ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Lingjiao Li,Chengyao Feng,Wenchao Zhang,Lin Qi,Binfeng Liu,Hua Wang,Chenbei Li,Zhihong Li,Chao Tu,Wenhu Zhou
Cisplatin, a frontline chemotherapeutic agent against cancer, faces challenges in clinical application due to significant toxicities and suboptimal efficacy. Renal toxicity, a dose-limiting factor of cisplatin, results from multifactorial processes including cisplatin-induced cellular pyroptosis, oxidative damage, and inflammatory responses. Our findings reveal that Tea Polyphenols Nanoparticles (TPNs) derived from Epigallocatechin gallate (EGCG) effectively could address these diverse mechanisms, comprehensively alleviating cisplatin-induced nephrotoxicity. Leveraging TPNs as carriers, chemical conjugation enables the encapsulation of tetravalent cisplatin prodrug, extending its systemic half-life, enhancing tumor tissue accumulation, while simultaneously mitigating renal toxicity. Concurrently, employing a CRISPR/Cas9 kinase library, we identified CSNK2A1 as a target sensitizing tumor cells to cisplatin, enabling specific siRNA sequences to augment cisplatin susceptibility, thereby minimizing the dosage requirement. Benefiting from the versatile carrier properties of TPNs to codeliver cisplatin prodrug and anti-CSNK2A1 siRNA, we developed a codelivery system, Pt-TPNs/siRNA. Pt-TPNs/siRNA not only enhances the anticancer effects but also mitigates cisplatin-induced renal toxicity, achieving efficacy while reducing toxicity. Mechanistic and safety assessments of these nanoparticles were conducted at both cellular and animal levels, opening new avenues for improved clinical utilization of cisplatin.
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高影响因子
Interdisciplinary Medicine
·
2026
·
IF 13.6
Albert Yu,Yibo Hou,Kaibin Huang,Xucan Gao,Rong Zeng,Chaowei Zhu,Chunhui Sun,Guocai Wang,Lei Ye,Shaohua Ma,Tian Meng,Bing Guo,Yubo Zhang,Xiaoyong Dai
For colorectal cancer (CRC), treatment outcomes and prognosis remain poor even when using first-line chemotherapeutics and immunotherapeutics. The main reasons include (i) lack of tumor specificity, severe off-target cytotoxicity leading to adverse side effects, and occurrence of chemoresistance, and (ii) the immunosuppressive “cold” tumor microenvironment (TME). Herein, we demonstrate an example of highly efficient targeted CRC chemoimmunotherapy with cisplatin (CDDP)-containing nanomedicine (CDDP@MSN-Anti-CD47) in a patient-derived organoids xenograft model. The CDDP@MSN-Anti-CD47 is composed of CDDP-loaded mesoporous silica nanoparticles with superficially functionalized anti-CD47 antibodies to target cluster of differentiation CD47, a transmembrane integrin-associated protein that is over-expressed in CRC cells and can bind with signal regulatory protein α on tumor-associated macrophages (TAMs) to maintain the immunosuppressive TME. Our results demonstrated that CDDP@MSN-Anti-CD47 achieved targeted delivery of CDDP to CRC cells with extended release, and induced reactive oxygen species overproduction to inhibit CRC cells and CRC patient-derived organoids growth via activating caspase-3-related apoptosis and immunogenic cell death. DAMPs released following CDDP@MSN-Anti-CD47 treatment promoted the polarization of TAMs from immunosuppressive M2 to pro-inflammatory M1 phenotype and also synergized with the functionalized anti-CD47 antibodies to restore macrophage phagocytic activity against CRC cells. In both CRC cell and patient-derived organoid xenograft models, CDDP@MSN-Anti-CD47 could specifically target the tumor, showing strong anti-tumor effects, prolonged survival rate, and low systemic cytotoxicity. Overall, CDDP@MSN-Anti augments combination chemotherapy and immunotherapy, and can be developed as a novel and promising strategy for the clinical treatment of CRC.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Yaowei Bai,Mengqin Guo,Kexin Wang,Yu Lei,Jun Wu,Bo Sun,Wenlong Wu,Xiatong Bai,Yang Su,Ling Li,Yanbing Zhao,Chuansheng Zheng,Hongsen Zhang
