Nanoscale
·
2015
·Vol. 8
·期 1
·283-291
·
IF 7.394
Haijie Han,Haibo Wang,Yangjun Chen,Zuhong Li,Yin Wang,Qiao Jin,Jian Ji
A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and “click” reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy.
研究领域:
药学
·
癌症治疗
·
纳米技术
·
生物医学工程
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DOI
PubMed
高影响因子
Iranian Journal of Basic Medical Sciences
·
2022
·
IF 2.532
Hongxia Wang,Zhiyu Shao,Zhiwen Xu,Binghao Ye,Ming Li,Qiaoqiao Zheng,Xingyuan Ma,Ping Shi
Objective(s): Gemcitabine is a first-line drug for the treatment of bladder cancer. One of the most important mechanisms of gemcitabine resistance is the low expression of cellular membrane transporter hENT1. Various derivatives containing fatty acid side chains have been developed in order to facilitate gemcitabine uptake and prolong its retention in cells, such as CP-4126. In this study, the anti-tumor effect and mechanism of a new derivative of gemcitabine named SZY-200 on bladder cancer cells were investigated. SZY-200 was assembled from the gemcitabine-lauric acid conjugate. Materials and Methods: Antiproliferative activities of SZY-200 and lauric acid were evaluated using CCK-8 assay and clonogenic survival assay. The hENT1 inhibitor NBMPR was employed to determine the role of hENT1 in the apoptotic activity of GEM, CP-4126, and SZY-200. RT-qPCR, flow cytometry, fluorescence microscope, western blotting, and wound healing assay were used to study the mechanisms of SZY-200. The target genes were predicted using the BATMAN-TCM database. Results: Our data showed that SZY-200 could inhibit the proliferation of bladder cancer cells by inducing cell cycle arrest and apoptosis. The inhibitory effects were comparable to gemcitabine and CP-4126. SZY-200 does not rely on hENT1 to help it enter bladder cancer cells. Also, we found that lauric acid could inhibit the proliferation of bladder cancer cells. SZY-200 could down-regulate the expressions of PPARG and PTGS2 which were related to the occurrence and development of bladder cancer. Conclusion: SZY-200 has the same or more advantages as CP-4126 and could be an ideal candidate drug for further in vivo investigation.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Zhuo Yao,Qida Hu,Piaopiao Jin,Bowen Li,Yong Huang,Fu Zhang,Meng Wang,Junming Huang,Jing Huang,Shiyi Shao,Xinyu Zhao,Yuan Ping,Tingbo Liang
Gemcitabine (GEM), as a first-line chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment, still faces several clinical challenges, restricted by instability in blood circulations, low tumor selectivity, and acquired nature characteristics of chemo-resistance. To solve these challenges, the rational design of combination therapy with GEM and other therapy modalities is imperative. Herein, a small molecular self-assembly nano-prodrug is developed, which can achieve the co-delivery of GEM, Ferrocene and nutlin-3a on the achievement of GEM-induced apoptosis with ferroptosis. In this nano-prodrug, the disulfide linkage not only acts as a GSH-responsive trigger but also plays an important role in self-assembly behavior of nanoparticle that can load nutlin-3a. Interestingly, nutlin-3a plays an important role in both ferroptosis and apoptosis, one is effectively sensitized cells to ferroptosis by inhibiting cystine uptake, and the other is promoted apoptosis by elevating p53 expression. To further enhance the drug tumor accumulation and maintain stability in systemic circulations, this nano-prodrug is then encapsulated into plectin1 receptor-targeting phospholipid micelles (DSPE-PEG-PTP), which displays high selective tumor inhibition and good biosafety on different mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The findings provide new insights into the combination therapy of GEM with ferroptosis for reduced chemo-resistance on PDAC treatment.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Peng Hong,Mengshuo Wu,Xingchuan Wei,Xuetao Xu,Panpan Wu,Lishe Gan,Rihui Wu,Jingwei Jin,Kun Zhang,Dongli Li,Min Chen,Wingleung Wong,Wenfeng Liu,Xi Zheng
