Pharmaceutics
·
2025
·Vol. 17
·期 7
·945
·
IF 5.5
Yin Wang,Fanyu Wu,Tan Yang,Bin Li,Han Wang,Peng Ye,Weijie Li
Background/Objectives:Cisplatin remains a cornerstone chemotherapeutic agent for non-small-cell lung cancer (NSCLC) treatment, yet its clinical utility is substantially limited by acquired resistance and the inadequate suppression of tumor metastasis. Emerging evidence implicates interleukin 6 (IL-6) as a critical mediator of chemoresistance through cancer stem cell (CSC) enrichment and metastasis promotion via epithelial–mesenchymal transition (EMT) induction, ultimately contributing to cisplatin therapy failure. This study sought to address these challenges by designing a nanoplatform with two innovative aims: (1) to achieve active tumor targeting through binding to the IL-6 receptor (IL-6R), and (2) to concurrently inhibit IL-6-mediated chemoresistance signaling pathways.Methods:A lipid–polymer hybrid nanoparticle (LPC) encapsulating cisplatin was synthesized and subsequently surface-functionalized with tocilizumab (TCZ), a monoclonal antibody that targets IL-6R. The therapeutic efficacy of this TCZ-modified nanoparticle (LPC-TCZ) was assessed through a series of in vitro and in vivo experiments, focusing on the inhibition of EMT, expression of CSC markers, tumor growth, and metastasis.Results:Systematic in vitro and in vivo evaluations revealed that LPC-TCZ synergistically attenuated both EMT progression and CSC marker expression through the targeted blockade of IL-6/STAT3 signaling. This multimodal therapeutic strategy demonstrated superior tumor growth inhibition and metastatic suppression compared to conventional cisplatin monotherapy.Conclusions:Our findings establish a nanotechnology-enabled approach to potentiate cisplatin efficacy by simultaneously countering chemoresistance mechanisms and metastatic pathways in NSCLC management.
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JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Can Hong,Yiming Liu,Dingwen Shi,Chao Liu,Shidong Zou,Mengqin Guo,Xingyu Chen,Chuansheng Zheng,Yanbing Zhao,Xiangliang Yang
Radiofrequency-responsive nanoparticles (RFNPs) have drawn increasingly attentions as RF energy absorbing antenna to enhance antitumor efficacy of radiofrequency ablation (RFA). However, it remains a huge challenge for inorganic RFNPs to precisely synergize RFA with other antitumor modes in a clinically acceptable way on bio-safety and bio-compatibility. In this work, RF-responsive black phosphorus (BP) nanogel (BP-Pt@PNA) was successfully fabricated by crosslinking coordination of cisplatin with BP and temperature sensitive polymer PNA. BP-Pt@PNA exhibited strong RF-heating effect and RF-induced pulsatile release of cisplatin. Under RF irradiation, BP-Pt@PNA exhibited cytotoxic enhancement on 4T1 cells. By the synergistic effect of BP and cisplatin, BP-Pt@PNA achieved RF-stimulated systemic immune effect, thus induced enhance suppression on tumor growth and metastasis. Moreover, BP-Pt@PNA realized long-term drug retention in tumor and favorable embolization to tumor-feeding arteries. With high drug loading capacity and favorable bio-safety and bio-degradability, BP-Pt@PNA is expected as an ideal RFNP for precisely synergizing RFA with other antitumor modes in clinical application.