A cisplatin/EGCG-loaded RF-responsive nanogel was developed for HCC interventional therapy. • Cisplatin amplifies RF deposition; EGCG inhibits HSP90-mediated thermotolerance, reducing residual tumors. • EGCG/CDDP@PNA induced ICD and remodeled TME via inhibiting the HSP90-STAT3-PD-L1 axis. Radiofrequency ablation (RFA) is a guideline-recommended first-line curative local treatment for hepatocellular carcinoma (HCC). Sublethal temperature zones at the tumor margin often lead to residual tumor survival, recurrence, and immune escape. To overcome these limitations, we developed a radiofrequency-responsive thermosensitive nanogel co-loading cisplatin and the HSP90 inhibitor epigallocatechin gallate (EGCG), termed EGCG/CDDP@PNA, which is administered via transcatheter arterial chemoembolization (TACE) followed by RFA to enhance ablation efficacy. The nanogel undergoes a body-temperature-triggered sol-gel transition, enabling tumor embolization and localized drug retention, and exhibits strong radiofrequency-responsive heating capability. Cisplatin increases intratumoral ionic conductivity, thereby amplifying radiofrequency energy deposition and accelerating intratumoral heating, while EGCG inhibits HSP90-mediated thermotolerance by disrupting the HSP90-STAT3-PD-L1 axis. In VX2 rabbit and Hepa1–6 orthotopic mouse hepatocellular carcinoma models, EGCG/CDDP@PNA significantly expanded the ablation zone, reduced sublethal residual tumor lesions, suppressed tumor progression, and prolonged survival. From the perspective of the tumor immune microenvironment, the nanogel induced immunogenic cell death, promoted dendritic cell activation and CD8 + T-cell infiltration, inhibited regulatory T cells, and remodeled the tumor immune microenvironment toward an immune-activated phenotype. Biosafety evaluations demonstrated good hemocompatibility and negligible systemic toxicity. Overall, EGCG/CDDP@PNA integrates physical energy modulation, molecular pathway inhibition, and immune microenvironment remodeling, providing a promising strategy to overcome thermotolerance and improve interventional treatment outcomes for HCC. Schematic Diagram of the Research. (A) Schematic diagram of EGCG/CDDP@PNA synthesis. (B) Investigation of the radiofrequency responsiveness of EGCG/CDDP@PNA in the VX2 rabbit orthotopic hepatocellular carcinoma model. (C) Investigation of the effect of EGCG/CDDP@PNA on immune activation in the C57BL/6 mouse orthotopic hepatocellular carcinoma model. Download: Download high-res image (157KB) Download: Download full-size image
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MATERIALS & DESIGN
·
2026
·
IF 8.2
Ruilin Ding,Hai Lin,Yinying Wu,Xuyuan Dong,Yangwei Fan,Longxia Chen,Gaochen Lan,Yu Shi,Meichen Wang,Enxiao Li
Virus-mimetic hollow Gd-Fe nanocarriers enable co-delivery of cisplatin and TGF-βRI inhibitor for synergistic chemo-ferroptosis therapy. • The nanoparticle trigger iron-dependent cell death while blocking TGF-β signaling, synergistically suppressing tumor growth. • The nanoparticle overcomes resistance to immune checkpoint therapy by shifting the tumor microenvironment toward an immune-active state. Ovarian carcinoma remains poorly responsive to immune checkpoint blockade, partly because of a TGF-β-enriched and immunosuppressive tumor microenvironment. Here, we developed a virus-mimetic hollow Gd-Fe nanocarrier for the co-delivery of cisplatin (DDP) and the TGF-β receptor I inhibitor TGFβRI-IN-3 (IN-3), aiming to integrate chemotherapy, ferroptosis induction, and