Gemcitabine ( GEM ) is a standard chemotherapeutic agent for patients with pancreatic cancer; however, GEM -based chemotherapy has a high rate of toxicity. A combination of GEM and active constituents from natural products may enhance its therapeutic efficacy and reduce its toxicity. This study investigated the synergistic effects of the combination of liriopesides B (LirB) from Liriope spicata var. prolifera and GEM on human pancreatic cancer cells. The results of our study showed that the combination of LirB and GEM synergistically decreased the viability of pancreatic cancer cells. The combination also caused a strong increase in apoptosis and a strong decrease in cell migration and invasion. Furthermore, LirB combined with GEM had potent inhibitory effects on pancreatic cancer stem cells (CSCs). Studies on the mechanisms of action showed that the combination more potently inhibited protein kinase B (Akt) and nuclear factor kappa B (NF-κB), as well as the downstream antiapoptotic molecules B-cell lymphoma 2 (Bcl-2) and survivin than either agent used alone. The results of this study suggest that the combination of LirB with GEM may improve the efficacy of GEM for the treatment of pancreatic cancer.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Yijing Zhang,Han Gao,Aiwen Tang,Haiwen Lyu,Zongmin Fan,Jiahui Guo,Yuzhi Wang,Hairong Yi,Qihao Pan,Haidan Luo,Baifu Qin,Boyu Zhang,Xiangqi Meng,Qingxin Liu,Mong-Hong Lee
Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer with poor prognosis. COP9 signalosome subunit 6 (CSN6), a key regulator of different E3 ubiquitin ligases, plays oncogenic roles in various cancers. However, its function in PDAC remains elusive. Here, this demonstrates that human PDAC tumors expressing high levels of CSN6 present with poor prognosis and gemcitabine resistance. Conditional knockout (KO) of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model. Proteomic analysis indicates that CSN6 promotes ribosome biogenesis by activating rDNA transcription and protein synthesis. Mechanistically, CSN6 antagonizes DDB1-CUL4 associated factor 1 (DCAF1)-mediated ubiquitination of Nucleophosmin (NPM1), thereby promoting NPM1-orchestrated ribosome biogenesis. In line with CSN6-mediated gemcitabine resistance, CSN6-NPM1 axis enhances ribosome biogenesis, thereby promoting translation of gemcitabine resistance genes, including Cytidine deaminase (CDA), Ribonucleotide reductase subunit M1/2 (RRM1/2). Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high pancreatic cancer xenografts. Clinically, CSN6 expression positively correlates with NPM1 in PDAC tissues, and their concurrent high expression is significantly associated with poor clinical outcomes. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2021
·
IF 3.517
Xue Li,Shuxin Xu,Haojiang Wang,Anjie Dong
For the past few years, organic-inorganic hybrid nanocarriers have been widely explored for effective drug delivery and preferable disease treatments. In this article, hydrothermal method was utilized to prepare fine dispersed layered double hydroxide (Mg-Al LDH) suspension. Polyethylene glycol (PEG) was grafted on the surface of LDH lamella in order to improve the dispersibility of LDH. Besides, the anti-cancer drug gemcitabine was grafted on the surface of LDH lamellas through chemical grafting. Hence a novel new type of organic-inorganic hybrid drug delivery system LDH-mPEG-Gemcitabine was obtained. In addition, the siRNA was intercalated into the LDH interlamination by ion exchange method to realize drug and gene co-delivery. The loading capacity of LDH and LDH-mPEG-Gemcitabine was evaluated by agarose gel electrophoresis. The characterization by laser particle size analyzer, TEM, FT-IR, XRD, in vitro cell viability and in vitro drug release demonstrated that LDH-mPEG-Gemcitabine possessed fine dispersibility, uniform morphology and particle size, fine biocompatibility, ideal drug loading and releasing capacity and held great potential to be used as a desired co-delivery system for drug and gene.