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Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Tianyue Xu,Dan Zheng,Meixu Chen,Linlin Song,Zhihui Liu,Yan Cheng,Yujie Zhao,Liwen Huang,Yixuan Li,Zhankun Yang,Cong Li,Biao Dong,Jing Jing,Hubing Shi
Lacking therapeutic targets highlights the crucial roles of chemotherapy and radiotherapy in the clinical management of triple-negative breast cancer (TNBC). To relieve the side effects of the chemoradiotherapy combination regimen, we design and develop a self-assembled micelle nanosystem consisting of perfluorocarbon chain-modified cisplatin prodrug. By incorporating perfluorodecalin, this nanosystem can effectively carry ozone and promote irradiation-derived reactive oxygen species (ROS) production. By leveraging the perfluorocarbon sidechain, the nanosystem exhibits efficient internalization by TNBC cells and effectively escapes from lysosomal entrapment. Under X-ray irradiation, ozone-generated ROS disrupts the intracellular redox balance, thereby facilitating the release of cisplatin in a reduction-responsive manner mediated by reduced glutathione. Moreover, oxygen derived from ozone decomposition enhances the efficacy of radiotherapy by alleviating tumor hypoxia. Notably, the combination of irradiation with ozone-loaded cisplatin prodrug nano system synergistically prompts antitumor efficacy and reduces cellular/systemic toxicity in vitro and in vivo . Furthermore, the combo regimen remodels the tumor microenvironment into an immune-favored state by triggering immunogenic cell death and relieving hypoxia, which provides a promising foundation for a combination regimen of immunotherapy. In conclusion, our nanosystem presents a novel strategy for integrating chemotherapy and radiotherapy to optimize the efficacy and safety of TNBC clinical treatment.
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iScience
·
2025
·
IF 4.1
Qian Wang,Jie Chen,Huini Chen,Dongning Liang,Hong Zhou,Juanjuan Chen,Yuan Gui,Fang Yao,Yudan Chen,Xi Zeng,Yaxiang Ma,Dong Zhou,Haiyan Fu
Cisplatin is a commonly used chemotherapy agent for treating various solid tumors, but its clinical application is limited by nephrotoxicity. While the potential for cisplatin to cause chronic kidney disease (CKD) following repeated administration has been underexplored, effective therapeutic strategies for cisplatin-induced CKD are lacking. We found that cisplatin-induced CKD is characterized by renal dysfunction and inflammation, along with intestinal barrier impairment. 16S rRNA and metabolomics revealed that cisplatin disrupts the gut microbiome and raises levels of tryptophan metabolites- Indole-3-propionic acid (IPA). Notably, oral administration of IPA reproduced similar harmful effects in cisplatin-induced CKD. Integrated analyses of the microbiome, metabolomics, Raman spectroscopy and DESI-MSI indicated that IPA supplementation exacerbates the production of uremic toxins linked to tryptophan metabolism and promotes the growth of pathogenic bacteria. Our findings demonstrates that IPA exacerbates renal inflammation and fibrosis by regulating AHR/NF-κB signaling pathways, altering intestinal microbiome composition, and disrupting tryptophan metabolism.
研究领域:
肾脏病学
·
肿瘤学
·
毒理学
·
微生物组研究
·
代谢组学
·
分子信号通路
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Nanoscale
·
2017
·Vol. 9
·期 28
·10002-10019
·
IF 7.367
Yanjuan Huang,Yuanfeng He,Ziyuan Huang,Yali Jiang,Weijing Chu,Xiaoqi Sun,Liangfeng Huang,Chunshun Zhao
Cisplatin (CDDP) is a potent anti-carcinogen that is widely used for various solid tumors; however, its clinical application is limited by its severe nephrotoxicity. Novel platinum–bisphosphonate polymer–metal complex nanoparticles (Pt–bp NPs), based on platinum–bisphosphonate coordination, have been established. Three polymer carriers bearing alendronate (ALN) ligands, while containing different lengths of alkyl hydrophobic chains, were synthesized. Their structures were characterized by 1H NMR, 31P NMR and FTIR. The ALN was used to coordinate to the CDDP precursor [Pt(NH3)2(OSO3)(OH2)], and the Pt–bp NPs were formed spontaneously. The Pt–bp NPs formed by the polymer carrier, ALN-PEG2k-ASAC18, which contained the poly(ethylene glycol) chain with ALN on one side and the octadecyl hydrophobic chain on the other side, was denoted as ALN-ASAC18-CDDP; its diameter was within 200 nm. CDDP was released in a Cl− or pH-dependent manner. The cytotoxic effects to the HeLa, A549 and MCF-7 cell lines were relatively weak, compared to CDDP. However, ALN-ASAC18-CDDP showed significantly prolonged blood circulation time and tumor accumulation of platinum of 2.5-fold, compared to CDDP at 8 h. Besides, ALN-ASAC18-CDDP was demonstrated to remarkably reduce systemic toxicity without compromising in vivo antitumor activity. These results indicate that the facilely prepared ALN-ASAC18-CDDP has great utilization potential for CDDP delivery in a clinical setting.