TGF-β pathway blockade into a single therapeutic platform. DDP/IN-3@Gd-Fe nanoparticles (NPs) were prepared using a hard-template strategy. Cellular uptake, cytotoxicity, apoptosis, and ferroptosis-associated biochemical changes were evaluated in SKOV3 cells. In tumor-bearing mice, biodistribution, T1-weighted MRI contrast, biosafety, and antitumor efficacy were further investigated. The prepared NPs exhibited uniform size, good stability, and high drug loading with sustained release. In vitro , DDP/IN-3@Gd-Fe NPs were effectively internalized by SKOV3 cells and demonstrated superior cytotoxicity, apoptosis induction, and ferroptosis promotion compared to free drugs. In vivo , DDP/IN-3@Gd-Fe NPs exhibited the strongest tumor growth inhibition, involving synergistic induction of apoptosis and ferroptosis and effective suppression of the TGF-β signaling pathway. Finally, DDP/IN-3@Gd-Fe NPs were found to remodel the immunosuppressive TME by increasing inflammatory mediators and promoting tumor infiltration of cytotoxic T cells and dendritic cells. In conclusion, DDP/IN-3@Gd-Fe NPs provide an MRI-traceable chemo-ferroptosis platform that may attenuate TGF-β-associated immunosuppression and improve checkpoint blockade responses in ovarian carcinoma. Download: Download high-res image (168KB) Download: Download full-size image
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JOURNAL OF CONTROLLED RELEASE
·
2014
·
IF 7.261
Haiyang Yu,Zhaohui Tang,Dawei Zhang,Wantong Song,Ying Zhang,Yan Yang,Zaheer Ahmad,Xuesi Chen
Platinum-based polymeric nano-drugs, especially cisplatin-loaded polymeric nanoparticles (CDDP-NPs), have been extensively exploited for the treatment of solid tumors . However, it is still unclear what role the processing procedure and the properties of the polymeric carrier materials may play in influencing the plasma pharmacokinetics , biodistribution and in vivo efficacy of CDDP-NPs. In this study, a series of poly( l -glutamic acid)- g -methoxy poly(ethylene glycol) (PLG- g -mPEG) copolymers were synthesized for the preparation of CDDP-loaded PLG- g -mPEG (CDDP/PLG- g -mPEG) nanoparticles . All of the parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length, ultrafiltration purification and cisplatin loading content, were found to have a significant influence on the plasma pharmacokinetics of the CDDP/PLG- g -mPEG nanoparticles . The blood circulation time of the nanoparticles was prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and CDDP loading content. The use of ultrafiltration purification could prolong the blood circulation time of the nanoparticles as well. Experiments to measure the pharmacokinetics and biodistribution demonstrated that the selected CDDP/PLG- g -mPEG nanoparticles, NP10, had a long blood circulation time and could achieve selective and significant accumulation in Lewis lung carcinoma (LLC) tumors. The platinum plasma concentrations in the LLC tumor-bearing mice receiving NP10 remained up to 46-fold higher than that of mice receiving equivalent doses of free CDDP. In addition, the plasma area under the concentration time curve (AUC) of NP10 was 31-fold higher than that of free CDDP in 48 h. The platinum concentration ratio of NP10 to free CDDP in tumors reached as high as 9.4. The tumor AUC ratio of NP10 to CDDP was 6. Using a mouse C26 tumor model, here we demonstrate that NP10 improves the safety and tolerance in vivo when compared to CDDP and effectively inhibits the growth of C26 tumors. Furthermore, increasing the dosage of NP10 by 2 or 3-fold of free CCDP improved its anticancer efficacy to comparable or higher levels. These results indicate that CDDP/PLG- g -mPEG nanoparticles have greater potential for the treatment of solid tumors in clinical application.
