ACS Nano
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2023
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IF 17.1
Wenqing Zang,Duo Gao,Miaorong Yu,Manmei Long,Zhuan Zhang,Tianhai Ji
The clinical utility of gemcitabine, an antimetabolite antineoplastic agent applied in various chemotherapy treatments, is limited due to the required intravenous injection. Although chemical structure modifications of gemcitabine result in enhanced oral bioavailability, these modifications compromise complex synthetic routes and cause unexpected side effects. In this study, gemcitabine-loaded glycocholic acid-modified micelles (Gem-PPG) were prepared for enhanced oral chemotherapy. The in vitro transport pathway experiments revealed that intact Gem-PPG were transported across the intestinal epithelial monolayer via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway. In mice, the pharmacokinetic analyses demonstrated that the oral bioavailability of Gem-PPG approached 81%, compared to less than 20% for unmodified micelles. In addition, the antitumor activity of oral Gem-PPG (30 mg/kg, BIW) was superior to that of free drug injection (60 mg/kg, BIW) in the xenograft model. Moreover, the assessments of hematology, blood chemistry, and histology all indicated the hypotoxicity profile of the drug-loaded micelles.
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JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Xiaowei Wang,Hongwei Lu,Fang Luo,Dan Wang,Apeng Wang,Xuelei Wang,Wenkai Feng,Xiaobo Wang,Jiayi Su,Mingliang Liu,Guimin Xia
Gemcitabine (GEM) is a non-selective chemotherapeutic agent used in the treatment of pancreatic cancer . Its antitumor efficacy is limited by a short plasma half-life and severe adverse reactions. To overcome these shortcomings, four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes . Through optimization, dimyristoyl GEM (dmGEM)-loaded liposomes (LipodmGEM) were successfully obtained with an almost complete encapsulation efficiency. Compared to free GEM, LipodmGEM showed enhanced cellular uptake and cell apoptosis, improved inhibition of cell migration on AsPC-1 cells and a greatly extended half-life (7.22 vs. 1.78 h). LipodmGEM succeeded in enriching the drug in the tumor (5.28 vs. 0.03 μmol/g at 8 h), overcoming a major shortcoming of GEM, showed excellent anticancer efficacy in vivo and negligible systemic toxicity, superior to GEM. Attractive as well, suspensions of LipodmGEM remained stable at 2–10 °C away from light for no <2 years. Our results suggest that LipodmGEM might become of high interest for treating pancreatic cancer while the simple strategy we reported might be explored as well for converting other antitumor drugs with high water-solubility and short plasma half-life into attractive nanomedicines .
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Journal of Materials Chemistry B
·
2014
·Vol. 2
·期 38
·6560-6570
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IF 0
Haiqin Song,Haihua Xiao,Minhua Zheng,Ruogu Qi,Lesan Yan,Xiabin Jing
Anticancer drugs of gemcitabine and oxaliplatin combined in a clinic regimen (GEMOX regimen) were co-loaded to a biodegradable polymer platform for drug delivery.
