. The block PHQ with 8-hydroxyquinoline groups can coordinate with metal ions to form the crosslinked core for micellization , while the other block PHEMA in the shell of the micelle improves its solubility. The morphological characteristics and the coordinating interaction between the metal ions and the core segment were characterized by DLS and TEM . The magnetic measurement found that the Curie-Weiss temperature T θ of the metalized micelle was 56 K and its hysteresis loop exhibited the typical ‘S’ shape with low H c and M r at 5 K, indicating that this micelle had the properties of soft ferromagnetic materials .
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JOURNAL OF MOLECULAR LIQUIDS
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2024
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IF 5.3
Hong Shen,Changwei Zhang,Hao Zhou,Wenjun Li,Zhenkai Tong,Chengzhang Wang,Jianxin Jiang
Phytol, as a potential drug-carrier, can regulate the cellular reactive oxygen species (ROS) levels in a dose-dependent manner, decreasing them at lower doses and increasing them at higher doses. In this study, we developed phytol-based micelles composed of phytol, PEG, and OE, which can clearly enhance drug delivery efficacy and simultaneously protect normal cells. Drug-loading and -releasing mechanisms of phytol-based micelles were investigated combined with dissipative particle dynamics (DPD) simulations and experimental. The simulation results indicate that Ph 4 EO 22 Ph 4 exhibits the most desirable properties for forming phytol-based micelles compared with other phytol-based polymers we designed. We found that co-loading (purpurin 18 a) P18 and paclitaxel (PTX) within the Ph 4 EO 22 Ph 4 micelle not only enhances the encapsulation efficiency (EE) of P18 (P18’s EE rised from 85.16 % to 91.17 %) but also optimizes the overall micellar structure, exhibiting excellent DL capability along with sustained release (75.2 % PTX releasing after 72 h) performance under acidic conditions. The release mechanism varies with the loaded drugs, in which PTX is released in its molecular form while P18 is released through P18/Ph 4 particles. In the latter case, Ph4 within the particles significantly facilitates cellular uptake of P18 drugs by 4T1 cells, thereby enhancing therapeutic efficacy. Interestingly, Ph 4 EO 22 Ph 4 exhibited significantly higher cytotoxicity towards 4T1 cells compared to HC11. Therefore, the phytol-based micelles incorporating a concentration-dependent hydrophobic block and a steric effect-driven hydrophilic block composed of PEG demonstrated enhanced efficacy and reduced toxicity. The present study presents a novel phytol-based micelle system incorporating DPD simulation and experimental validation, which effectively addresses the challenges encountered by P18 and PTX. Moreover, it comprehensively investigates drug loading and releasing behaviors in phytol-based micelles from various perspectives, thereby offering valuable insights for the design of alternative drug delivery systems.
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RSC Advances
·
2024
·Vol. 14
·期 39
·28753-28767
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IF 3.9
Yu Hu,Tian Lan,Ji Li,Lingjun Li,Jizheng Song
Cantharidin (CTD) has been widely used to treat hepatocellular carcinoma (HCC) in clinical practice. However, the current CTD preparations may induce hepatic and renal damage due to their non-specific distribution. Therefore, redox-sensitive polymer Pluronic F127-disulfide bond-poly(D,L-lactide) (F127-SS-PDLA) and active targeting polymer F127-glycyrrhetinic acid (F127-GA) were synthesized to prepare mixed micelles (GA/F127-SS-PDLA/CTD) for effective delivery of CTD. Fourier transform infrared (FTIR) spectroscopy and 1H nuclear magnetic resonance (1H-NMR) spectroscopy were used to verify the successful synthesis of F127-SS-PDLA and F127-GA. During the preparation, this study was the first to screen the density of GA by cellular uptake assay. The results indicated that mixed micelles with 10% and 15% F127-GA (weight fraction) exhibited superior cellular uptake in comparison to micelles with 5% and 20% F127-GA. GA/F127-SS-PDLA/CTD micelles prepared by thin film hydration method demonstrated excellent drug loading capacity for CTD (16.12 ± 0.11%). The particle size and zeta potential of GA/F127-SS-PDLA/CTD micelles were 85.17 ± 1.24 nm and −11.71 ± 0.86 mV, respectively. Hemolysis and stability assay showed that the mixed micelles had good blood compatibility and could remain stable for 30 days at 4 °C. The redox-sensitivity of GA/F127-SS-PDLA/CTD micelles in vitro was verified under reducing conditions through dynamic light scattering (DLS) and an in vitro drug release experiment, which showed obvious particle size variation and rapid drug release ability. In cellular experiments, GA/F127-SS-PDLA/CTD micelles could induce superior cytotoxicity, apoptosis and intracellular reactive oxygen species (ROS) levels compared with free CTD, non-sensitive F127-PDLA/CTD micelles and redox-sensitive F127-SS-PDLA/CTD micelles. The cellular uptake ability of nile red-labeled GA/F127-SS-PDLA micelles, which was evaluated via fluorescent microscope and flow cytometry, indicated that the modification of GA significantly increased micelle uptake in HepG-2 cells. Consequently, GA/F127-SS-PDLA/CTD micelles could be considered as a satisfactory drug administration strategy in the treatment of HCC.
