查找使用阿拉丁产品的科研文献

Mild photothermal therapy/photodynamic therapy/chemotherapy of breast cancer by Lyp-1 modified Docetaxel/IR820 Co-loaded micelles

WenTing Li,JinRong Peng,LiWei Tan,Jing Wu,Kun Shi,Ying Qu,XiaWei Wei,ZhiYong Qian

Patients suffering from cancer have benefited from combination therapy. Nanocarriers are the ideal candidates for combination therapy. In this study, we constructed docetaxel (DTX) loaded micellar nanomedicines co-loaded with near infrared (NIR) dye-IR820 for photothermal therapy (PTT)/photodynamic therapy (PDT)/chemotherapy of breast cancer. Lyp-1, a tumor homing peptide, was introduced into the nanosystems to construct the active targeting nanomedicine. In order to deliver IR820 to the tumor site and overcome its short lifetime in vivo , a PEI derivative—PCL-g-PEI was introduced. IR820 with negative charge was formed stable static interaction with the amine groups, meanwhile, the absorption of IR820 in the NIR region was weakened. It indicated that the nanosystem constructed in this study may provide an alternative candidate for mild PTT. By the evaluation of the photothermal conversion in vivo , we can confirm that IR820 has been successfully delivered and effectively accumulated in the tumor site. Furthermore, the tumor cells targeting and anticancer performances of this nanosystem have been studied in vitro and in vivo . The results demonstrated Lyp-1 modification has enhanced the tumor targeting delivery of DTX and IR820. By combining PTT and PDT, DTX nanomedicine efficiently inhibited the growth and metastasis of breast cancer in mice. This nanosystem is a promising candidate for combination therapy of breast cancer.

Inhibition of the cGAS-STING pathway mitigates liver injury induced by docetaxel-carboplatin neoadjuvant chemotherapy via autophagy promotion

Song Hu,Linghui Kong,Mo Chen,Cheng Teng,Ying Zhao,Xiaohong Yuan,Shunv Cai,Xiaoyan Zhu,Pingbo Xu

The docetaxel-carboplatin (TCb) combination is a widely used neoadjuvant chemotherapy regimen, yet its clinical application is frequently accompanied by hepatotoxicity and drug-induced liver injury (DILI). However, the underlying molecular mechanisms remain incompletely understood. This study investigates the role of cGAS-STING-mediated autophagy in TCb-induced DILI. A TCb-induced DILI mouse model is established by intraperitoneal administration of docetaxel (10 mg/kg) and carboplatin (50 mg/kg) once weekly for two weeks, alongside an in vitro AML12 hepatocyte model (docetaxel 20 μM + carboplatin 100 μM). Liver injury, apoptosis, autophagy, and cGAS-STING signaling are evaluated using histopathological staining, biochemical assays, RT-qPCR, western blotting, immunofluorescence, and immunohistochemistry. TCb treatment induces significant liver injury, as evidenced by elevated serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL), histopathological damage, and increased collagen deposition. TCb markedly promotes hepatocyte apoptosis, characterized by increased expression of Bcl-2 associated X protein (BAX) and decreased expression of Bcl-2. Concomitantly, TCb suppresses basal autophagy, as indicated by p62 accumulation, reduced Beclin-1 expression, decreased LC3-II/I ratio, and diminished autophagosome formation. Mechanistically, TCb robustly activates the cGAS-STING pathway, accompanied by enhanced phosphorylation of TBK1 and IRF3. Notably, pharmacological inhibition of STING with C-176 or siRNA-mediated STING knockdown restores autophagic flux and significantly attenuates TCb-induced apoptosis. Collectively, these findings suggest that sustained activation of the cGAS-STING pathway contributes to TCb-induced DILI by impairing autophagic homeostasis and promoting hepatocyte apoptosis. Targeting cGAS-STING-mediated autophagy represents a potential therapeutic strategy for preventing chemotherapy-associated hepatotoxicity.

Precisely albumin-hitchhiking tumor cell-activated reduction/oxidation-responsive docetaxel prodrugs for the hyperselective treatment of breast cancer

Wei Wei,Cong Luo,Jincheng Yang,Bingjun Sun,Dongyang Zhao,Yan Liu,Yingli Wang,Wenqian Yang,Qiming Kan,Jin Sun,Zhonggui He