研究领域:
药剂学
·
生物材料学
·
纳米医学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2020
·
IF 2.734
Nan Zhang,Jing Zhang,Baocheng Tian,Keke Li,Baohuan Wu,Jingtian Han
CD44 play a pivotal role in tumor progression and metastasis. Targeting CD44 expressing cells using hyaluronic acid (HA) is a promising approach in the treatment of many types of tumors. Here, CD44-targeted conjugate was introduced by hyaluronic acid-deoxycholic acid (HA-DOCA) through the connection of the ester bond. Hydrophilic drug Gemcitabine (GEM) and hydrophobic DOCA are linked by the amide linkage. The DOCA-GEM was mixed with HA-DOCA to form mixed micelles (MMs) with low critical micelle concentration . Dynamic laser light scattering and transmission electron microscope measurements revealed that HA-DOCA/DOCA-GEM MMs displayed sphericity, with an average diameter of 149 ± 3 nm, and negative zeta potential . Hemolysis and cytotoxicity studies confirmed the safety of the HA-DOCA conjugate. The in vitro drug release was investigated, demonstrating that the intracellular-mimicking microenvironment could accelerated the GEM release of the HA-DOCA/DOCA-GEM MMs. The HA-DOCA/DOCA-GEM MMs showed higher cellular uptake efficiency by MCF-7 cells according to confocal laser scanning microscopy and flow cytometry, therefore achieving much stronger anticancer efficacy than free GEM and DOCA-GEM micelles. Our results suggest that HA-DOCA/DOCA-GEM MMs might be a potential candidate for cancer therapy.
研究领域:
药剂学
·
肿瘤学
·
生物医学工程
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DOI
高影响因子
CHEMICAL PAPERS
·
2026
·
IF 2.7
Weng Xuling,Guo Fang,Zhong Yu,Feng Wanyun,Shang Xiaoqiang,Chen Yufeng
A drug delivery system based on magadiite for gemcitabine (namely GEM-Mag) has been constructed by protonation, intercalation with tetrabutylammonium ions (TBA + ), and ion exchange. Various measurements were used to characterize the samples. XRD results showed that the basal spacing of Na-magadiite (15.17 Å) decreased to 11.40 Å after protonation. Following intercalation with TBA + , the basal spacing increased to 25.79 Å. After further ion exchange with the positively charged GEM, the basal spacing reduced to 18.21 Å. FT-IR and TG-DTG indicated that the GEM was incorporated into the magadiite. Based on CHN elemental analysis and EDS results, the chemical formula of GEM-Mag was estimated to be H 1.59 (C 9 H 12 F 2 N 3 O 4 ) 0.41 Si 14 O 29 ·2.33H 2 O. According to the chemical formula, the loading capacity of GEM-Mag for GEM was 10.74%. Drug release tests were carried out either in phosphate buffered solution (PBS, pH = 7.40) or in HCl solution (pH = 1.35). Results revealed that the GEM-Mag exhibited sustained-release of GEM. While the drug released for 96 h in the PBS, the cumulative release percentage of GEM from drug delivery system was only 53.46%; whereas in the HCl solution (pH = 1.35), the cumulative release percentage was 52.15% after 700 min. Cytotoxicity assay confirmed that the magadiite-based drug delivery system for GEM exhibited stronger inhibitory effects on HepG2 cells compared with that of the free GEM. In addition, the drug-loading process and mechanisms have been discussed in detail.
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DOI
高影响因子
BIOMATERIALS
·
2026
·
IF 13.6
Ziyao Zhang,Fangming Zhang,Wangting Yang,Jingxia Xu,Zhuyuan Peng,Xinyu Zhao,Yen Wei,Guofeng Li,Wensheng Xie,Xing Wang
Pancreatic cancer has a dismal five-year survival rate of only ∼13%, owing to its insidious onset, rapid progression, and frequent primary or acquired resistance to gemcitabine (Gm). Moreover, intratumoral bacteria capable of expressing cytidine deaminase (CDD) can undermine the therapeutic efficacy of Gm and contribute to chemoresistance. To address this challenge, antibiotic-drug conjugates (AiDCs, Tob-SS-Gm NPs) were developed by covalently linking tobramycin (Tob) and Gm via disulfide bonds. Tob-SS-Gm NPs retained antibacterial activity against E. coli and chemotherapeutic activity in Panc02 cells, indicating that the conjugation preserves the functional properties of both components. Meanwhile, disulfide linkage enables these AiDCs to remain stable under physiological conditions while undergoing cleavage in the high GSH tumor microenvironment, thereby releasing Tob and Gm for coordinated antibacterial and antitumor effects. In vivo evaluation demonstrated that Tob-SS-Gm NPs effectively reduced intratumoral bacterial burden and were associated with improved therapeutic response to Gm under bacteria-colonized tumor conditions. Furthermore, bacterial elimination and tumor cell damage were accompanied by modulation of the tumor immune microenvironment, including enhanced dendritic cell maturation and increased cytotoxic CD8 + T-cell infiltration. Collectively, this AiDCs strategy provides a promising approach for the treatment of intratumoral bacteria-associated, drug-resistant malignancies.