研究领域:
药剂学
·
肿瘤学
·
材料科学
·
药物递送系统
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AAPS PHARMSCITECH
·
2018
·Vol. 19
·期 5
·2048-2057
·
IF 2.666
Zhai Qingqing,Li Hailong,Song Yanlin,Wu Ruijiao,Tang Chuanfang,Ma Xiaodong,Liu Zhihao,Peng Jinyong,Zhang Jianbin,Tang Zeyao
This work aimed to develop and optimize several lipid nanocapsule formulations (LNCs) to encapsulate cisplatin (CDDP) for treatment of hepatocellular carcinoma. By comparing the effect of oil/surfactant ratio, lecithin content, and oil/surfactant type on LNC characteristics, two LNCs were selected as optimal formulations: HS15-LNC (Solutol HS 15/MCT/lecithin, 54.5:42.5:3%, w / w ) and EL-LNC (Cremophor EL/MCT/lecithin, 54.5:42.5:3%, w / w ). Both LNCs could effectively encapsulate CDDP with the encapsulation efficiency of 73.48 and 78.84%. In vitro release study showed that both LNCs could sustain the release CDDP. Moreover, cellular uptake study showed that C6-labeled LNCs could be effectively internalized by HepG2 cells. Cellular cytotoxicity study revealed that both LNCs showed negligible cellular toxicity when their concentrations were below 313 μg/mL. Importantly, CDDP-loaded LNCs exhibited much stronger cell killing potency than free CDDP, with the IC50 values decreased from 17.93 to 3.53 and 5.16 μM after 72-h incubation. In addition, flow cytometric analysis showed that the percentage of apoptotic cells was significantly increased after treatment with LNCs. Therefore, the prepared LNC formulations exhibited promising anti-hepatocarcinoma effect, which could be beneficial to hepatocellular carcinoma therapy.
研究领域:
药学
·
肿瘤学
·
纳米技术
·
药物递送系统
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Li Dafei,Zhao Haiyan,Xu Piao,Lin Qiongping,Zhao Tingting,Li Chubing,Cui Zhong-Kai,Tian Guangyong
Irreversible sensorineural hearing loss is one of the most common side effects after cisplatin treatment. Prevention and reversal of hearing loss caused by cisplatin are of great importance for cancer patients, especially children. Oxidative stress is an important cause of hearing loss resulted from cisplatin, unfortunately, there is no drug yet available that can completely prevent and reverse the ototoxicity from cisplatin. Polydatin (PD) possesses excellent antioxidant and anti-inflammatory effects, however, its role in the cisplatin-induced hearing loss has not been investigated. Herein, we have explored the preventive and therapeutic effects of PD on cisplatin-induced hearing loss and the possible underlying mechanisms. In the in vivo setting with guinea pigs, we have demonstrated that PD can reduce the threshold shift of auditory brainstem response (ABR) caused by cisplatin, promote the nuclear translocation of Nuclear factor erythroid-2 related factor 2 (Nrf2), increase the expression of Nrf2 and heme oxygenase-1 (HO-1), and thus reduce the loss of outer hair cells (OHCs). PD can ameliorate cisplatin-induced hearing loss through activating the Nrf2/HO-1 signaling pathway. This study provides a potential strategy for preventing and improving hearing loss resulted from cisplatin treatment in clinics.
