JOURNAL OF VIROLOGY
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2024
·
IF 4
Qiankai Shi,Ran Zhao,Linna Chen,Tianyi Liu,Tao Di,Chunwei Zhang,Zhiying Zhang,Fangfang Wang,Zongxi Han,Junfeng Sun,Shengwang Liu
As an intrinsic cellular mechanism responsible for the internalization of extracellular ligands and membrane components, caveolae-mediated endocytosis (CavME) is also exploited by certain pathogens for endocytic entry [e.g., Newcastle disease virus (NDV) of paramyxovirus]. However, the molecular mechanisms of NDV-induced CavME remain poorly understood. Herein, we demonstrate that sialic acid-containing gangliosides, rather than glycoproteins, were utilized by NDV as receptors to initiate the endocytic entry of NDV into HD11 cells. The binding of NDV to gangliosides induced the activation of a non-receptor tyrosine kinase, Src, leading to the phosphorylation of caveolin-1 (Cav1) and dynamin-2 (Dyn2), which contributed to the endocytic entry of NDV. Moreover, an inoculation of cells with NDV-induced actin cytoskeletal rearrangement through Src to facilitate NDV entry via endocytosis and direct fusion with the plasma membrane. Subsequently, unique members of the Rho GTPases family, RhoA and Cdc42, were activated by NDV in a Src-dependent manner. Further analyses revealed that RhoA and Cdc42 regulated the activities of specific effectors, cofilin and myosin regulatory light chain 2, responsible for actin cytoskeleton rearrangement, through diverse intracellular signaling cascades. Taken together, our results suggest that an inoculation of NDV-induced Src-mediated cellular activation by binding to ganglioside receptors. This process orchestrated NDV endocytic entry by modulating the activities of caveolae-associated Cav1 and Dyn2, as well as specific Rho GTPases and downstream effectors.
研究领域:
病毒学
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细胞生物学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Nanomedicine
·
2019
·
IF 4.717
Xiao Wei,Rui Wei,Guiying Jiang,Yijuan Jia,Hua Lou,Zongyuan Yang,Danfeng Luo,Quanfu Huang,Sen Xu,Xin Yang,Ying Zhou,Xiaoting Li,Teng Ji,Junbo Hu,Ling Xi,Ding Ma,Fei Ye,Qinglei Gao
Aim: To investigate the influence of tissue mechanics on the cellular uptake efficiency of nanoparticles (NPs) in cancer. Materials & methods: Collagen-coated polyacrylamide gels were prepared as model substrates. Coumarin 6-loaded poly(lactic-co-glycolic) acid micelles (C6-NPs) were prepared to investigate the cellular uptake of NPs. Results: We demonstrated that substrate stiffness modulated the cellular uptake of NPs of cancer. Mechanistically, mechanical cues exerted influence on the clathrin-mediated endocytosis and caveolae-mediated endocytosis pathways, which mediated stiffness-regulated cellular uptake of NPs. Conclusion: Our findings shed light on the regulatory role of the mechanical cues on the cellular uptake of NPs and will facilitate the selection of clinical patients who might benefit from a given nanotherapy.
研究领域:
生物医学工程
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癌症研究
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纳米技术
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2014
·Vol. 4
·期 3
·413-419
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IF 4.88
Ye Tian,Man Wu,Xiangxiang Liu,Zhi Liu,Quan Zhou,Zhongwei Niu,Yong Huang
Viral nanoparticles have attracted extensive research interests in diverse applications of diagnosis and therapy. In particular, filamentous M13 bacteriophages have shown great potential in biomedical applications. However, its pathways entering into cells still remain unclear, and this greatly hinders its further use as a drug or gene carrier. Here, a ratiometric M13 pH probe is designed by conjugating two fluorescent dyes onto the surface of M13. Since the intensity ratio is not influenced by probe concentration, ion strength, temperature, photobleaching, and optical path length, this ratiometric probe can be used to investigate the intracellular pH map of M13. More importantly, the internalization mechanism of M13 can be elucidated. It is found that this filamentous phage shows great cell-type dependence in interaction with cells and internalization mechanism. The phage tends to be bounded on the cell membrane of only epithelial cells, not endothelial cells. Furthermore, the M13 phage enters into cells through endocytosis with specific mechanism: clathrin-mediated endocytosis and macropinocytosis for HeLa; vesicular transport, clathrin-mediated endocytosis, and macropinocytosis for MCF-7; caveolae-mediated endocytosis for human dermal microvascular endothelial cell (HDMEC). This work provides key notes for cancer diagnosis and therapy based on filamentous bacteriophage, especially for design of pH-sensitive drug delivery systems.