The anticancer efficacy of chemotherapy is greatly limited by short blood circulation and poor tumor selectivity. Thus, anticancer prodrugs with prolonged systemic circulation , tumor-specific distribution and bioactivation , could significantly strengthen the chemotherapy efficacy. Herein, we design two novel tumor cell reduction/oxidation-responsive docetaxel (DTX) prodrugs, DTX-maleimide conjugates with disulfide bond (DSSM) or thioether bond (DSM) linkages, to evaluate the roles of different sensitive linkages in drug release, pharmacokinetics and therapeutic efficacy. An ester bond-linkage prodrug (DM) is utilized as a non-sensitive control. DSSM and DSM show reduction- or oxidation-sensitive release behavior, respectively, and exhibit hyperselective bioactivation and cytotoxicities between cancerous and normal cells. They could instantly hitchhike blood circulating albumin after i.v. administration with albumin-binding half-lives as short as 1 min, resulting in prolonged systemic circulation, increased tumor accumulation. In response to the upregulated reduction/oxidation environment within tumor cells, DSSM and DSM exhibit selectively release capacity in tumor tissues, their TAI Tumor/Liver values are over 30-fold greater than DM. Combining the above delivery advantages into one, DSSM and DSM achieve enhanced antitumor efficacy of DTX. Such a uniquely developed strategy, integrating high albumin-binding capability and reduction/oxidation-sensitive drug superselective release in tumors, has great potential to be applied in clinical cancer therapy.

Significant Suppression of Non-small-cell Lung Cancer by Hydrophobic Poly(ester amide) Nanoparticles with High Docetaxel Loading

Chen Xing,Zhao Lili,Kang Yang,He Zhiyu,Xiong Fei,Ling Xiang,Wu Jun

Non-small-cell lung cancer (NSCLC) accounts for over 85% of clinical lung cancer cases, which is the leading cause of cancer-related death. To develop new therapeutic strategy for NSCLC, a library of L-phenylalanine-based poly(ester amide) (Phe-PEA) polymers was synthesized and assembled with docetaxel (Dtxl) to form Dtxl-loaded Phe-PEA nanoparticles (NPs). The hydrophobic Phe-PEA polymers were able to form NPs by nanoprecipitation method and the characterization results showed that the screened Dtxl-8P4 NPs have small particle size (∼100 nm) and high Dtxl loading (∼20 wt%). In vitro experiments showed that Dtxl-8P4 NPs were rapidly trafficked into cancer cells, then effectively escaped from lysosomal degradation and achieved significant tumor cell inhibition. In vivo results demonstrated that Dtxl-8P4 NPs with prolonged blood circulation could efficiently deliver Dtxl to A549 tumor sites, leading to reduced cell proliferation, block metastasis, and increase apoptosis, then persistent inhibition of tumor growth. Therefore, Phe-PEA NPs are able to load high amount of hydrophobic drugs and could be a promising therapeutic approach for NSCLC and other cancer treatments.

Targeted delivery of docetaxel via Pi-Pi stacking stabilized dendritic polymeric micelles for enhanced therapy of liver cancer

Xiaolong Tang,Shuping Zhou,Xinrong Tao,Jian Wang,Fangyu Wang,Yong Liang

Delivery of taxane-based chemotherapeutics including Docetaxel (DTX) by conventional polymeric micelles still suffers from insufficient stability and rapid premature release during the circulation, which limits their targeting and anticancer efficiency. To conquer these challenges, we developed a novel DTX-loaded Pi-Pi stacking-stabilized dendritic polymeric micelle for targeted therapy of liver cancer. This dendritic polymeric micelle, referred to DPM-DTX-cRGD, was self-assembled from DTX and biodegradable dendritic block copolymers Poly(amidoamine)-poly(γ-benzyl- l -Glutamate)- b -polyethylene glycol-cRGD (PAM-PBLG- b -PEG-cRGD). DPM-DTX-cRGD held robust stability due to its covalent dendritic structure and would load abundant DTX with excellent retention via Pi-Pi stacking between DTX and the aromatic groups of the PBLG segments. The cellular uptake studies demonstrated that the cRGD-conjugated dendritic polymeric micelle (DPM) exhibited much higher cellular uptake in human liver cancer HepG2 cells than non-targeted DPM. The MTT assay also confirmed that DPM-DTX-cRGD caused much greater cytotoxicity than non-targeted DPM-DTX and a clinically available DTX formulation (Taxotere®). Therefore, this DPM-DTX-cRGD provides a novel attractive approach for targeted therapy of liver cancer.

