ACS Applied Materials & Interfaces
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2017
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IF 7.504
Dishi Wang,Yanxia Zhou,Xinru Li,Xiaoyou Qu,Yunqiang Deng,Ziqi Wang,Chuyu He,Yang Zou,Yiguang Jin,Yan Liu
pH-responsive polymeric micelles have shown promise for the targeted and intracellular delivery of antitumor agents. The present study aimed to elucidate the possible mechanisms of pH-sensitivity and cellular internalization of PEOz-b-PLA micelles in detail, further unravel the effect of hydrophilic/hydrophobic ratio of the micelles on their cellular internalization, and examine the intracellular trafficking routes and fate of PEOz-b-PLA after internalization of the micelles. The results of variations in the size and Zeta potential of PEOz-b-PLA micelles and cross-sectional area of PEOz-b-PLA molecules with pH values suggested that electrostatic repulsion between PEOz chains resulting from ionization of the tertiary amide groups along PEOz chain at pH lower than its pKa was responsible for pH-sensitivity of PEOz-b-PLA micelles. Furthermore, the studies on internalization of PEOz-b-PLA micelles by MCF-7 cells revealed that the uptake of PEOz-b-PLA micelles was strongly influenced by their structural features, and showed that PEOz-b-PLA micelles with hydrophilic/hydrophobic ratio of 1.7–2.0 exhibited optimal cellular uptake. No evident alteration in cellular uptake of PEOz-b-PLA micelles was detected by flow cytometry upon the existence of EIPA and chlorpromazine. However, the intracellular uptake of the micelles in the presence of MβCD and genistein was effectively inhibited. Hence, the internalization of such micelles by MCF-7 cells appeared to proceed mainly through caveolae/lipid raft-mediated endocytosis without being influenced by their hydrophilic/hydrophobic ratio. Confocal micrographs revealed that late endosomes, mitochondria and endoplasmic reticulum were all involved in the intracellular trafficking of PEOz-b-PLA copolymers following their internalization via endocytosis, and then part of them was excreted from tumor cells to extracellular medium. These findings provided valuable information for developing desired PEOz-b-PLA micelles to improve their therapeutic efficacy and reducing the potential safety risks associated with their intracellular accumulation.
研究领域:
药剂学
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分子生物学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2019
·Vol. 20
·期 20
·5074
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IF 4.183
Mingzhuo Cao,Yong Gao,Mengling Zhan,Nasha Qiu,Ying Piao,Zhuxian Zhou,Youqing Shen
In the last 2–3 decades, gene therapy represented a promising option for hepatocellular carcinoma (HCC) treatment. However, the design of safe and efficient gene delivery systems is still one of the major challenges that require solutions. In this study, we demonstrate a versatile method for covalent conjugation of glycyrrhizin acid (GL) or glycyrrhetinic acid (GA) to increase the transfection efficiency of Polyethyleneimine (PEI, Mw 1.8K) and improve their targeting abilities of hepatoma carcinoma cells. GA and GL targeting ligands were grafted to PEI via N-acylation, and we systematically investigated their biophysical properties, cytotoxicity, liver targeting and transfection efficiency, and endocytosis pathway trafficking. PEI-GA0.75, PEI-GL10.62and PEI-GL20.65conjugates caused significant increases in gene transfection efficiency and superior selectivity for HepG2 cells, with all three conjugates showing specific recognition of HepG2 cells by the free GA competition assay. The endocytosis inhibition and intracellular trafficking results indicated that PEI-GA0.75and GL10.62conjugates behaved similarly to SV40 virus, by proceeding via the caveolae- and clathrin-independent mediated endocytosis pathway and bypassing entry into lysosomes, with an energy independent manner, achieving their high transfection efficiencies. In the HepG2 intraperitoneal tumor model, PEI-GA0.75and PEI-GL10.62carrying the luciferase reporter gene gained high gene expression, suggesting potential use for in vivo application.Keywords:gene therapy;glycyrrhizin acid;glycyrrhetinic acid;hepatic tumor targeting;caveolae- and clathrin-independent pathway;HepG2 intraperitoneal tumor model
研究领域:
药理学
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分子生物学
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基因治疗
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癌症研究
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2021
·
IF 6.986
Yingcui Bu,Xiaojiao Zhu,Haoran Wang,Jie Zhang,Lianke Wang,Zhipeng Yu,Yupeng Tian,Hongping Zhou,Yi Xie
Considering the multiple biological barriers before the entry of photosensitizers (PSs) into cytoplasm, it is of paramount importance to track PSs to elucidate their behaviors and distributions to guide the photodynamic therapy (PDT). Also, the developed PSs suffer from strong oxygen dependency. However, reports on such ideal theranostic platforms are rare. Herein, we developed a theranostic platform (CMTP-2) based on the coumarin-based D-π-A system, which, for the first time, can reveal the holistic intracellular delivery pathway and near-infrared (NIR)-activated mitophagy to guide synergistic type-I PDT and photothermal therapy. The dynamic endo-lysosomal escape of CMTP-2 was monitored, as well as its changeable distributions in endosomes, lysosomes, and mitochondria, demonstrating the preferential accumulation in mitochondria at the end. Upon NIR-I irradiation, CMTP-2 generated toxic radicals and heat, triggering the execution of mitophagy and apoptosis. In vivo experiments on mice indicated that CMTP-2 under 808 nm irradiation realized complete cancer ablation, showing great potential for advancements in synergistic phototherapy.