研究领域:
药理学
·
耳鼻喉科学
·
肿瘤学
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JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
·
2026
·Vol. 37
·期 1
·42
·
IF 4.7
Xiaomei Ye,Shuzhen Lu,Hao Peng,Zhirong Huang,Chunyu Pan,Yayan Huang,Kangrui Yuan,Youfa Qin
Mesoporous metal-organic frameworks (MOFs) have the advantages of high specific surface area, tunable pore size, and favorable biocompatibility, making them promising candidates for drug delivery in cancer therapy. In this study, a series of mesoporous zinc-based MOF, constructed using cyclopentane dicarboxylic acid as the organic linker, was successfully synthesized via a surfactant-assisted solvothermal method. Surface characterization revealed that MOF-2 exhibited high surface area (1325 m 2 /g), pore volume (0.273 cm 3 /g), and average pore diameter (5.69 nm). UV-Vis analysis showed that MOF-2 demonstrated improved drug loading (18% w/w), encapsulation efficiency (86%), and cumulative release (96%), along with both pH-responsive degradation and drug release properties. Furthermore, cisplatin-loaded MOF-2 exhibited potent antitumor activity against A549 cells and effectively inhibited cell migration and invasion, while maintaining minimal cytotoxicity toward LO2 normal hepatic cells. These findings suggest MOF-2 as a promising nanocarrier for pH-responsive anticancer drug delivery.
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ADVANCED MATERIALS
·
2026
·
IF 29.1
Yijie Fan,Jingning Zhang,Cong Liu,Wei Liu,Ruizeng Luo,Yingying Ren,Zhou Li,Zhong Lin Wang,Dan Luo
The clinical efficacy of platinum-based chemotherapeutics is frequently diminished by the emergence of resistance during prolonged treatment. Cisplatin (DDP)-resistant tumors adapt to chemotherapeutic stress by establishing a new state of adaptive homeostasis that sustains cellular survival under drug pressure, albeit at the expense of high metabolic burden and acquired vulnerability. Exploiting this intrinsic weakness, we designed a DDP-doped black phosphorus (BP) nanomedicine protected by polydopamine coating (DDP-BP@PDA) that synergistically delivered DDP and piezoelectric BP to precisely disrupt resistance homeostasis and thereby reverse DDP resistance. DDP-BP@PDA altered the intracellular uptake pathway of DDP and disrupted the redox balance of resistant cells via piezocatalysis. Concurrently, piezoelectric polarization enhanced the peroxidase-like activity via electron injection, leading to the generation of substantial reactive oxygen species (ROS). This ROS burst compromised the integrity of the endoplasmic reticulum (ER) membrane and exacerbated the protein-folding burden, thereby amplifying ER stress. Mechanism study reveals that excessive ER stress downregulated the expression of DNA repair proteins, making resistant cells highly sensitive to DDP-induced DNA damage. Through these synergistic effects, DDP-BP@PDA disrupted the adaptive homeostasis of DDP-resistant cells, thereby significantly inhibiting the progression of DDP-resistant tumors. This study establishes a promising therapeutic strategy to combat DDP-resistance via piezoelectric-driven disruption of adaptive homeostasis.
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MOLECULAR PHARMACEUTICS
·
2026
·Vol. 23
·期 8
·4341-4359
·
IF 4.9
Zhang Jieke,Li Yafang,Tian Chaoying,Zhang Xiaodi,Guo Jialing,Liu Chenxin,Wu Ligang,Du Bin,Cheng Genyang
Acute kidney injury (AKI) is a clinical syndrome with
high incidence
and mortality involving oxidative stress, ferroptosis, and inflammation,
yet there are no clinically effective interventions. Herein, HA@PDA@EGCG
nanoparticles were constructed using polydopamine (PDA) as carriers,
loaded with epigallocatechin gallate (EGCG) via π-π stacking,
and further surface-modified with hyaluronic acid (HA) through electrostatic
interaction. The nanoparticles had uniform morphology with a size
of approximately 50 nm and an EGCG loading capacity of 15.4 ±
0.8%. They exhibited prominent broad-spectrum antioxidant activity
and hydrogen peroxide-responsive EGCG release, with a cumulative release
rate of 58.2 ± 2.2% within 2 h and close to 80% at 12 h. Cellular
uptake and in vivo distribution confirmed the efficient CD44 receptor-mediated
internalization of the nanoparticles by human kidney-2 (HK-2) cells
as well as renal-targeted accumulation. Reactive oxygen species (ROS)
staining, mitochondrial morphology and apoptosis assays showed that
the nanoparticles effectively scavenged ROS, alleviated mitochondrial
damage, and inhibited cell apoptosis. In a cisplatin-induced in vivo
AKI model, HA@PDA@EGCG significantly restored renal function: blood
urea nitrogen and creatinine decreased to 12.3% and 27.2% of model
group levels, respectively, while alleviating renal pathological damage
and inflammation. Mechanistically, HA@PDA@EGCG inhibited ferroptosis
by downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4)
to suppress lipid synthesis, chelating ferrous ions, and stabilizing
glutathione peroxidase 4 (GPX4) protein. Collectively, HA@PDA@EGCG
achieved renal protection by ameliorating oxidative stress, suppressing
inflammation and inhibiting ferroptosis through multiple pathways,
offering a novel strategy for targeted AKI therapy.