研究领域:
生物技术
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纳米技术
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细胞生物学
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药学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2020
·Vol. 12
·期 2
·167
·
IF 4.421
Yu Wang,Xu Bai,Bo Hu,Maochen Xing,Qi Cao,Aiguo Ji,Shuliang Song
Detailed knowledge of the intestinal transport of polymannuronic acid (PM) and polyguluronic acid (PG) is critical for understanding their biological activities. To investigate the transport in the gastrointestinal tract, PM and PG were chemically modified with tyramine and conjugated with fluorescein isothiocyanate (FITC) to synthesize FITC-PM (F-PM) and FITC-PG (F-PG) successfully. The transport mechanisms of F-PM and F-PG across the intestinal epithelial cell monolayers (Caco-2 cell monolayers) were then investigated. The results demonstrated that the transport of F-PM and F-PG into epithelial cells was time- and energy-dependent, which was mediated by the macropinocytosis pathway and the clathrin- and caveolae (or lipid raft)-mediated endocytic pathway. The transport process of F-PM and F-PG in Caco-2 cells depended on the acidification of endosomes and involved lysosomes. Tubulin mediated the transport of F-PM, but not of F-PG. Moreover, the absorption enhancer chitosan (CS) promoted the transport of F-PM and F-PG, increasing the apparent permeability coefficient (Papp) by 1.9-fold and 2.6-fold, respectively, by reversibly opening the tight junction (TJ). In summary, this study provided a comprehensive understanding of the transport of PM and PG in the small intestinal epithelial cells, which will provide a theoretical basis for the development of PM and PG with good intestinal absorption.Keywords:polymannuronic acid;polyguluronic acid;transport mechanisms;Caco-2 cell monolayers
研究领域:
药理学
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生物药剂学
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细胞生物学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2022
·
IF 5.395
Chunlu Wang,Yaoyao Zheng,Yaxin Zheng,Can Wu,Xiujie Wang,Menghua Huang,Xiaoxing Wu,Wenying Zhong,Keming Xu
Non-steroidal anti-inflammatory drugs (NSAIDs) have drawn considerable attention in the field of cancer treatment, yet these drugs display limited potency and selectivity against cancer cells. To address these problems, we designed a peptide-based self-delivery system [Indomethacin-Phe-Phe-Tyr (H2PO3)-Ser-Val, IDM-FFpYSV] that combines an NSAID molecule (indomethacin, or IDM) and a segment of anticancer tripeptide (tyroservatide, or YSV). IDM-FFpYSV is capable of self-assembling in an aqueous solution to afford nanofibrillar hydrogels under the catalysis of alkaline phosphatases (ALPs), which are overexpressed on the plasma membrane of cancer cells. The IDM-FFpYSV + ALP hydrogel displays a continuous release profile of peptide drugs, whereas a solution mixture of pure drugs (IDM-OH + pYSV + ALP) shows burst release of drug moieties. The treatment of IDM-FFpYSV selectively inhibits the proliferation of HeLa cells in vitro, with precise regulations of intracellular targeting proteins (COX-2 and AC-H3). The enhanced potency and selectivity of IDM-FFpYSV are found to be attributed to enhanced cellular uptake of peptide drugs, which involves a caveolae-mediated endocytosis pathway. Furthermore, intravenous administration of the IDM-FFpYSV formulation significantly inhibits the tumor growth in a HeLa-xenografted mouse model, whereas treatment of solution mixtures of pure drugs (IDM-OH + pYSV) fails to do so. Taken together, the study provides a viable strategy to augment anticancer efficacies of self-delivery system through molecular integration of multiple anticancer elements with an enzyme-instructed self-assembly process.
研究领域:
药物科学
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癌症研究
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纳米技术
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Dan Wang,Xiaobo Wang,Yan Li,Xiaowei Wang,Xuelei Wang,Jiayi Su,Apeng Wang,Kai Lv,Mingliang Liu,Guimin Xia
Background Gemcitabine (Gem) is one of the first-line chemotherapy drugs for pancreatic cancer treatment. However, its short half-life in plasma and adverse effects limited its broader application.Methods A novel Gem derivative (N4-tetradecyloxycarbonyl gemcitabine, tcGem) was synthesized and encapsulated into liposomes (LipotcGem) to overcome the above shortcomings.Results LipotcGem has been successfully formulated, with the average size of 115 nm, zeta potential values of −36 mV, encapsulation efficiency of up to 98%, and drug loading capacity of 8.1%. Compared to Gem, LipotcGem improved in vitro antitumor activity significantly, as evidenced by the lower IC50, the higher percentage of apoptotic cells, the stronger ability to inhibit cell migration and invasion due to the higher cellular accumulation (100 times). Additionally, the endocytosis of LipotcGem was mainly mediated by caveolae, and was then processed in the lysosome, where tcGem was released and hydrolyzed into Gem. LipotcGem inhibited tumor growth by 70% in subcutaneous xenograft model and 90% in orthotopic xenograft model, respectively. LipotcGem suppressed tumor metastasis and prolonged survival without perceptible systemic toxicity, which may be caused by the longer t1/2 in vivo (3.5 times, 5.23 vs 1.46 h) and more enrichment in tumor tissue (750 times).Conclusion LipotcGem significantly increased the anti-tumor efficiency and decreased the toxicity for chemotherapy of pancreatic cancer.