研究领域:
生物医学工程
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诊疗学
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癌症研究
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纳米医学
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DOI
高影响因子
CELL PROLIFERATION
·
2019
·Vol. 52
·期 3
·e12586
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IF 5.039
Yuanyuan Wei,Xiaoye Jin,Tingting Kong,Wenqing Zhang,Bofeng Zhu
Objectives This study aimed at investigating cellular uptake pathways of carbon dots (CDs) in human adenoid cystic carcinoma cell line ACC-2. Materials and methods We synthesized CDs using a hydrothermal method with citric acid and polyethylenimine (PEI, Mw = 25 000). The CDs incubated with the ACC-2 cells showed their bioimaging capabilities using a confocal microscopy test. Flow cytometry was used to analyse cellular uptake pathways of CDs in ACC-2 cells. Results Our findings indicated that CDs possessed good biocompatibility in ACC-2 cells. CDs were endocytosed mainly via micropinocytosis and energy-dependent pathways. Conclusions In general, these findings suggested that CDs had excellent biomedical imaging properties for ACC-2 cells and there was a potential opportunity to develop biomedical applications.
研究领域:
纳米技术
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生物医学工程
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癌症研究
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
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2024
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IF 15.8
Yuan-Qiang Chen,Meng-Die Xue,Jia-Li Li,Da Huo,Hong-Ming Ding,Yuqiang Ma
The cellular uptake of nanoparticles (NPs) by biological cells is an important and fundamental process in drug delivery. Previous studies reveal that the physicochemical properties of nanoparticles as well as those of functionalized ligands can both critically affect the uptake behaviors. However, the effect of the conjugation strategy (i.e., the “bond” between the ligand and the NP) on the cellular uptake is overlooked and remains largely elusive. Here, by taking the broadly employed gold nanoparticle as an example, we comprehensively assessed the relationship between the conjugation strategy and uptake behaviors by introducing three ligands with the same functional terminal but different anchoring sites. As revealed by in vitro cell experiments and multiscale molecular simulations, the uptake efficiency of gold NPs was positively correlated with the strength of the “bond” and more specifically the ligand mobility on the NP surface. Moreover, we validated the results presented above by proposing a thermodynamic theory for the wrapping of NPs with mobile ligands. Further, we also showed that the endocytic pathway of NPs was highly dependent on ligand mobility. Overall, this study uncovered a vital role of conjugation strategy in the cellular uptake and may provide useful guidelines for tailoring the biobehaviors of nanoparticles.
研究领域:
纳米技术
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生物物理学
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细胞生物学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2023
·Vol. 9
·期 9
·e20028
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IF 4
Qingyuan Cheng,Yiping Duan,Wei Fan,Dongxu Li,Cuiwen Zhu,Tiantian Ma,Jie Liu,Mingxia Yu
Quantum Dots (QDs) modified with branched Polyethylene Glycol-amine (6- or 8-arm PEG-amine) coupled with methoxy PEG (mPEG) hold great promise for in vivo biomedical applications due to a long half-life in blood and negligible toxicity. However, the potential risks regarding their concomitant prolonged co-incubation with cardiovascular and blood cells remains inconclusive. In the present study, the feasible, effective and convenient proliferating-restricted cell line models representing the circulatory system were established to investigate the cellular internalization followed by intracellular outcomes and resulting acute/sub-acute cytotoxicity of the 6-arm PEG-amine/mPEG QDs. We found a dose-, time- and cell type-dependent cellular uptake of the 6-arm PEG-amine/mPEG QDs, which was ten-fold lower compared to the traditional linear PEG-modified counterpart. The QDs entered cells via multiple endocytic pathways and were mostly preserved in Golgi apparatus for at least one week instead of degradation in lysosomes, resulting in a minimal acute cytotoxicity, which is much lower than other types of PEG-modified QDs previously reported. However, a sub-acute cytotoxicity of QDs were observed several days post exposure using the concentrations eliciting no-significant acute cytotoxic effects, which was associated with elevated ROS generation caused by QDs remained inside cells. Finally, a non-cytotoxic concentration of the QDs was identified at the sub-acute cytotoxic level. Our study provided important information for clinical translation of branched PEG-amine/mPEG QDs by elucidating the QDs-cell interactions and toxicity mechanism using the proliferation-restricted cell models representing circulatory system. What's more, we emphasized the indispensability of sub-acute cytotoxic effects in the whole biosafety evaluation process of nanomaterials like QDs.
