查找使用阿拉丁产品的科研文献

Molecular pharmacokinetic mechanism of quercetin-encapsulated polymeric micelles in alleviating cisplatin-induced nephrotoxicity and enhancing antineoplastic effects

Tangna Hao,Xiaokui Huo,Zhen Li,Changyuan Wang,Sha Wu,Anni Song,Fengyu Zhang,Kexin Liu

Introduction: Cisplatin (DDP), a platinum-based chemotherapy drug, shows broad antineoplastic activity, however, its clinical use is limited by dose-dependent nephrotoxicity, a major challenge in cancer therapy. The purpose of this study was to investigate the mechanism by which quercetin-polyethylene glycol-polycaprolactone (Que-PEG-PCL) micelles simultaneously enhance the cytotoxicity of DDP against cancer cells and reduce its nephrotoxicity.Methods: Rodent models and HEK293 cells were used to evaluate the renoprotective effects of Que-PEG-PCL micelles. Pharmacokinetics focused on OCT2-mediated renal DDP disposition. Antitumor activity was assessed in CT26 cells and syngeneic tumors. Key assessments included oxidative stress, apoptosis, renal markers, and histopathology.Results:: Que-PEG-PCL reduced DDP-induced nephrotoxicity, lowering creatinine and BUN to 42% and 38%. It also reduced oxidative stress and improved antioxidant activity. DDP plasma exposure increased to 323%, with renal clearance reduced to 14%, due to OCT2 inhibition. In a CT26 syngeneic model, combination therapy inhibited tumor volume by 84% compared to control group.Discussion: Que-PEG-PCL enhanced DDP’s therapeutic window by limiting renal accumulation and promoting tumor cell apoptosis. This dual-action strategy provides a novel approach for improving the clinical efficacy of DDP-based cancer therapy.

Coordination self-assembly of platinum–bisphosphonate polymer–metal complex nanoparticles for cisplatin delivery and effective cancer therapy

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.

Preparation and Optimization Lipid Nanocapsules to Enhance the Antitumor Efficacy of Cisplatin in Hepatocellular Carcinoma HepG2 Cells

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.

Polydatin activates the Nrf2/HO-1 signaling pathway to protect cisplatin-induced hearing loss in guinea pigs

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.

SOX2 mediates cisplatin resistance in small-cell lung cancer with downregulated expression of hsa-miR-340-5p

Fei Cui,Zhe-xue Hao,Jin Li,Ya-lei Zhang,Xu-kai Li,Jian-xing He

Background This study is aimed to unravel the genetic factors associated with microRNA (miRNA) expression in regulating sex-determining region Y-box 2 ( SOX2 )-mediated cisplatin resistance in small-cell lung cancer (SCLC). Methods The relevance of SOX2 expression in SCLC was analyzed in a panel of SCLC cells by quantitative real-time PCR (qPCR) and western blot (WB). We selected DMS114 cell line, in which SOX2 was amplified via lentiviral vector-mediated transfection of the SOX2 genes and tested for the half-maximal inhibitory concentration (IC 50 ) by MTS assay. High-throughput sequencing and screening of differentially expressed miRNAs between SOX2 -overexpressing and normal control cells were performed. Finally, miRanda software was used to verify the miRNAs bound with SOX2 and qPCR was used to identify the expression of miRNAs which were binding with SOX2 . Results Cisplatin-resistant SOX2 -overexpressing DMS114 cell lines were successfully developed, showing a statistically significant increase in SOX2 expression by qPCR and WB. Our results showed a typically higher IC 50 value in SOX2 -overexpressing cells compared with the negative controls. The high-throughput sequencing analysis revealed that 68 miRNAs were upregulated and 24 miRNAs were downregulated in the SOX2 -overexpressing cells. The 24 downregulated miRNAs were further verified. Of them, a cancer-related miRNA, hsa-miR-340-5p, showed a higher binding affinity with SOX2 in network regulation mapping, which was also found to be markedly downregulated under qPCR analysis. Conclusion We demonstrated that downregulated expression of hsa-miR-340-5p may affect cisplatin resistance by mediating SOX2 expression in SCLC cells, which may provide a potential target for the therapy of chemoresistant SCLCs.

