PLoS One
·
2011
·Vol. 6
·期 9
·e25433
·
IF 4.411
Lihua Cheng,Chengmeng Jin,Wen Lv,Qiuping Ding,Xu Han
Background
Cisplatin is a potent anticancer drug, but its clinical application has been limited due to its undesirable physicochemical characteristics and severe side effects. Better drug formulations for cisplatin are highly desired.
Methodology/Principal Findings
Herein, we have developed a nanoparticle formulation for cisplatin with high encapsulation efficiency and reduced toxicity by using cisplatin-crosslinked carboxymethyl cellulose (CMC) core nanoparticles made from poly(lactide-co-glycolide)-monomethoxy-poly(polyethylene glycol) copolymers (PLGA-mPEG). The nanoparticles have an average diameter of approximately 80 nm measured by transmission electron microscope (TEM). The encapsulation efficiency of cisplatin in the nanoparticles is up to 72%. Meanwhile, we have also observed a controlled release of cisplatin in a sustained manner and dose-dependent treatment efficacy of cisplatin-loaded nanoparticles against IGROV1-CP cells. Moreover, the median lethal dose (LD 50 ) of the cisplatin-loaded nanoparticles was more than 100 mg/kg by intravenous administration, which was much higher than that of free cisplatin.
Conclusion
This developed cisplatin-loaded nanoparticle is a promising formulation for the delivery of cisplatin, which will be an effective therapeutic regimen of ovarian cancer without severe side effects and cumulative toxicity.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
·
IF 5.6
Sichen Li,Difei Zhang,Yi Li,Jingjing Zhou,Jinghua Chen,Yan Zhang
Cisplatin (CDDP) as a first-line chemotherapy drug has long suffered drawbacks of severe side effects and poor pharmacokinetics. Thus, various nano-carriers of complex architectures and multi-step modifications have been developed to overcome these challenges, but a simple delivery system with integrated multi-functions is still in demand. Herein, we synthesized a new type of glyco-based triple hydrophilic block copolymers for the delivery of CDDP and thereof cancer therapy. The incorporated glucuronic acid part is complexed with CDDP with high entrapment efficiency, while providing pH-responsive release in the acidic tumor microenvironment. The galactose segment is implanted for liver-targeting effect, which can also significantly lower the side effects of CDDP. As a result, the CDDP-loaded nanoparticle PGG2/Pt showed selectively faster endocytosis rates into HepG2 cells in vitro, with the calculated IC 50 value even comparable to that of free CDDP. The in vivo experiments on a HepG2-bearing mouse model, PGG2/Pt showed excellent anti-tumor activity and enhanced drug accumulation on tumor, together with much lowered nephrotoxicity, hepatotoxicity, and splenic toxicity. This work provides a new strategy for CDDP delivery with higher loading efficiency as well as biosafety.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Borui Zhao,Xuan Qin,Rui Fu,Maosen Yang,Xin Hu,Shaorong Zhao,Yange Cui,Qingxiang Guo,Wei Zhou
Chemoresistance to cisplatin remains a significant challenge affecting the prognosis of advanced oral squamous cell carcinoma (OSCC). However, the specific biomarkers and underlying mechanisms responsible for cisplatin resistance remain elusive. Through comprehensive bioinformatic analyses, we identified a potential biomarker, BCL2 associated athanogene-1 (BAG1), showing elevated expression in head and neck squamous cell carcinoma (HNSCC). Since OSCC represents the primary pathological type of HNSCC, we investigated BAG1 expression in human tumor tissues and cisplatin resistant OSCC cell lines, revealing that silencing BAG1 induced apoptosis in cisplatin-resistant cells both in vitro and in vivo . This effect led to impaired cell viability of cisplatin resistant OSCC cells and indicated a positive correlation between BAG1 expression and the G1/S transition during cell proliferation. Based on these insights, the administration of a CDK4/6 inhibitor in combination with cisplatin effectively overcame cisplatin resistance in OSCC through the CDK4/6-BAG1 axis. Additionally, to enable simultaneous drug delivery and enhance synergistic antitumor efficacy, we developed a novel supramolecular nanodrug LEE011-FFERGD/CDDP, which was validated in an OSCC orthotopic mouse model. In summary, our study highlights the potential of a combined administration of CDK4/6 inhibitor and cisplatin as a promising therapeutic regimen for treating advanced or cisplatin resistant OSCC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
