JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2024
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IF 9.4
Ying Chen,Qiang Zhang,Jian Shen,Zhiran Liu,Xiaoyu Cui,Li Ma,Yuanyi Zheng,Longchen Wang,Tao Ying
Chemotherapy is the main clinical treatment for ovarian cancer, but still faces challenges of low drug targeting efficiency and insufficient drug permeability. Drug-loaded nanoparticle collectives, which are actuated by magnetic field, could be targeted to a designated location and achieve targeted drug delivery. In this work, we report a strategy that utilizes magnetic mesoporous silica nanoparticles loaded with cis -diaminodichloroplatinum (Fe 3 O 4 @SiO 2 -CDDP) for targeted delivery of chemotherapeutic drugs and enhances penetration into deep tumors. The Fe 3 O 4 @SiO 2 -CDDP collectives actively moved to the target tumor site, and this movement was regulated by a magnetic actuation system. Under the action of a torque-force hybrid magnetic field (TFMF), Fe 3 O 4 @SiO 2 -CDDP could further penetrate into the interior of tumors and achieve pH-responsive drug release in the tumor environment. The feasibility of this strategy was verified in three-dimensional cell spheres in vitro and in a tumor-bearing mouse model in vivo. This magnetically actuated nanoparticle collectives enhanced drug penetration strategy provides a new paradigm for targeted drug delivery and potentiated tumor therapy.
研究领域:
肿瘤学
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纳米技术
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药学
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生物医学工程
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DOI
PubMed
高影响因子
Anti-Cancer Agents in Medicinal Chemistry
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2024
·Vol. 24
·期 18
·1360-1370
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IF 2.6
Linjin Li,Chengpeng Li,Feilong Miao,Wu Chen,Xianghui Kong,Ruxian Ye,Feng Wang
Background Cisplatin is a key therapeutic agent for bladder cancer, yet the emergence of cisplatin resistance presents a significant clinical challenge. Objective This study aims to investigate the potential and mechanisms of cyclanoline (Cyc) in overcoming cisplatin resistance. Methods Cisplatin-resistant T24 and BIU-87 cell models (T24/DR and BIU-87/DR) were established by increasing gradual concentration. Western Blot (WB) assessed the phosphorylation of STAT3, JAK2, and JAK3. T24/DR and BIU-87/DR cell lines were treated with selective STAT3 phosphorylation modulators, and cell viability was evaluated by CCK-8. Cells were subjected to cisplatin, Cyc, or their combination. Immunofluorescence (IHC) examined p-STAT3 expression. Protein and mRNA levels of apoptosis-related and cell cycle-related factors were measured. Changes in proliferation, invasion, migration, apoptosis, and cell cycle were monitored. In vivo, subcutaneous tumor transplantation models in nude mice were established, assessing tumor volume and weight. Changes in bladder cancer tissues were observed through HE staining, and the p-STAT3 was assessed via WB and IHC. Results Cisplatin-resistant cell lines were successfully established, demonstrating increased phosphorylation of STAT3, JAK2, and JAK3. Cisplatin or Cyc treatment decreased p-STAT3, inhibited invasion and migration, and induced apoptosis and cell cycle arrest in the G0/G1 phase in vitro. In vivo, tumor growth was significantly suppressed, with extensive tumor cell death. IHC and WB consistently showed a substantial downregulation of STAT3 phosphorylation. These changes were more pronounced when cisplatin and Cyc were administered in combination. Conclusion Cyc reverses cisplatin resistance via JAK/STAT3 inhibition in bladder cancer, offering a potential clinical strategy to enhance cisplatin efficacy in treating bladder 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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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2018
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IF 3.909
Junqiang Qiu,Hua Zhang,Zhenyu Wang
The Auricularia auriculajudae polysaccharide-cisplatin complex (AAP-CDDP) was synthesized and characterized. The drug release, hemocompatibility, anti-tumor activity, and targeting ability of the complex were studied. The results of cell assay showed that the FA-AAP-CDDP complex showed better anti-tumor activity (IC 50 lower 49.5%), and displayed higher uptake rate (higher 2–11-fold) than the AAP-CDDP complex. In vivo experiments showed that the FA-AAP-CDDP complex had the same ability as free cisplatin to decrease subcutaneous tumor growth and reduce the level of serum tumor markers in nude mice. Meanwhile, western blotting analysis showed that the FA-AAP-CDDP complex induced apoptosis by activating Bax, Cytochrome- c , and Caspase-3, and downregulating Bcl-2, which suggested that the FA-AAP-CDDP complex may induce apoptosis through the endogenetic-mitochondrion signaling apoptosis pathways and intrinsic apoptotic pathways. In addition, the organ weights of FA-AAP-CDDP complex treated mice were significant higher than the cisplatin; and these mice had higher superoxide dismutase, catalase, and glutathione peroxidase activities, and less malondialdehyde in the serum. Thus, the FA-AAP-CDDP complex seems to be an effective, potential, and clinically feasible tumor cell-targeted preparation which shows a better clinical efficacy in treatment of cervical cancer, with improved quality of life, immune function and survival rate.