研究领域:
药理学
·
肿瘤学
·
纳米医学
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American Journal of Cancer Research
·
2025
·Vol. 15
·期 6
·2618
·
IF 2.9
Yixin Wang,Lang Jin,Chuanjie Zong,Xidong Zhang
Osteosarcoma is a prevalent primary malignant bone tumor in young adults and adolescents, characterized by a high recurrence rate despite advancements in chemotherapy and surgical methods. This study investigated the effects of integrating high-dose methotrexate with cisplatin and paclitaxel on survival outcomes in osteosarcoma patients, and to identify prognostic factors influencing these outcomes. A retrospective analysis was conducted on 208 osteosarcoma patients treated between January 2013 and December 2018. Patients were divided into two groups: standard chemotherapy group (SC, n = 104) and cisplatin + paclitaxel + high-dose methotrexate (CPM, n = 104). The primary endpoints were progression-free survival (PFS) and overall survival (OS), while secondary endpoints included efficacy assessments. Kaplan-Meier survival curves were used to assess survival distributions, and statistical analyses were performed using SPSS 29.0. The CPM group demonstrated significantly longer PFS (16.85 ± 3.40 months vs. 15.72 ± 3.21 months, P = 0.015) and higher 5-year OS rates (54.81% vs. 40.38%, P = 0.037) compared to the SC group. Completion of chemotherapy and a response rate greater than 90% were identified as strong positive prognostic indicators. In contrast, pathologic fractures at diagnosis, lung metastases, and elevated lactate dehydrogenase levels were associated with poorer outcomes. Multivariate analysis underscored chemotherapy response and treatment adherence as independent survival predictors. The combination of cisplatin and paclitaxel with high-dose methotrexate significantly improves PFS and OS compared to standard chemotherapy. Moreover, treatment completion and achieving a chemotherapy response greater than 90% are critical factors for favorable prognosis.
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ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Mingli Wei,Ying Jiang,Rong Sun,Liangyi Fang,Chenxiao Chu,Haibing He,Jingxin Gou,Tian Yin,Yongbo Song,Xing Tang,Fan Zhao,Yinglei Zhai,Yu Zhang
Combination chemotherapy has been proved to be an effective strategy in the clinic, and nanoformulations have drawn much attention in the field of drug delivery. However, conventional nanocarriers suffer from shortcomings such as inefficient coloading and undesired molar ratios of the combined drugs, preleakage of cargos during systemic circulation, and lack of cancer-selective drug release. To achieve tumor-specific codelivery of cisplatin (CDDP) and norcantharidin (NCTD) for synergistic treatment of liver cancer, a novel linear–dendritic polymer, termed as G1(PPDC)x, was designed and synthesized, where a prodrug consisting of cisplatin (CDDP) and norcantharidin (NCTD) was conjugated to PEG2000 via ester bonds to fabricate linear polymer–drug conjugates, and the conjugates were subsequently grafted to the terminal hydroxyls of a dendritic polycarbonate core. Benefiting from the hydrogen bond interactions, G1(PPDC)x could spontaneously self-assemble into a unique type of raspberry-like multimicelle clusters in solution (G1(PPDC)x-PMs). G1(PPDC)x-PMs possessed an optimal synergistic ratio of CDDP and NCTD, without obvious premature release or disassembly in biological environments. Intriguingly, upon extravasation into the interstitial tumor tissues, G1(PPDC)x-PMs (132 nm in diameter) could disassemble and reassemble into smaller micelles (40 nm in diameter) in response to the mildly acidic tumor microenvironment, which would enhance the deep tumor penetration and cellular accumulation of drugs. In vivo delivery of G1(PPDC)x-PMs led to a significantly prolonged blood circulation half-life, which is beneficial to achieve sufficient tumor accumulation through the enhanced permeability and retention (EPR) effect. G1(PPDC)x-PMs displayed the best antitumor activity in H22 tumor-bearing mice with a tumor inhibition rate of 78.87%. Meanwhile, G1(PPDC)x-PMs alleviated both myelosuppression toxicities of CDDP and vascular irritation of NCTD. Our results demonstrated that G1(PPDC)x-PMs could serve as an effective drug delivery system for codelivery of CDDP and NCTD to treat liver cancer efficiently.