npj Precision Oncology
·
2025
·Vol. 9
·期 1
·1-21
·
IF 8
Li Xiaoli,Wang Jiashuo,Guo Jiaxing,Zhang Ming
Cisplatin resistance is a major challenge in laryngeal cancer treatment. Tumor necrosis factor-alpha-induced protein 2 (TNFAIP2) has been implicated in chemoresistance, though its role in laryngeal cancer remains unclear. We identified TNFAIP2 as a key gene associated with cisplatin resistance and developed a second near-infrared (NIR-II) light-responsive CRISPR-Cas9 nanosystem (APC@RBCs) to target it. In cisplatin-resistant Tu177/CDDP cells, light-activated knockout of TNFAIP2 significantly increased cisplatin sensitivity (IC50 reduced from 12.55 to 4.37 µg/mL). Mechanistic studies revealed that TNFAIP2 modulates cisplatin resistance via the NRF2 pathway, affecting oxidative stress response and epithelial-mesenchymal transition. TNFAIP2 deletion also suppressed cancer cell migration and invasion. Our results establish TNFAIP2 as a critical mediator of chemoresistance and demonstrate the potential of APC@RBCs as a precise, non-invasive gene therapy platform. This strategy offers a promising approach to overcoming cisplatin resistance and improving treatment outcomes in laryngeal cancer patients.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Wei Zhu,Sai Zhu,Shan Jiang,Jiuyu Yin,Yonggui Wu,Xiaomei Luo
Background Cisplatin (CIS), a widely administered chemotherapeutic agent, is associated with acute kidney injury (AKI). Lansoprazole (LPZ), commonly prescribed to mitigate chemotherapy-induced gastrointestinal complications, may further elevate AKI risk. Paeoniflorin (Pae), a bioactive compound derived from traditional Chinese medicine, demonstrates renal protective properties in AKI, yet its mechanism against CIS and LPZ induced AKI remains undefined. Methods A composite AKI model was established in vivo and in vitro using CIS and LPZ. The protective effect of Pae on the injury of renal tissue or renal tubular cells in mice was observed, followed by Pae pretreatment. The target of Pae was found through network pharmacology, and the binding ability of the target was verified by CETSA experiment and molecular docking. Finally, the target gene was knocked out or over expressed to verified whether Pae regulates necroptosis through this target. Results It was found that renal injury could be exacerbated by LPZ in the CIS induced AKI. Pae could alleviate CIS and LPZ induced AKI. The target gene of Pae was TNFAIP3, which played an important role in necroptosis. The TNFAIP3 could bind well to Pae in molecular docking and CETSA experiment. The necroptosis and inflammatory responses in AKI induced by CIS and LPZ could be also inhibited by Pae in vivo and in vitro. Overexpression of TNFAIP3 played the same cellular protective role as Pae preconditioning. In contrast, Pae could not continue to play a protective role after TNFAIP3 was knocked down. Conclusion The traditional Chinese medicine Pae holds promise as a potential therapeutic agent for AKI, with TNFAIP3 representing an effective therapeutic target in this pathology.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Ying-Da Zang,Hai-Jie Wu,Xin-Yi Chen,Zhi-Ling Ma,Chuang-Jun Li,Jie Ma,Xiao-Guang Chen,Li Sheng,Sen Zhang,Dong-Ming Zhang
Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs (G3-G10) and 40 simplifiers (G11-G50) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava. Among these compounds, (d)-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo, and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that (d)-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate–activated protein kinase (AMPK) signaling pathway. (d)-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Tingting Zhang,Chenxin Xu,Peisen Zheng,Xiaoxian Zhang,Chenyu Qiu,Fengjiao Wu,Jundixia Chen,Zhongxiang Xiao,Jiandong Zhu,Jingjing Zhang,Peng Zou,Daoyong Ni