研究领域:
药学
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肿瘤学
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WORLD JOURNAL OF GASTROENTEROLOGY
·
2019
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IF 3.411
Li Wei,Jing-Yun Wen,Jie Chen,Xiao-Kun Ma,Dong-Hao Wu,Zhan-Hong Chen,Jiang-Long Huang
BACKGROUND Pancreatic cancer is a major cause of cancer-related death, with a 5-year overall survival rate being below 5%. The main causes of poor prognosis in pancreatic cancer include easy metastasis, high recurrence rate, and robust drug resistance. Gemcitabine is a first-line drug for patients with unresectable pancreatic cancer. However, due to drug resistance, the clinical effect is not satisfactory. ADAM28 is reported as a tumor promoter in some cancers, but its role in pancreatic cancer and gemcitabine chemoresistance in pancreatic cancer has not been elucidated. AIM To identify if ADAM28 can act as an important target to reverse the gemcitabine drug resistance in pancreatic cancer. METHODS RNA-sequence analysis was applied to explore the potential targets involved in the gemcitabine of pancreatic cancer. SW1990 pancreatic cancer cells were treated with an increased dose of gemcitabine, and the mRNA levels of ADAM28 were evaluated by RT-PCR. The protein and mRNA levels of ADAM28 were confirmed in the gemcitabine resistant and parallel SW1990 cells. The ADAM28 expression was also assessed in TCGA and GEO databases, and the results were confirmed in the collected tumor and adjacent normal tissues. The overall survival (OS) rate and relapse-free survival (RFS) rate of pancreatic cancer patients with high ADAM28 level and low ADAM28 level in TCGA were evaluated with Kaplan-Meier Plotter. Furthermore, the OS rate was calculated in pancreatic cancer patients with high tumor mutation burden (TMB) and low TMB. CCK-8 assay was used to examine the effect of ADAM28 on the viability of SW1990 cells. The ADAM28 and its co-expressed genes were analyzed in the cBioPortal for cancer genomics and subjected to GSEA pathway analysis. The correlations of ADAM28 with GSTP1, ABCC1, GSTM4, and BCL2 were analyzed based on TCGA data on pancreatic cancer. RESULTS RNA-sequence analysis identified that ADAM28 was overexpressed in gemcitabine-resistant cells, and gemcitabine treatment could induce the expression of ADAM28. The mRNA and protein levels of ADAM28 were elevated in gemcitabine-resistant SW1990 cells compared with parallel cells. Also, the expression of ADAM28 was upregulated in pancreatic tumor tissues against normal pancreatic tissues. Notably, ADAM28 was highly expressed in the classical type than in the basal tumor type. Furthermore, the high expression of ADAM28 was associated with low OS and RFS rates. Interestingly, the high levels of ADAM28 was associated with a significantly lower OS rate in the high TMB patients, but not in the low TMB patients. Moreover, overexpression of ADAM28 could reduce the cell viability inhibition by gemcitabine, and knockdown of ADAM28 could enhance the proliferation inhibition by gemcitabine. The GSEA analysis showed that ADAM28 was related to the regulation of drug metabolism, and ADAM28 was significantly positively correlated with GSTP1, ABCC1, GSTM4, and BCL2. CONCLUSION This study demonstrates that ADAM28 is overexpressed in pancreatic cancer, and closely involved in the regulation of gemcitabine resistance. Overexpression of ADAM28 is a novel prognostic biomarker in pancreatic cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症基因组学
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ADVANCED FUNCTIONAL MATERIALS
·
2024
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IF 18.5
Wen Pan,Yangyi Wang,Shaomin Tian,Xiaopeng Ma,Yuanzeng Min
Drug resistance presents a significant challenge in cancer treatment. By far, there is no effective method to solve this issue. Therapeutic cancer vaccine, which uses tumor antigens, e.g. neoantigens, to activate the hosts’ immune system to eliminate tumor cells, may be effective for overcoming tumor resistance. So, it is hypothesized that resistant tumors may have much more abundant tumor mutations in comparison to naive tumors, and the corresponding vaccine may overcome drug resistance. The proteomics data confirmes that cell lysates from resistant tumors to gemcitabine (GEM), a model drug, contain abundant tumor-associated antigens, tumor-specific antigens, damage-associated molecular patterns, and neoantigens, which can activate immune responses. Herein, to enhance antigen presentation, a mesoporous silicon nanovaccine is developed, which is loaded with antigens from GEM treated GEM-resistant triple-negative breast cancer 4T1 cells. When mice bearing GEM-resistant tumors are vaccinated, the nanovaccine displays efficacy against GEM-resistant tumors. Moreover, when combined with immunotherapy, the efficacy of the developed nanovaccine on GEM-resistant tumors are further improved by increasing intratumoral T-cell infiltrations. The work presents a new strategy for overcoming drug resistance using cancer nanovaccine, which broadens clinical application prospects.