研究领域:
纳米技术
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生物医学工程
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毒理学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2021
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IF 3.981
Zhuxian Wang,Yaqi Xue,Quanfu Zeng,Zhaoming Zhu,Yuan Wang,Yufan Wu,Chunyan Shen,Hongxia Zhu,Cuiping Jiang,Li Liu,Qiang Liu
Licochalcone A (LicA) is a natural chalcones , well-known for its anti-melanogenic activity, however, its poor solubility leads to a limited topical bioavailability and clinical outcomes. Therefore, LicA-encapsulated glycyrrhiza acid (GA) (GA-LicA) micelles were formulated for higher cellular uptake and improved cutaneous applications. The physicochemical properties (morphology, size and charge), topical penetration, endocytic pathways, cellular uptake amount (CUA) and intracellular distribution of the GA-LicA micelles were studied. Moreover, the anti-melanogenic mechanisms including antioxidant properties, melanogenesis-mediated enzymes and melanin generation as well as cell apoptosis in A375 cells were demonstrated. We found that significant increase amount of LicA was obtained into the epidermis after encapsulated in GA micelles, and the hair follicles were the preferential route for LicA permeation. Moreover, HaCaT and melanocytes possessed a significantly higher effective uptake and CUA for GA-LicA micelles than that of the crude LicA. Caveolae-mediated and actin filaments-mediated endocytosis, caveolae-mediated endocytosis were respectively involved in cellular uptake of GA-LicA micelles for HaCaT cells and melanocytes. Furthermore, GA-LicA micelles possessed a synergistic anti-melanogenic effect by scavenging the free radicals, reducing the activity of α-glucosidase and tyrosinase , and inducing the cell apoptosis. Taken together, GA micelles can enhance the bioavailability and anti-melanogenic effect of LicA, and the article provided principles for rational design of formulations in whitening cosmetics.
研究领域:
药学
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化妆品科学
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药理学
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细胞生物学
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皮肤科
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产品关联
DOI
高影响因子
AAPS PHARMSCITECH
·
2023
·Vol. 24
·期 2
·1-16
·
IF 3.3
Wu Wenting,Ding Quan,Zhou Zhiwei,Kuang Wenliang,Jiang Lipeng,Liu Peng,Ai Weiping,Zhu Weifeng
In order to better promote the application of the polymeric mixed micelles (PMMs) in oral delivery, in addition to focusing on the improvement of micellar structural stability, it is necessary to obtain the absorption characteristics of the intact micellar particles. In this work, the transport behavior across Caco-2 cells of FS/PMMs composed of Pluronic F127 and Solutol HS15 was tracked by encapsulating an environment-responsive probe into the particles. The specific property of the probe is the water-initiated aggregation-caused quenching (ACQ) ability, by which integral particles can be identified accurately. The influence of polymeric ratios (FS) on the transcellular behavior of FS/PMMs was explored and the single pass intestinal perfusion experiment was used to further illustrate it. Moreover, pharmacokinetics parameters were detected to analyze the relationship among FS ratios, transport behavior, and pharmacokinetic parameters. FS ratios were found to hardly affect the endocytosis pathways and intracellular itinerary of FS/PMMs, but do affect the proportion of each path. FS/PMMs with high HS15 content, namely System-I, were found to primarily undergo receptor-mediated endocytosis pathway and be less susceptible to lysosomal degradation, which would lead to more absorption and higher Cmax and AUC than drug suspension. In contrast, despite System-II with high F127 content cannot contribute to drug plasma concentration, it can prolong the in vivo retention time. These findings provided evidence for the role of polymeric ratios in modulating the transcellular absorption and pharmacokinetic parameters of the drug-loaded PMMs, and would be a step forward in helping PMMs’ design to enhance oral drug delivery. Graphical Abstract
研究领域:
药学
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药物递送系统
·
药理学
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生物药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）