Ovarian cancer is one of the fatal gynecological cancers around the world. Cisplatin is the first-line chemotherapy drug for the clinical treatment of ovarian cancer. However, many patients with ovarian cancer are still suffering from resistance to cisplatin. Therefore, the new drug combinations or treatment strategies for ovarian cancer are urgently needed. Glaucocalyxin B (GLB), a diterpenoid isolated from the aerial parts of Rabdosia japonica, has shown antitumor activity in some tumors. However, the mechanisms by which GLB inhibits ovarian cancer remain unclear. In the present study, we showed that GLB potently inhibits ovarian cancer cell growth in a dose-dependent manner. Furthermore, we found that GLB has a notably synergistic antitumor effect with cisplatin. Mechanistically, we found that GLB enhances the sensitivity of ovarian cancer cells to cisplatin via increasing reactive oxygen species (ROS) levels, the phosphorylation of c-Jun N-terminal kinase (JNK), and DNA damage. Interestingly, a synergistic inhibitory effect of GLB with cisplatin was also observed in the cells which were resistance to cisplatin. Together, these data suggest that GLB can sensitize ovarian cancer cells to cisplatin by increasing ROS levels.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Xuanbo Zhang,Shipeng Ning,Feng Fang,Cao Zhou,Zifan Yang,Liping Cao,Kaiyuan Wang,Zunyong Feng,Bingyu Li,Dixian Luo,Xiao Xu,Zhigang Liu,Xiaoyuan Chen,Zhiqiang Yu
Cisplatin’s clinical utility is limited by its toxicity, drug resistance, and promotion of immune suppression due to phosphatidylserine (PS) exposure during tumor cell apoptosis. This study introduces a novel approach that integrates cisplatin-derived lipid prodrugs into lipid nanoparticles (PtLNPs) to overcome these challenges. By converting cisplatin to lipid derivatives, we facilitate its incorporation into LNPs, enhancing both the delivery and protection of functional siRNA/mRNA molecules. The synthesized lipid–Pt prodrugs significantly improved the in vitro delivery efficiency and stability of these nucleic acids. Additionally, a codelivery system combining Xkr8 siRNA and annexin A5 (ANX5) mRNA within PtLNPs effectively mitigated cisplatin-induced PS exposure by inhibiting Xkr8 upregulation and promoting ANX5 expression to bind PS. In vivo studies demonstrated that the PtLNP system substantially enhanced the efficacy of combined chemotherapy and immunotherapy, offering a promising strategy to refine cisplatin-based cancer therapy by integrating nucleic acid delivery technologies.
研究领域:
肿瘤学
·
药剂学
·
分子生物学
·
免疫学
·
转化医学
·
药物代谢
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2014
·
IF 8.312
Wantong Song,Zhaohui Tang,Dawei Zhang,Ying Zhang,Haiyang Yu,Mingqiang Li,Shixian Lv,Hai Sun,Mingxiao Deng,Xuesi Chen
There are two important obstacles for the currently applied anti-cancer drug delivery systems. One is the conflict between long-circulation and cellular uptake while the other one is the achievement of ideal anti-cancer efficacy. To solve these problems, we designed a polypeptide-based micelle system that combined the advantages of receptor mediated endocytosis and multi-drug delivery. Firstly, an amphiphilic PLG- g -Ve/PEG graft copolymer was prepared by grafting α-tocopherol (Ve) and polyethylene glycol (PEG) to poly( l -glutamic acid) (PLG). Then docetaxel (DTX) and cisplatin (CDDP) were co-loaded into the PLG- g -Ve/PEG micelles via hydrophobic and chelation effect. After that, the surface of the dual-drug-loaded micelles was decorated with an α v β 3 integrin targeting peptide c(RGDfK). The targeted dual-drug-loaded micelles showed synergistic cytotoxicity and enhanced internalization rate in mouse melanoma (B16F1) cells. In vivo tests demonstrated that remarkable long circulation, anti-tumor and anti-metastasis efficacy could be achieved using this drug delivery system. This work revealed a strategy for the design and preparation of anti-cancer drug delivery systems with reduced side effect, enhanced anti-tumor and anti-metastasis efficacy.