研究领域:
肿瘤学
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药理学
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免疫学
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纳米技术
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癌症研究
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International Journal of Nanomedicine
·
2024
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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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高影响因子
Frontiers in Pharmacology
·
2026
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IF 5.4
Mengjie Gu,Yingxue Si,Kaizhi Luo,Chong Zhang,Tingting Xiong,Zhizhen Huang,Yijia Han,Xiaoli Zheng,Zejun Wang
Introduction Pancreatic cancer is a highly aggressive malignancy with a poor prognosis, largely owing to chemoresistance and frequent recurrence following gemcitabine-based therapy. This study investigated whether vortioxetine, a multimodal serotonin (5-HT) modulator, could enhance the antitumor efficacy of gemcitabine and explored the underlying molecular mechanisms. Methods The effects of vortioxetine alone and in combination with gemcitabine were evaluated in pancreatic cancer cells and xenograft models. Cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) were assessed using functional assays and relevant molecular markers. RNA sequencing was performed to identify potential molecular targets of vortioxetine, followed by molecular docking, thermal stability assays, and gene knockdown experiments for mechanistic validation. Results Vortioxetine significantly enhanced the inhibitory effects of gemcitabine on pancreatic cancer cell proliferation in vitro and tumor growth in xenograft models. The combination treatment markedly promoted apoptosis, as indicated by increased levels of cleaved poly(ADP-ribose) polymerase (PARP) and cleaved caspase-3. It also suppressed cancer cell migration and invasion and reversed EMT-related changes, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin and Snail. RNA sequencing identified monoamine oxidase B (MAOB; EC 1.4.3.4) as a potential molecular target associated with vortioxetine treatment, which was further supported by molecular docking and thermal stability assays. Moreover, MAOB knockdown phenocopied the effects of vortioxetine by enhancing gemcitabine sensitivity and suppressing EMT-associated phenotypes. Discussion Vortioxetine potentiates the antitumor efficacy of gemcitabine against pancreatic cancer, with its effects associated with reduced MAOB expression, enhanced apoptosis, and suppression of EMT. These findings support further investigation of vortioxetine combined with gemcitabine as a potential therapeutic strategy for overcoming chemoresistance in pancreatic cancer.
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JOURNAL OF CELLULAR BIOCHEMISTRY
·
2018
·Vol. 120
·期 1
·634-644
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IF 2.959
Shengcai Yang,Dawei Zhang,Na Shen,Guanyi Wang,Zhaohui Tang,Xuesi Chen
Ovarian cancer is the major cause of death in women gynecological malignancy and gemcitabine (GEM) is commonly used in related chemotherapy. However, more than 90% GEM is catalyzed into an inactive metabolite 2′-deoxy-2′,2′-difluorouridine by stromal and cellular cytidine deaminase (CDA). Dihydroartemisinin (DHA), which possesses an intramolecular endoperoxide bridge, could be activated by heme or ferrous iron to produce reactive oxygen species (ROS). The excess ROS generation will excite expression of heme oxygenase-1 and suppress CDA expression. Under low CDA expression, the inactivation of GEM is decreased in turn to exert excellent therapeutic efficiency. Herein, we first studied the ROS generation by DHA in vitro with A2780 cells by means of flow cytometry and confocal laser scanning microscopy. Furthermore, cytotoxicity assay in vitro showed that DHA + GEM had synergistic effect, with molar ratio of DHA and GEM at 10. Eventually, in A2780 ovarian cancer xenograft tumor model, DHA + GEM exhibited significant antitumor efficiency with lower blood toxicity than GEM alone. Noteworthy, the combination treatment group completely eliminated the tumors on day 14.
研究领域:
肿瘤学
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药理学
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分子生物学
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2015
·
IF 4.152
Yanfen Fang,Fang Du,Yanyun Xu,Haijing Meng,Jin Huang,Xiongwen Zhang,Wei Lu,Shiyuan Liu,Jiahui Yu
Gemcitabine, 2′,2′-difluoro-2′-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N 4 -amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N 4 -amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of −33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5 + cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC-3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity.