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高影响因子
ONCOLOGY REPORTS
·
2024
·Vol. 52
·期 6
·1-9
·
IF 3.8
Qiongying Wei,Jinquan Lin,Zhuangbin Lin,Nanding Yu,Yingxiao Wu,Xuexue Tan,Dan Xue
Cisplatin resistance is common in non‑small cell lung cancer (NSCLC); however, the molecular mechanisms remain unclear. The present study aimed to identify a new function of Golgi phosphoprotein 3 (GOLPH3) in NSCLC‑associated cisplatin resistance. Using A549 human NSCLC cells and the cisplatin‑resistant variant, stable cell lines with GOLPH3 knockdown or overexpression were established using lentiviral vectors. Through Cell Counting Kit‑8 and EdU assays, it was revealed that knockdown of GOLPH3 significantly enhanced cisplatin sensitivity in NSCLC cells. Specifically, flow cytometric analysis showed that GOLPH3 knockdown promoted apoptosis and G2‑phase cell cycle arrest in A549 cells. Mechanistically, intracellular reactive oxygen species (ROS) and glutathione (GSH) levels were measured using assay kits, and it was demonstrated that GOLPH3 knockdown decreased intracellular GSH levels, and further attenuated intracellular cisplatin efflux and GSH/ROS imbalance. In addition, tumor‑sphere formation assays verified that GOLPH3 knockdown mitigated the stem cell‑like phenotype of NSCLC cells. In conclusion, the present findings indicated the relevance of GOLPH3 in NSCLC‑associated cisplatin resistance, and thus targeting GOLPH3 may be developed into a combination therapy to overcome cisplatin resistance.
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Evidence-based Complementary and Alternative Medicine
·
2021
·
IF 2.63
Wen-Jie Wu,Yu-Fang Tang,Shuang Dong,Jie Zhang
Objective. The research aimed to confirm the role of the transforming growth factor-β (TGF-β) in cisplatin- (CPT-) evoked kidney toxicity and elucidate the mechanism that ginsenoside Rb3 (Rb3) could alleviate the kidney toxicity by CPT during its treatment to oral cancer via TGF-β-mediated mitochondrial apoptosis. Methods. The model of xenograft nude mice bearing oral carcinoma cells ACC83 was established and treated with CPT and/or Rb3, respectively. Bodyweights of the treated mice were weighed, and the kidney tissues were collected; following, the histopathology and the expression of TGF-β were examined using H&E staining and immunohistochemistry. Afterward, the renal cells GP-293 were treated with CPT and/or Rb3. The expression and phosphoration of TGF-β, Smad2, Smad3, Bcl-2, and Bax in GP-293 cells were detected by Western blotting. The cellular apoptosis and mitochondrial membrane potential were analyzed using flow cytometry. Results. The xenograft nude mice exposure to CPT presented the bodyweight loss, necrotic areas, and the increased expression of TGF in kidney tissue, and Rb3 pretreatment relieved these changes evoked by CPT. In GP-293 cells, CPT administration induced the phosphorylation of Smad2 and Smad3, and Rb3 pretreatment suppressed the induced phosphorylation by CPT. Besides, flow cytometry analysis showed that Rb3 inhibited the CPT-evoked cellular apoptosis ratio and mitochondrial membrane depolarization. The Western blotting test indicated that Rb3 alleviated the cleavage of PARP, caspase 3, caspase 8, and caspase 9, the induction of Bax expression, and inhibition of Bcl-2 expression. Additionally, after treating with the TGF inhibitor of disitertide, Rb3 exhibited no alleviation effects on CPT-evoked cellular apoptosis ratio, inhibition of Bax expression, and induction of Bcl-2 expression in GP-293 cells. Conclusion. Rb3 could alleviate CPT-evoked toxic effects on kidney cells during its treatment to oral cancer via TGF-β-mediated mitochondrial apoptosis.