研究领域:
药学
·
肿瘤学
·
生物材料
✓ 已验证
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Zixu Liu,Wei Chu,Qianhe Sun,Linxuan Zhao,Xinyi Tan,Yu Zhang,Tian Yin,Haibing He,Jingxin Gou,Xing Tang
Combination, synergistic chemotherapy with gemcitabine (GEM) and cisplatin (CDDP) is a common strategy, and has been recommended for tumor treatment due to its promoted therapeutic effect and reduced systemic toxicity. However, this process involves the intravenous infusion of GEM prior to that of CDDP, which is inconvenient for patients and staff. Here, a novel hybrid nano-carrier system comprised of micelles encapsulated within PEGylated liposomes is proposed, in order to combine the unique strengths of each component. CDDP was bonded with PLG-PEG, and then the formed CDDP@PLG-PEG micelles and GEM were co-loaded inside PEGylated liposomes. The hybrid liposomes with the optimized GEM/CDDP ratio (1:0.6) showed a roughly spherical morphology, appropriate drug loading, and sustained release behavior. In vitro, the hybrid liposomes had 1.72-fold increased cellular uptake, and 57.42%-fold decreased IC 50 value. In vivo , pharmacokinetic studies showed increased t 1/2 values (125.64%- and 128.57%-folds for GEM and CDDP), decreased clearance (41.90%- and 2.37%-folds), and promoted AUC (262.76%- and 4577.24%-folds). Finally, an in vivo antitumor study showed effective activity in regards to lung tumor size and weight, which were 40.48%- and 33.11%-folds that of GEM/CDDP solution. In summary, we demonstrated the development of an effective micelle-containing PEGylated hybrid liposomes for combined GEM/CDDP delivery.
研究领域:
药剂学
·
肿瘤学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Lixia Feng,Simei Zhao,Zheng Wei,Wenwen Wang,Feiquan Ying,Lin Huang,Mengna Zhu,Mengqing Chen,Qiang Yang,Si Sun,Dawei Jiang,Lingling Gao,Jing Cai
Therapy targeting cancer stem cells (CSCs) has been proposed as a promising strategy to reduce chemoresistance and relapse risks in ovarian cancer (OC) patients. However, the lack of targetable markers impedes research progress. Here, we demonstrate that CXC motif chemokine receptor 4 (CXCR4) may be a targetable functional marker of ovarian CSCs and propose a new translational model incorporating targeted imaging and CXCR4 blockade in CXCR4 + tumors. Expression profile analysis of chemoresistant CSC-like ovarian cancer cells highlighted that CXCR4 functions as a potential stemness marker. CXCR4 + ovarian cancer cells exhibited high self-renewal capacity in vitro and in vivo, and an association with chemoresistance. CXCR4 inhibitor AMD3100 significantly impaired the self-renewal ability of CSC-like ovarian cancer cells and enhanced their sensitivity to cisplatin. CXCR4-targeted [ 68 Ga]Ga-Pentixafor was highly specific in delineating CXCR4-high cell line-derived xenografts and patient-derived xenografts (PDXs) via positron emission tomography (PET) imaging, with precise tumor-targeting and persistent retention. A combination of AMD3100 and CDDP exerted an excellent antitumor effect in CXCR4-high PDXs, but not in CXCR4-low PDXs. These results suggest that CXCR4 may represent a functional CSC marker associated with chemoresistance. Moreover, [ 68 Ga]Ga-Pentixafor PET imaging can guide decision-making for AMD3100 therapy, paving the way for further clinical translation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Liang Xu,Wanying Xiang,Xinyue Wang,Yue Pan,Jing Gao,Jiezhen Yang,Yufei Wang,Zhipu Zhu,Man Tong,Lei Jin,Yan Ye
Platinum-based chemotherapy resistance remains a major obstacle in gastric cancer (GC) treatment. Through integrated transcriptomic profiling of cisplatin-resistant xenografts and pharmacogenomic interrogation of the NCI-60 dataset, we identified Prohibitin-2 (PHB2) as a previously unrecognized determinant of chemoresistance. PHB2 was consistently upregulated in resistant tumors and associated with poor clinical outcomes. Mechanistically, PHB2 binds the lipid-metabolic enzyme ACSL3 through a defined AMP-binding–domain interface (residues W244/H254/E260), enhancing ACSL3 activity to promote monounsaturated fatty acid incorporation into phospholipids. This phospholipid remodeling suppresses lipid peroxidation and establishes a ferroptosis-resistant state. Structure-based virtual screening of an FDA-approved drug library nominated the CXCR4 antagonist Mavorixafor as a potent inhibitor of the PHB2–ACSL3 interaction. Mavorixafor disrupted lipid remodeling, restored ferroptosis susceptibility, and resensitized cisplatin-resistant GC in cell line–derived xenografts (CDOs) and patient-derived organoids (PDOs). The therapeutic effect was abrogated by the ferroptosis inhibitor Liproxstatin-1, confirming ferroptosis dependence. Collectively, our findings define a PHB2–ACSL3 lipid-metabolic axis that drives ferroptosis escape and identify Mavorixafor repurposing as an immediately translatable strategy to overcome cisplatin resistance in treatment-refractory GC.
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）