研究领域:
药理学
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肿瘤学
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纳米医学
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Nano Today
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2023
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IF 17.4
Yuehua Wang,Bingchen Zhang,Qiye Xi,Chaojie Chen,Zhenjie Wang,Fangzhou Li,Shengtao Wang,Wei Yang,Xing-Jie Liang,Zhiqiang Yu,Meng Yu
High-rate aerobic glycolysis and abnormal glutamine metabolism in tumor cells lead to their unlimited malignant proliferation and induce immune escape in the tumor microenvironment . In this study, the GLS1 inhibitor BPTES and the PDHC inhibitor CPI-613 were co-delivered by an ROS-sensitive GEM nano-prodrug (PD-G@BC), and a simultaneous inhibition of glycolysis and glutamine metabolism was achieved to deprive tumor cells of nutrient supply. In addition, this metabolism reprogramming effectively weakened the sources of glucose and glutamine in tumor cells, correspondingly thrived metabolism in antitumor immune cells , thereby increasing the intratumoral infiltration and functions of the immunogenic cells to alleviate the immunosuppressive responses. This multifunctional combination strategy will provide new insights into the design of synergistic cancer immunotherapy based on metabolic interventions.
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Nano Research
·
2024
·
IF 9.5
Hong Jiawei,Xian Shiyun,Zheng Shusen,Wang Hangxiang,Jiang Donghai
Resistance to gemcitabine in pancreatic cancer poses a significant clinical challenge. Further investigation is warranted to assess whether nano-formulation strategy can be employed to enhance the sensitivity of resistant strains to gemcitabine therapy. In this study, using gemcitabine-resistant pancreatic cancer cell lines, we examined the therapeutic potential of a gemcitabine nanodelivery platform and assessed the ability to overcome drug resistance against resistant strains. Silencing of human equilibrative nucleoside transporter 1 (hENT1) led to reduced cellular uptake of gemcitabine, resulting in chemoresistance in pancreatic cancer. Gemcitabine nanoparticles circumvented the entry blockade caused by hENT1 silencing through endocytosis. Nanoparticle entry via clathrin-mediated endocytosis increased intracellular gemcitabine accumulation in gemcitabine-resistant pancreatic cancer cells. Moreover, gemcitabine nanoparticles are preferential in vivo delivery to tumor tissues, likely due to the enhanced permeability and retention effect. In comparison to free gemcitabine, gemcitabine nanoparticles demonstrate a more pronounced cytotoxic effect on gemcitabine-resistant pancreatic cancer cells, with favorable biosafety. This study improved the efficacy of gemcitabine through nanotechnology, providing a novel strategy to address gemcitabine-resistant pancreatic cancer.
研究领域:
肿瘤学
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药学
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纳米技术
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RSC Advances
·
2026
·Vol. 16
·期 28
·25944-25963
·
IF 6.1
Fengbo Yu,Jingdan Cao,Xingjun Fan,Junxia Gao,Guifang Liu,Chonghuan Lin,Ying Zhu,Qiang Wang
To mitigate the dose-limiting toxicity of gemcitabine (GEM) in lung cancer therapy, we developed a targeted hyaluronic acid (HA)-based nanoplatform with sustained drug-release capabilities—GEM@HA-(HAP/PSI). The system consisted of a hydroxyapatite/polysuccinimide (HAP/PSI) composite core for efficient drug loading, with surface-conjugated HA serving as a CD44-targeting ligand. Following systematic optimization using response surface methodology, the resulting spherical nanoparticles (∼100–200 nm) exhibited pH-responsive drug release, good biocompatibility, and negligible hemolytic activity. In vitro studies using CD44-high A549 and CD44-low H358 cells confirmed that CD44-mediated active endocytosis was the predominant uptake pathway for the nanoplatform. Treatment with the optimized formulation (GEM@HA-(HAP/PSI)10) led to significantly greater cytotoxicity, inhibition of cell migration and colony formation, and apoptosis induction than treatment with a non-targeted control formulation. Importantly, in A549 xenograft mouse models, GEM@HA-(HAP/PSI)10 achieved superior tumor growth suppression relative to free GEM while also maintaining a favorable safety profile. Collectively, these findings indicate that the HA-targeted nanoplatform developed in this study enhances the precision and therapeutic efficacy of GEM delivery and holds promise for reducing its systemic toxicity.
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