研究领域:
肿瘤学
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药学
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药物递送系统
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癌症研究
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产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2021
·
IF 9.381
Yu Zhang,Junxi Liu,Pengfei Dou,Zhijing Wu,Ziming Zheng,Xianglin Pan,Tao Zhou,Kaiping Wang
The elucidation of the oral absorption of natural polysaccharides contributes to their further research and utilization. Herein, to explore the absorption of a pectin-type polysaccharide from Smilax china L. (SCLP), SCLP was respectively fluorescently labeled with fluorescein-5-thioicarbazide (FSCLP) and Cyanine7 amine (Cy7-SCLP) for in vitro and in vivo tracking. The near-infrared imaging demonstrated that Cy7-SCLP was absorbable in the small intestine and distributed in the liver and kidney after oral administration. Subsequently, in vitro intestinal epithelial tissue experiments showed that the jejunum was the dominant site of FSCLP transport. Further transport studies in the Caco-2 cell monolayer illustrated that FSCLP was delivered across the monolayer via transcellular transport by caveolae-mediated endocytosis and macropinocytosis together with paracellular transport by reversibly affecting tight junctions. In summary, this work presents the oral absorption characteristics and mechanisms of SCLP through the intestinal epithelium, which will facilitate the further development of SCLP and pectin polysaccharides.
研究领域:
药理学
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营养学
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生物学
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生物技术
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药剂学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2020
·
IF 4.845
Ruoning Wang,Xin Wang,Xiaoshun Jia,Honglan Wang,Wen Li,Junsong Li
To evaluate the effect of particle size on the cellular internalization, tissue distribution, and bioavailability of betulinic acid nanosuspensions (BA/NSs) and further investigate the combined effect of BA/NSs and Taxol® on breast cancer, BA/NSs with different particle sizes (160 nm, 400 nm, and 700 nm) were prepared by an efficient universal green technology. The use of BA/NS (160 nm) was more likely to increase the BA release rate and enhance bioavailability compared with the use of larger size particles. BA/NSs were internalized by 4T1 cells in different ways, including clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis. For the 4T1 orthotopic tumor model, BA/NS (160 nm) showed a tendency to accumulate at a higher level in tumor tissue. Moreover, combination therapy with BA/NSs and Taxol® showed remarkable potential to enhance antitumor activity in vitro and in vivo . The cytotoxicity and apoptotic ability of the different preparations decreased in the following order: BA/NS (160 nm) + Taxol®, BA/NS (400 nm) + Taxol®, and BA/NS (700 nm) + Taxol®. The tumor inhibition rates of BA/NSs (160 nm, 400 nm, and 700 nm) combined with Taxol® were 2.35-, 1.74- and 1.12-fold higher than that of free BA, respectively. The combined chemotherapy showed good safety, indicating that it had the effect of enhancing treatment and reducing toxicity.
研究领域:
药学
·
肿瘤学
·
纳米技术
·
生物药剂学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2011
·
IF 7.883
Yun Jin,Yupin Song,Xi Zhu,Dan Zhou,Chunhui Chen,Zhirong Zhang,Yuan Huang
The present study was to demonstrate the effects of goblet cell-targeting nanoparticles on the oral absorption of insulin in vitro , ex vivo and in vivo , and identify the targeting mechanism as well as the influence of mucus. The insulin loaded nanoparticles were prepared using trimethyl chitosan chloride (TMC) modified with a CSKSSDYQC (CSK) targeting peptide. Compared with unmodified nanoparticles, the CSK peptide modification could facilitate the uptake of nanoparticles in villi, enhance the permeation of drugs across the epithelium, meanwhile, induce a significantly higher internalization of drugs via clathrin and caveolae mediated endocytosis on goblet cell-like HT29-MTX cells. In transport studies across Caco-2/HT29-MTX co-cultured cell monolayer (simulating intestinal epithelium), the CSK peptide modification also showed enhanced transport ability, even if the targeting recognition was partially affected by mucus. Moreover, it was found the existence of mucus was propitious to the transport of insulin from both modified and unmodified nanoparticles. In the pharmacological and pharmacokinetic studies in diabetic rats, the orally administrated CSK peptide modified nanoparticles produced a better hypoglycemic effect with a 1.5-fold higher relative bioavailability compared with unmodified ones. In conclusion, CSK peptide modified TMC nanoparticles showed sufficient effectiveness as goblet cell-targeting nanocarriers for oral delivery of insulin.
研究领域:
药学科学
·
纳米技术
·
药物递送系统
·
糖尿病研究
✓ 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）