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Advanced Science
·
2025
·
IF 14.1
Jizhuo Li,Wenze Xun,Xijie Wang,Ruiguang Luo,Qifan Hu,Zhaocai Zhou,Jian Yuan,Yanan Wang,Xiaorui Wan,Tao Zhao,Tianyu Han,Jian-Bin Wang
Lactylation is a novel post-translational modification closely related to the glycolytic process, but the regulatory mechanisms between lactylation and glycolysis are far from being elucidated. Lactate dehydrogenase A (LDHA) catalyzes the formation of lactate, which provides the modifying group for protein lactylation. However, whether lactylation occurs on LDHA itself remains unknown. Here, it is found that lactylation promotes the enzymatic activity of LDHA in lung adenocarcinoma (LUAD), which in turn enhances the overall level of cellular lactylation through a positive feedback loop. Screening identified Lys81 and Lys318 as key LDHA lactylation sites, with alanyl-tRNA synthetase 1 (AARS1) serving as the mediating lactyltransferase. Mass spectrometry reveals that numerous proteins involved in DNA nonhomologous end junction (NHEJ), including FEN1, XRCC5, and XRCC6 might be regulated by lactylation. Delactylation of these proteins significantly hinders the formation of FEN1-RAD1-RAD9A-HUS1 complex, thereby leading to dysfunction of NHEJ and increasing the sensitivity of cancer cells to cisplatin. In summary, this work identifies LDHA lactylation as a critical mechanism for accelerating the progression of LUAD and reveals how this lactylation influenced cisplatin sensitivity of LUAD cells, which deepen the understanding of lactylation-mediated tumor progression and provide a potential new anticancer strategy.
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RARE METALS
·
2026
·Vol. 45
·期 9
·e70620
·
IF 12.1
Minghe Jiang,Ruikai Zhu,Shurong Chen,Xuwen Pan,Leiyuan Peng,Yaohui Huang,Wenquan Lv,Mingjing Yin,Xiaoxuan Guan,Mingyang Jiang,Ming Gao,Wei Wang,Yan Liu
en This link goes to a English section zh This link goes to a Chinese section Cisplatin-related acute kidney injury (CP-AKI) is a serious complication of cisplatin (CP) treated patients with cancer with high morbidity and mortality rates. It is directly related to the abnormal accumulation of CP in renal tubular epithelial cells, causing metabolic toxicity, DNA damage, and oxidative stress. Herein, we developed a polyphenol nanozyme (SrEG) by the coordination of strontium ions (Sr 2+ ) and epigallocatechin gallate. It was demonstrated that SrEG, combined with NIR irradiation, exhibited excellent capabilities of scavenging various types of reactive oxygen species (ROS). It was also determined that SrEG + NIR efficiently eliminated intracellular ROS levels, inhibited inflammation related cytokines expression, and induced macrophage M2 directional polarization, thus preventing cellular damage. By intravenous (IV) administration, SrEG was efficiently accumulated in the kidney and gradually degraded. Accordingly, the administration of SrEG + NIR offered the perfect therapeutic effects in CP-AKI rats by inhibiting the PI3K/AKT pathway, thus accelerating kidney function repair. Overall, the strategy of SrEG + NIR showed substantial clinical promise as a potential therapeutic strategy in ROS-related diseases. 摘要 en This link goes to a English section zh This link goes to a Chinese section 顺铂相关的急性肾损伤(CP-AKI)是癌症患者进行顺铂(CP)治疗时的严重并发症,具有较高的致病率和死亡率。CP-AKI与CP在肾小管上皮细胞中的异常积聚直接相关,从而导致代谢毒性、DNA损伤和氧化应激。在此,我们通过锶离子(Sr 2+ )和表没食子儿茶素没食子酸酯的配位开发了一种多酚纳米酶(SrEG)。结果表明,SrEG结合近红外光照展现出优异的清除各种类型活性氧(ROS)的能力。而且SrEG + NIR有效地降低细胞内ROS水平,抑制炎症相关因子的表达,并诱导巨噬细胞M2定向极化,从而防止细胞损伤。通过静脉注射(IV)给药,SrEG在肾脏中有效积聚并逐渐降解。因此,SrEG + NIR的治疗策略通过抑制PI3K/AKT通路,从而加速肾功能修复,为CP-AKI大鼠提供了完美的治疗效果。总体而言,SrEG + NIR作为ROS相关疾病的潜在治疗策略显示出巨大的临床前景。
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Experimental and Therapeutic Medicine
·
2026
·Vol. 32
·期 2
·1-19
·
IF 2.2
Bin Xia,Jianglong Chen,Jinhui Wang,Dalong Li,Lixia Zhang,Jing Su,Xuan Ding,Yana Lv,Shifang Liu,Xue Zhang,Tianzhen Wan,Guang Li
Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.
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