研究领域:
药理学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2026
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IF 8.1
Hanfei Xie,Wumin Dai,Lu Sun,Wangang Gong,Tao Zhu,Yingli Zhang
Ovarian cancer (OV) is a highly lethal gynecological tumor, often developing platinum chemotherapy resistance and treatment failure. With their diverse and complex structures, natural products offer potential solutions to drug resistance. This study systematically examines chaetocin's effects on cisplatin-resistant OV cells and its underlying molecular mechanisms. We utilized a cell counting Kit-8, transwell assays, flow cytometry, immunohistochemistry, and western blotting to evaluate chaetocin's effects on cisplatin-resistant OV cells. Proteomic analysis and bioinformatics were utilized to identify the molecular targets of chaetocin, which were validated via cell transfection and co-immunoprecipitation. Additionally, a cisplatin-resistant OV xenograft model was developed for in vivo studies. Chaetocin suppressed the malignancy of cisplatin-resistant OV cells in a dose-dependent manner to suppress cell proliferation, impede cell migration and invasion, and induce both cell apoptosis and cell cycle arrest. Furthermore, in vivo studies showed that chaetocin inhibited tumor growth in a cisplatin-resistant OV xenograft model. In terms of mechanism, chaetocin induced ferroptosis in these cells, inhibiting TFRC ubiquitination and upregulating its expression by reducing the levels of cullin1 and its neddylation binding (cullin1-NEDD8). Our study uncovers a previously unrecognized mechanism: Chaetocin induces ferroptosis by inhibiting TFRC neddylation to upregulate its expression in OV. Unlike its known role as an SUV39H1 inhibitor, chaetocin functions through the neddylation-TFRC-ferroptosis axis, a pathway not previously linked to this compound. Moreover, while neddylation has recently been reported to regulate ferroptosis via SLC7A11, our study reveals an entirely distinct mechanism involving TFRC-mediated iron transport. This epigenetic regulation stabilizes TFRC, sensitizing resistant cells to ferroptosis, providing a dual-mechanistic insight not found in existing literature. By linking chaetocin's gene regulation to iron-dependent cell death, we offer new insights and potential therapies for cisplatin-resistant OV.
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高影响因子
ACS Applied Materials & Interfaces
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2017
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IF 7.504
Haiqiu Wu,Haojie Jin,Cun Wang,Zihao Zhang,Haoyu Ruan,Luyan Sun,Chen Yang,Yongjing Li,Wenxin Qin,Changchun Wang
Combination chemotherapy has been proposed to achieve synergistic effect and minimize drug dose for cancer treatment in clinic application. In this article, the stimuli-responsive polymeric nanogels (<100 nm in size) based on poly(acrylic acid) were designed as codelivery system for doxorubicin and cisplatin to overcome drug resistance. By chelation, electrostatic interaction, and π–π stacking interactions, the nanogels could encapsulate doxorubicin and cisplatin with designed ratio and high capacity. Compared with free drugs, the nanogels could deliver more drugs into MCF-7/ADR cells. Significant accumulation in tumor tissues was observed in the biodistribution experiments. The in vitro antitumor studies demonstrated the superior cell-killing activity of the nanogel drug delivery system with a combination index of 0.84, which indicated the great synergistic effect. All the antitumor experimental data revealed that the combination therapy was effective for the multidrug-resistant MCF-7/ADR tumor with reduced side effects.