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JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Sufen Li,Jingyan Zhang,Tong Yu,Guangtao Song,Jia Ke,Kai Wang,Yichong Xu,Yiling Hong,Tingting Meng,Yun Hong,Hong Yuan,Fuqiang Hu
Glioblastoma-associated macrophages & microglia (GAMs) are critical immune cells within the glioblastoma (GBM) microenvironment. Their phagocytosis of GBM cells is crucial for initiating both innate and adaptive immune responses. GBM cells evade this immune attack by upregulating the anti-phagocytic molecule CD47 on their surface. Although CD47 knockdown has shown promise in reducing tumor volume and increasing survival in GBM models, the efficacy of anti-CD47 antibodies remains limited clinically, partly due to the blood-brain tumor barrier (BBTB) and the insufficient pro-phagocytosis efficacy of CD47 blockade alone. Here, we introduce CSSOssMIT@MM-PEP 20 , a PEP 20 -linked microglia membrane (MM) camouflaged CSSOssMIT prodrug micelle. The MM targets vascular cell adhesion molecule-1 on the BBTB and enhances the penetration of CSSOssMIT@MM-PEP 20 into the GBM tissue. CSSOssMIT@MM-PEP 20 disassembles into MM-PEP 20 and CSSOssMIT through the proton sponge effect in the acidic microenvironment. MM-PEP 20 blocks the CD47-SIRPα axis, disabling the ‘don't eat me’ signal, while CSSOssMIT releases MIT within tumor cells to promote immunogenic cell death and amplify the ‘eat me’ signal. In an orthotopic GBM mouse model, CSSOssMIT@MM-PEP 20 increased GAMs-mediated phagocytosis of GBM cells by 5.01-fold and enhanced CD8 + T cell infiltration by 8.63-fold, demonstrating significant GBM inhibition. Overall, this study presents a noninvasive strategy to traverse the BBTB and modulate GAMs phagocytosis, thereby facilitating effective anti-GBM chemo-immunotherapy.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2018
·
IF 5.091
Ying Du,Wei Yan,Hua Lian,Chenyang Xiang,Lijie Duan,Chunsheng Xiao
In this work, a new kind of polyion complex (PIC) micelles with pH and reduction dual responsiveness was developed for effective intracellular drug delivery. The PIC micelles can be readily prepared by mixing a polycationic block polymer, methoxy poly(ethylene glycol)- b -poly( l -lysine) (mPEG-PLL), with a small molecule polyacid, 2, 2′-dithiodisuccinic acid (DTS) in aqueous media. The resultant PIC micelles are of uniform spherical shapes with hydrodynamic radii ranging from 65 to 75 nm based on different feeding ratios of mPEG-PLL and DTS. Interestingly, by using the small molecule polyacid DTS, the obtained PIC micelles show distinct pH-responsive disintegration in acid solution. Meanwhile, the PIC micelles were also assessed to be reduction-responsive due to the presence of disulfide bond in DTS. In view of these stimuli-responsive properties, the potential use of this PIC micelle as smart drug carrier was then investigated. Doxorubicin (DOX), a cationic anticancer drug, was loaded into the PIC micelles with high efficiency. In vitro drug release studies revealed that release of DOX from the PIC micelles was suppressed in neutral solutions due to the stable electrostatic interactions between PIC micelles and DOX, but could be accelerated in acidic solutions or under high GSH condition. Furthermore, flow cytometry and confocal laser scanning microscopy (CLSM) studies indicated that the DOX-loaded PIC micelles could be effectively internalized by MCF-7 human breast cancer cells and release the loaded DOX in intracellular environment. Consequently, the DOX-loaded PIC micelles were capable of inhibiting the proliferation of C26 murine colon cancer and MCF-7 human breast cancer cells in high efficiency, showing similar IC 50 values as free DOX. Thus, this biocompatible PIC micelle may be promising for intracellular drug delivery.