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Advanced Healthcare Materials
·
2026
·
IF 11
Xiangdong Wang,Nan Sheng,Feng Luo,Guiqing Jia,Ao Wang,Dan Lu,Zhen Li,Jiehua Li,Hong Tan,Gaoping Zhao
Colorectal cancer peritoneal metastasis (CRC-PM) often has poor prognosis after traditional hyperthermic intraperitoneal chemotherapy (HIPEC) due to constraints of respiratory movements, intestinal peristalsis and peritoneum plasma barrier. Herein, cisplatin and 17AAG were loaded into a thermoresponsive biodegradable polyurethane (PU) hydrogel, forming the CDDP/17AAG@PU system. This system showed favorable in vitro sustained release properties, controllable thermosensitive gelation at 43°C and excellent biocompatibility. Benefiting from the hydrogel's sustained release at safe doses, compared with the free drug group, this system significantly reduced serum biochemical abnormalities, as indicated by lower serum ALT/CREA levels and less apoptosis of normal intestinal cells. Moreover, its thermosensitive treatment enhanced antitumor efficacy by promoting DNA cross-linking and inhibiting oncogenic signaling-related proteins (p-PI3K, p-AKT, MMP2). In vivo experiments showed it more effectively inhibited CRC-PM compared to single-drug treatment and the control group. In conclusion, the safe, degradable CDDP/17AAG@PU system spreads to cover CRC-PM tumors at 37°C and gels rapidly at 43°C (clinical HIPEC temperature). It reduces antitumor drug induced hepatorenal toxicity, exerts good efficacy against CRC-PM and thus hold considerable potential for clinical translation.
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Chinese Journal of Natural Medicines
·
2026
·Vol. 24
·期 8
·972-986
·
IF 7.5
Chao Chen,Mengqi Wan,Zhixu Zhu,Zhaoyu Xie,Yu Zhang,Tao Xu,Han Meng,Miaomiao Wu,Liangfeng Gui,Hongbo Lv,Guodong Wang,Jun Han,Hui Che
Cisplatin (DDP) remains a standard therapy for triple-negative breast cancer (TNBC), yet intrinsic or acquired resistance often limits its efficacy; here, we report that Ramulus Mori alkaloids (SZ-A), an approved botanical α -glucosidase inhibitors, synergize with DDP to suppress TNBC progression in vitro and in vivo by driving PLA2G2A-dependent ceramide accumulation. Combining SZ-A with DDP synergistically inhibits viability, clonogenicity, migration, and invasion, induces S-phase arrest and apoptosis, and attenuates tumor growth in xenograft models. Mechanistically, SZ-A directly binds to and stabilizes PLA2G2A, blocking its autophagic-lysosomal degradation, leading to accumulated PLA2G2A that suppresses fatty acid oxidation and triggers ceramide accrual via ADIPOR2 inhibition. Genetic ablation of PLA2G2A abrogates these effects. DDP further enhances SZ-A-induced PLA2G2A upregulation and ceramide accumulation, resulting amplified cytotoxicity. Our findings reveal SZ-A as a chemosensitizing agent that enhances the efficacy of DDP in TNBC.
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