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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DOI
PubMed
高影响因子
PLoS One
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2017
·Vol. 12
·期 3
·e0173712
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IF 2.806
Xianzhi Qu,Jiyao Sheng,Luyan Shen,Jing Su,Yunjie Xu,Qi Xie,Yao Wu,Xuewen Zhang,Liankun Sun
The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma.
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
DYES AND PIGMENTS
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2017
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IF 3.473
Yanhua Lai,Ping Zhao,Zhan Zhang,Bai Li,Junchen Wu
The self-assembled peptide cargo carrier with the ability of probe offered an effective strategy to deliver and track the anticancer drug, cisplatin (DDP) in ovarian cancer cells. This simple peptide system containing a pyrene fluorogen and arginine-glycine-aspartic acid (RGD) sequence could be utilized to release DDP in situ by the specific recognition between an RGD motif and α v β 3 integrin that was over-expressed on ovarian cancer cells. Importantly, we found that the disassembly-triggered peptide nanofibers , PA1, could effectively combine with DDP and release DDP in the cytoplasm with the pyrene fluorescence restoring. Moreover, the peptide cargo carrier efficiently penetrated tumour cells for enhancing therapeutic efficacy. Our system could open the door for the delivery of anticancer drug in cancer-related therapy.
研究领域:
生物化学
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肿瘤学
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药物递送系统
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产品关联
DOI
高影响因子
International Journal of Nanomedicine
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2018
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IF 4.37
Xueling Wang,Yuming Chen,Yong Tao,Yunge Gao,Dehong Yu,Hao Wu
Background The delivery of treatment agents to inner ear with drug delivery system (DDS) has been under investigation to overcome the limitations of the conventional therapeutic agents in curing or alleviating the cisplatin ototoxicity. Methods In the present study, a novel targeted dexamethasone (DEX)-loaded DDS, A666-DEX-NP, was constructed for prevention from cisplatin-induced hearing loss. A666-(CLEPRWGFGWWLH) peptides specifically bind to prestin, which is limited to the outer hair cells (OHCs). HEI-OC1 and cisplatin-treated guinea pigs (12 mg/kg, intraperitoneal) were used as in vitro and in vivo models for investigating the targeting and protective efficiency against cisplatin. Results As expected, compared to A666-unconjugated nanoparticles (NP), A666-conjugated coumarin 6-labeled NP showed active targeting to OHCs. Furthermore, A666-coumarin 6-labeled NP could be significantly internalized by HEI-OC1 cells via the A666–prestin interaction. This facilitated the uptake of cells pretreated with A666-DEX-NP, followed by the cisplatin-treated group, which led to enhanced cell viability, reduced apoptotic properties, and decreased reactive oxygen species levels as compared to cells pretreated with DEX or DEX-NP, 4 hours in advance of cisplatin treatment. In cisplatin-treated guinea pigs, pretreatment with A666-DEX-NP effectively preserved OHCs and showed significant hearing protection at 4, 8, and 16 kHz as compared to pretreatment with saline, DEX, or DEX-NP formulation. Conclusion This OHC-targeting DDS provides a novel strategy for DEX application that can be potentially used to combat cisplatin ototoxicity.
研究领域:
药理学
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耳鼻喉科学
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纳米技术
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药物递送系统
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DOI
PubMed
高影响因子
BIOMACROMOLECULES
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2013
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IF 5.371
Yue Huang,Zhaohui Tang,Xuefei Zhang,Haiyang Yu,Hai Sun,Xuan Pang,Xuesi Chen
A series of pH-responsive random copolymer poly(l-glutamic acid-co-l-lysine) [P(Glu-co-Lys)] were synthesized through the ring-opening polymerization (ROP) of γ-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA) and 3-benzyloxycarbonyl-l-lysine N-carboxyanhydride (ZLys-NCA) and the subsequent deprotection. The chemical structure of the P(Glu-co-Lys)s was confirmed by NMR. Critical aggregation concentration and transmission electron microscopy measurements indicated that the P(Glu-co-Lys)s could self-assemble into aggregates in phosphate buffer. The surface charge of P(Glu-co-Lys) aggregates was greatly affected by the solution’s pH and l-glutamic acid/l-lysine ratio because the carboxyl and amino groups present on the P(Glu-co-Lys) aggregates could be protonated or deprotonated to become charged. The pH value of the solution at which the surface charge of the P(Glu-co-Lys) aggregates reversed could be manipulated by the feed ratio of BLG-NCA and ZLys-NCA. In vitro methyl thiazolyl tetrazolium assays demonstrated that negatively charged P(Glu-co-Lys)s were nontoxic and biocompatible. Positive charged P(Glu-co-Lys)s showed some cytotoxicity to Hela cells. Cisplatin (CDDP) was used as a model anticancer drug to evaluate the charge-reversal drug delivery system. By the manipulation of CDDP loading content, the surface charge of the CDDP/P(Glu-co-Lys) nanoparticles could be reversed to positive from negative at tumor extracellular pH (pHe 6.5–7.2). An enhanced drug uptake and inhibition of cancer cell proliferation were observed for the tumoral pHe triggered charge-reversal CDDP/P(Glu-co-Lys) drug delivery system. These indicated that the CDDP/P(Glu-co-Lys) nanoparticles could be used as intelligent drug delivery systems for cancer therapy.