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ACS Biomaterials Science & Engineering
·
2018
·
IF 4.432
Xu Hu,Ruiling Liu,Di Zhang,Jing Zhang,Zhonghao Li,Yuxia Luan
The application of anticancer drug chlorambucil (CLB) in chemotherapy is severely restricted by its insolubility, lability, and toxic side effects; therefore, it is challenging to realize a highly efficient anticancer therapy of chlorambucil. To solve the above drawbacks encountered by chlorambucil, herein we proposed an amphiphilic chlorambucil prodrug-based self-assembled micelle strategy to realize the highly efficient anticancer therapy of chlorambucil. 1,6-Hexanediamine hydrochloride (HDH) serving as the hydrophilic segment was covalently bound to hydrophobic CLB to prepare an amphiphilic prodrug CLB-HDH which could self-assemble into micelles in aqueous solution. These micelles can passively target tumor tissues via the enhanced permeability and retention (EPR) effect, leading to enhanced cellular internalization. Both the cytotoxicity assay in vitro and anticancer study in vivo confirmed the excellent therapeutic activity of CLB-HDH micelles in comparison with free chlorambucil. Moreover, the hemolysis examination and histological analysis demonstrated the designed CLB-HDH micelles are safe in drug delivery. Therefore, our designed amphiphilic prodrug CLB-HDH micelles bring new opportunity for chlorambucil clinical application to combat cancers.
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Nanomedicine-Nanotechnology Biology and Medicine
·
2024
·
IF 4.2
Yuxiang Dai,Yuanping Min,Lu Zhou,Longyang Cheng,Hongbin Ni,Yang Yang,Wendi Zhou
Glioblastoma (GBM) is a central nervous system cancer with high incidence and poor survival rates . Enhancing drug penetration of the blood-brain barrier (BBB) and targeting efficacy is crucial for improving treatment outcomes. In this study, we developed a redox-sensitive targeted nano-delivery system (HCA-A2) for temozolomide (TMZ) and β-lapachone (β-Lapa). This system used hyaluronic acid (HA) as the hydrophilic group, arachidonic acid (CA) as the hydrophobic group, and angiopep-2 (A2) as the targeting group. Control systems included non-redox sensitive (HDA-A2) and non-targeting (HCA) versions. In vitro, HCA-TMZ-Lapa micelles released 100 % of their payload in a simulated tumor microenvironment within 24 h, compared to 43.97 % under normal conditions. HCA-A2 micelles, internalized via clathrin-mediated endocytosis, showed stronger cytotoxicity and better BBB penetration and cellular uptake than controls. In vivo studies demonstrated superior tumor growth inhibition with HCA-A2 micelles, indicating their potential for GBM treatment.
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CARBOHYDRATE POLYMERS
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2011
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IF 3.463
Xiujuan Huang,Yan Xiao,Meidong Lang
Micelles/sodium-alginate composite gel beads (micelles/SA beads) were constructed from SA matrix and indomethacin (IND) loaded six-arm block copolymer poly( ɛ -caprolactone)- block -(dimethylamino)ethyl methacrylate (S(PCL- b -PDMA) 6 ) micelles. The morphology, swelling property and drug loading level of the beads were investigated. The release behavior of IND from three matrices including micelles, SA beads and micelles/SA beads was evaluated at pH 1.2, 6.8 and 7.4, as well as in the simulated gastrointestinal (GI) tract. Significant differences in the release of IND from each matrix were observed in the acidic and near neutral pH fluids. The results suggested that IND could be protected by the micelles/SA beads from being released under acidic conditions in the stomach and would be mainly delivered to the small intestine and the colon. The release behavior was dependent on the initial concentrations of SA and calcium chloride (CaCl 2 ) due to the different crosslinking densities. The results demonstrated that these micelles/SA beads could represent a promising oral drug delivery system for drugs with poor water solubility.
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危险品化学品经营许可证（带存储）