Combination therapy based on dual-target biomimetic nano-delivery system for overcoming cisplatin resistance in hepatocellular carcinoma

Huang Yufen,Kou Qinjie,Su Yanrong,Lu Lu,Li Xisheng,Jiang Haiye,Gui Rong,Huang Rong,Nie Xinmin,Li Jian

Strategies to overcome toxicity and drug resistance caused by chemotherapeutic drugs for targeted therapy against hepatocellular carcinoma (HCC) are urgently needed. Previous studies revealed that high oxidored-nitro domain-containing protein 1(NOR1) expression in HCC was associated with cisplatin (DDP) resistance. Herein, a novel dual-targeting nanocarrier system AR-NADR was generated for the treatment of DDP resistance in HCC. The core of the nanocarrier system is the metal–organic frameworks (MOF) modified with nuclear location sequence (NLS), which loading with DDP and NOR1 shRNA (R). The shell is an A54 peptide inserted into the erythrocyte membrane (AR). Our results show that AR-NADR efficiently internalized by tumor cells due to its specific binding to the A54 receptors that are abundantly expressed on the surface of HCC cells and NLS peptide-mediated nuclear entry. Additionally, DDP is more likely to be released due to the degradation of Ag-MOF in the acidic tumor microenvironment. Moreover, by acting as a vector for gene delivery, AR-NADR effectively inhibits tumor drug resistance by suppressing the expression of NOR1, which induces intracellular DDP accumulation and makes cells sensitive to DDP. Finally, the anti-HCC efficacy and mechanisms of AR-NADR were systematically elucidated by a HepG2/DDP cell model as well as a tumor model. Therefore, AR-NADR constitutes a key strategy to achieve excellent gene silencing and antitumor efficacy, which provides effective gene therapy and precise treatment strategies for cisplatin resistance in HCC. Graphical Abstract

An engineered nanoplatform inhibiting energy metabolism and lysosomal activity of tumor cells to multiply cisplatin-based chemotherapy

Wei Jiang,Zuoxiu Tie,Chi Yu,Yu Chen,Dan Liu,Bin Li

Although inhibiting the energy metabolism of tumor cells has become an effective measure to enhance chemotherapy, tumor cells can still escape the lethal effect of chemotherapy by entering a dormancy state with low-energy expenditure. Herein, the glutathione (GSH)-responsive nanoplatform (C-A-D NPs) were constructed to inhibit energy metabolism and lysosomal activity of tumor cells, thereby forcing tumor cells to remain vulnerable to cisplatin . In this system, cisplatin prodrug was reduced to cisplatin by GSH, and D-peptide and apoptozole (Az) were released to inhibit the energy metabolism and autophagy-lysosome pathway of tumor cells. The suppressed autophagy-lysosome pathway prevents tumor cells from entering a low-energy dormancy state, resulting in the loss of resistance to the lethal effect of cisplatin with high-energy expenditure and insufficient energy supply. Such engineered nanoplatform effectively enhances the chemotherapeutic effect of cisplatin by inhibiting intracellular energy metabolism and lysosomal activity, showing great clinical prospects.

Using a High Quantum Yield Fluorescent Probe with Two-Photon Excitation to Detect Cisplatin in Biological Systems

Fang Fan,Li Zhang,Fangya Mu,Guoyue Shi

A direct detection protocol for the anticancer drug of cisplatin is highly desirable for studying its actions and side effects. In this work, a high quantum yield fluorescent probe with two-photon excitation to detect cisplatin was designed. The probe (RD640-TC) was based on the rhodamine 640 (Rh640) fluorophore, responding to cisplatin with red fluorescence. It showed an excellent linear correlation between the fluorescence response and the concentration of cisplatin over the range of 2–50 μM, suggesting a feasible tool for convenient detection of cisplatin. RD640-TC had high fluorescence quantum yield (Φ = 0.68) and two-photon absorption properties, which made it more favorable to probe cisplatin in biological systems. We exemplified RD640-TC for the detection of cisplatin in cells and zebrafish, providing an accessible tool for in vivo tracking of cisplatin, which has great potential value for studying how cisplatin is processed at cellular level and further for facilitating the investigation into the origin of cisplatin’s toxicity.

TMTP1-Modified, Tumor Microenvironment Responsive Nanoparticles Co-Deliver Cisplatin and Paclitaxel Prodrugs for Effective Cervical Cancer Therapy

Guiying Jiang,Xueqian Wang,Ying Zhou,Chenming Zou,Ling Wang,Wei Wang,Danya Zhang,Hanjie Xu,Jie Li,Fei Li,Danfeng Luo,Xiangyi Ma,Ding Ma,Songwei Tan,Rui Wei,Ling Xi

A DiR loaded tumor targeting theranostic cisplatin-icodextrin prodrug nanoparticle for imaging guided chemo-photothermal cancer therapy