研究领域:
药剂学
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生物材料
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肿瘤学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
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2017
·Vol. 38
·期 6
·3668-3676
·
IF 2.662
Yulin Jiang,Feihu Ji,Yifeng Liu,Mengjia He,Zhiqian Zhang,Junhong Yang,Nian Wang,Changli Zhong,Qianni Jin,Xiangsen Ye,Tingmei Chen
Breast cancer is a common cause of cancer‑related deaths in women. Treatment with cisplatin exhibits some therapeutic efficacy. However, treatment optimization is required, and the mechanisms underlying the cisplatin's proapoptotic effects remain unclear. In the present study, we demonstrated that cisplatin induced apoptosis and autophagy in breast cancer cells. Autophagy induced by cisplatin played a protective role in breast cancer cells, which impaired its proapoptotic effect. Mechanistically, for the first time, we found that cisplatin treatment activated the MAPK signaling pathway and promoted autophagy via the ERK signaling pathway. Notably, we found that nuclear translocation of yes-associated protein (YAP) was regulated by cisplatin-induced autophagy, and we identified YAP as a survival input that promoted survival in cisplatin-treated breast cancer cells. These findings revealed that administration of cisplatin along with an autophagy inhibitor is a promising therapeutic strategy for treating breast cancer.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
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IF 10.8
Xiaomei Liang,Yulu Yang,Chuanqing Huang,Zhibin Ye,Wujiang Lai,Jiamao Luo,Xiaoxuan Li,Xiao Yi,Jun-Bing Fan,Ying Wang,Yifeng Wang
Resistance to the chemotherapeutic agent cisplatin (DDP) is the primary reason for invalid chemotherapy of ovarian cancer. Given the complex mechanisms underlying chemo-resistance, the design of combination therapies based on blocking multiple mechanisms is a rationale to synergistically elevate therapeutic effect for effectively overcoming cancer chemo-resistance. Herein, we demonstrated a multifunctional nanoparticle ( [email protected] ), which could simultaneously co-deliver DDP and Olaparib (Ola, DNA damage repair inhibitor) using targeted ligand cRGD peptide modified with heparin (HR) as nanocarrier, enabling the concurrent tackling of multiple resistance mechanisms to effectively inhibit the growth and metastasis of DDP-resistant ovarian cancer. In combination strategy, heparin could suppress the function of multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) to promote the intracellular accumulation of DDP and Ola by specifically binding with heparanase (HPSE) to down-regulate PI3K/AKT/mTOR signaling pathway, and simultaneously served as a carrier combined with Ola to synergistically enhance the anti-proliferation ability of DDP for resistant ovarian cancer, thus achieving great therapeutic efficacy. Our [email protected] could provide a simple and multifunctional combination strategy to trigger an anticipated cascading effect, thus effectively overcoming the chemo-resistance of ovarian cancer.
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PubMed
高影响因子
Journal of Zhejiang University-SCIENCE B
·
2023
·Vol. 24
·期 3
·207-220
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IF 5.1
Yuan Meng,Wu Qian,Zhang Mingyang,Lai Minshan,Chen Wenbo,Yang Jianfeng,Jiang Li,Cao Ji
A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
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PubMed
高影响因子
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