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Jing Gong,Chengjiang Fan,Jianing Chen,Shuhui Xu,Haizhong Jiang,Desen Sun,Qiang Chen,Qi Liao,Yang Xi
Colorectal cancer (CRC) remains one of the most prevalent and malignant cancers worldwide. Although various therapeutic strategies have been developed, CRC patients often exhibit poor responses. The combination of chemotherapy with immune checkpoint inhibitors represents a promising new treatment approach. However, pervasive drug resistance and significant interindividual variability in treatment efficacy remain major challenges, highlighting the urgent need to elucidate the underlying molecular mechanisms for improved therapy. In this study, we demonstrated that gemcitabine (GEM) exerts therapeutic effects against CRC. Notably, when combined with an anti-PD-L1 immune checkpoint inhibitor, GEM synergistically enhanced antitumor immunity, as evidenced by an increased infiltration of CD8 + T cells. Additionally, the population of anti-tumor IFN-γ and TNF-α-producing CD8 + T cells was elevated. We also observed significantly upregulated PD-L1 expression in both human and mouse CRC cell lines (HCT116, MC38, and CT26) following GEM treatment, which was further confirmed at the cell surface level. Mechanistically, GEM was found to stimulate lactate metabolism and promote lactylation of the PD-L1 protein, which could be reversed by inhibiting lactate dehydrogenase or pyruvate kinase. Furthermore, GEM delayed the degradation of PD-L1 protein confirmed by cycloheximide treatment. In addition, we also identified increased lactylation of H3 upon GEM treatment, suggesting transcriptional activation of PD-L1. Together, our findings provide novel insights into the mechanism of GEM in CRC treatment and support the future development of combined chemo-immunotherapeutic strategies.
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DOI
PubMed
高影响因子
Small
·
2025
·
IF 12.1
Qida Hu,Fu Zhang,Bowen Li,Piaopiao Jin,Junming Huang,Zhuo Yao,Xinyu Zhao,Shiyi Shao,Meng Wang,Yuan Ping,Tingbo Liang
The desmoplastic nature characterized by dense tissue and poor vascular conditions in pancreatic cancer (PDAC) poses a significant barrier to effective chemotherapy. Targeting the extracellular matrix and reducing desmoplasia in the tumor microenvironment is a rational approach to improve the penetration and efficacy of gemcitabine (GEM) in PDAC. Herein, a small molecular self-assembly nano-prodrug is developed for the “three-in-one” co-delivery of GEM chemotherapeutics, all-trans retinoic acid (ATRA), and nitric oxide (NO) donors, decorated with PDAC-homing targeting peptide. Stimulated by the PDAC microenvironment, the nano-prodrug releases ATRA that quiesces activated pancreatic stellate cells to alleviate stromal desmoplasia. Simultaneously, it generates abundant NO to induce a vasodilatory effect as well as a “nanomotor” effect. This combinational nano-prodrug delivery strategy, with a dual enhancement of drug penetration dynamics, effectively improves the distribution and bioavailability of the co-delivered GEM into the deep and dense pancreatic tumor tissue, which leads to significant amplification of tumor growth inhibition in different PDAC mouse models.
研究领域:
肿瘤学
·
药剂学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jiayu Guo,Xiaoxiao Zhang,Fudan Dong,Simeng Wang,Danping Wang,Yaqiao Li,Shiyi Zuo,Qing Wang,Wenxiao Li,Jin Sun,Zhonggui He,Tianhong Zhang,Qikun Jiang,Bingjun Sun
Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine ( GEM ) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.
研究领域:
药学
·
纳米医学
·
肿瘤学
✓ 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）