Jiankun Guan,Yuxin Wu,Huimin Wang,Haowen Zeng,Zifu Li,Xiangliang Yang

Imaging-guided diagnosis and chemo-photothermal combination therapy have promising applications for the treatment of cancer. Nevertheless, the accurate diagnosis and efficient treatment of tumors are not yet satisfactory. Herein, a tumor targeting DiR loaded cisplatin-icodextrin prodrug nanoparticle, with selective drug release, was fabricated as a multifunctional theranostic nanoplatform for chemo-photothermal combination therapy. By loading DiR into the hydrophobic domain of folic acid-icodextrin-polycaprolactone (FA-ICO-PCL, FIP) and cisplatin-icodextrin-polycaprolactone (Pt-ICO-PCL, PtIP) co-assembly, the resultant DiR@(PtIP + FIP) (DPtFIP) NPs had a diameter of around 70 nm and showed excellent tumor targeting ability and negligible side effects. Moreover, the DPtFIP NPs achieved real-time NIR fluorescence imaging of solid tumors with high contrast. By the accurate tumor imaging, local laser irradiation dramatically enhanced the chemotherapy for triple-negative breast cancer. Such a biocompatible nanotherapeutic holds great potential for tumor diagnosis and imaging-guided combinational cancer therapy.

Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation

Zhang Cheng-cheng,Li Chen-guang,Wang Yao-feng,Xu Li-hui,He Xian-hui,Zeng Qiong-zhen,Zeng Chen-ying,Mai Feng-yi,Hu Bo,Ouyang Dong-yun

Gasdermin E (GSDME) has an important role in inducing secondary necrosis/pyroptosis. Upon apoptotic stimulation, it can be cleaved by activated caspase-3 to generate its N-terminal fragment (GSDME-NT), which executes pyroptosis by perforating the plasma membrane. GSDME is expressed in many human lung cancers including A549 cells. Paclitaxel and cisplatin are two representative chemotherapeutic agents for lung cancers, which induce apoptosis via different action mechanisms. However, it remains unclear whether they can induce GSDME-mediated secondary necrosis/pyroptosis in lung A549 cancer cells. Here we showed that both paclitaxel and cisplatin evidently induced apoptosis in A549 cells as revealed by the activation of multiple apoptotic markers. Notably, some of the dying cells displayed characteristic morphology of secondary necrosis/pyroptosis, by blowing large bubbles from the cellular membrane accompanied by caspase-3 activation and GSDME-NT generation. But the ability of cisplatin to induce this phenomenon was much stronger than that of paclitaxel. Consistent with this, cisplatin triggered much higher activation of caspase-3 and generation of GSDME-NT than paclitaxel, suggesting that the levels of secondary necrosis/pyroptosis correlated with the levels of active caspase-3 and GSDME-NT. Supporting this, caspase-3 specific inhibitor (Ac-DEVD-CHO) suppressed cisplatin-induced GSDME-NT generation and concurrently reduced the secondary necrosis/pyroptosis. Besides, GSDME knockdown significantly inhibited cisplatin- but not paclitaxel-induced secondary necrosis/pyroptosis. These results indicated that cisplatin induced higher levels of secondary necrosis/pyroptosis in A549 cells than paclitaxel, suggesting that cisplatin may provide additional advantages in the treatment of lung cancers with high levels of GSDME expression.

Highly stable polyglutamate derivatives/siRNA polyplex efficiently down-relegate survivin expression and augment the efficacy of cisplatin

Zhongjuan Wang,Haijuan Zou,Zirui Wang,Jiamin Wu,Zhongsheng Xia,Min Feng

RNA interfere (RNAi)-based technology holds great promise in cancer treatment. The use of small interfering RNA (siRNA), however, is hampered by its low delivery efficiency in vivo when they are diluted in blood biofluids and in the presence of serum and salt. In this study, we developed the polyglutamate derivative polymer brush, poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (mPEG-b-PG-g-spermine, PPGS), which could efficiently deliver survivin-siRNA under ultra-high dilution and in the presence of salt (NaCl 150   mM) and serum (10% FBS), most likely due to its PEG-shelled polymer brush structure. On the contrary, aggregation occurred when PEI/siRNA polyplex dispersed in saline and serum-containing media and PEI polyplex dissociated after making a 256-fold dilution. PPGS/si-survivin polyplex exhibited high cellular uptake efficiency and efficiently down-regulated the expression of survivin mRNA in the cisplatin-resistance of non-small cell human lung adenocarcinoma (A549/DDP) cells in the presence of serum. However, either PEI polyplex or Lipofectmine 2000 complex was unstable in serum and salt-containing media and at high dilution rates, which resulted in their dramatical decrease of cellular uptake and gene-silencing efficiency in these conditions. The PPGS/si-survivin polyplex also exhibited synergistic effects of killing the cancer cells by combination treatment with cisplatin . Therefore, the PPGS gene carrier showed great potential in systemic siRNA delivery, and its combination with chemotherapeutic drug is promising in treating drug resistant cancers.