Tumor-targeted docetaxel-loaded hyaluronic acid-quercetin polymeric micelles with p-gp inhibitory property for hepatic cancer therapy

Chenfeng Xu,Yu Ding,Jiang Ni,Lifang Yin,Jianping Zhou,Jing Yao

Docetaxel (DTX) has profound effects on several hepatic cancer (HC) cells, but shows unsatisfactory clinical efficacy due to the lack of tumor specificity and p-gp mediated drug efflux. Herein, a novel targeted drug delivery nanosystem based on hyaluronic acid (HA) and quercetin (QU) was designed to improve the in vivo therapeutic efficacy of DTX on HC through HA-CD44 mediated targeting and QU-based p-gp efflux inhibition. DTX-loaded HA–QU polymeric micelles (DTX/HA–QU PMs) displayed a mean particle size of 176.8 ± 3.4 nm with a low polydispersity index (<0.2). The drug loading and entrapment efficiency were 23.6 ± 1.3% and 86.8 ± 1.8%, respectively. Not only did the nanosystem facilitate cellular uptake via HA-CD44 mediated endocytosis, but it also preferentially accumulated at the tumor site via the EPR effect. Moreover, DTX/HA–QU PMs showed prolonged circulation time and high stability in the bloodstream, and achieved AUC0–∞ and t1/2 values that were 3.0-fold and 5.51-fold higher than those of Taxotere®, respectively. In addition, an in vitro cytotoxicity study showed that DTX/HA–QU PMs were 13.6-fold more effective than Taxotere®, judging by the IC50. Importantly, DTX/HA–QU PMs presented the highest antitumor efficacy in a xenograft tumor-bearing mice model and the tumor inhibition ratio was 73.91%. Meanwhile, DTX/HA–QU PMs could down-regulate p-gp expression in tumor cells. These results suggested that the targeting moiety and p-gp efflux inhibitory property help DTX to accumulate at the tumor site and improve its antitumor efficacy in vivo.

Docetaxel-loaded exosomes for targeting non-small cell lung cancer: preparation and evaluation in vitro and in vivo

Ying Wang,Mimi Guo,Dingmei Lin,Dajun Liang,Ling Zhao,Ruizhi Zhao,Yan Wang

Non-small cell lung cancer (NSCLC) is a highly lethal disease and the majority of NSCLC patients are desperate for therapies that can effectively target their cancer and ultimately improve their overall survival. Docetaxel (DTX) represents the first-line of the antitumor agent that is used to treat NSCLC; however, it has poor solubility in water and unsatisfactory encapsulation efficiency. In our study, exosomes were isolated from A549 cancer cells by ultracentrifugation and then characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). The particle size changes of EXO and EXO-DTX were measured daily for seven days to test the stability. DTX was selected payload by electroporation (EXO-DTX). For the in vitro evaluation, cell proliferation, cell cycle, cell apoptosis, reactive oxygen species (ROS) assay and cellular uptake were evaluated in the A549 cells. Also, this study evaluated the target and therapeutic effect of DTX as an antitumor agent in vivo. As a result, EXO-DTX with a particle size of 149.5 nm were successfully prepared and the cytotoxicity of the EXO-DTX was much greater than that of DTX monomers. Exosomes significantly increased the cellular uptake in vitro evaluation and showed better targeting to tumor tissue compared to the free DTX in the mice. We also explored the potential of tumor cell-derived exosomes as a drug delivery agent to target the parent cancer. Hence, we conclude that exosomes might be used as a potential antitumor drug delivery system (DDS).

The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies

Shuo Wang,Tian Liu,Yuetong Huang,Chaoying Du,Danping Wang,Xiyan Wang,Qingzhi Lv,Zhonggui He,Yinglei Zhai,Bingjun Sun,Jin Sun

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C 16 , C 18 , C 20 , and C 24 ). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules’ sensitivity. The extension of the carbon chains improved the prodrugs’ self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C 20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.

Tumor cell membrane-camouflaged nanoparticles co-delivering docetaxel and metformin for enhanced synergistic therapy of HER2-positive breast cancer

Guodong Shen,Ting Zhao,Yi Shen,Yimin Zhu,Yuxin Mei,Xiaoyan Yang,Lian Lian

The clinical efficacy of docetaxel (DTX) in treating HER2-positive breast cancer is hampered by poor solubility and systemic toxicity, while metformin (Met) shows anti-cancer potential by targeting tumor metabolism. We hypothesized that a biomimetic nanoplatform co-delivering DTX and Met could achieve synergistic anti-tumor effects with enhanced safety. This study developed tumor cell membrane-camouflaged mesoporous silica nanoparticles co-loaded with DTX and Met (mem(DTX&Met@MSNs)). The nanoparticles were characterized for particle size, stability, drug loading, and membrane coating. In vitro assays were conducted to assess cellular uptake, cytotoxicity, and synergistic effects. In vivo studies were performed in HER2-positive breast cancer-bearing mice to evaluate biodistribution, anti-tumor efficacy, toxicity, and histopathology. The mem(DTX&Met@MSNs) nanoparticles showed a core-shell structure and pH-responsive release, with over 80% drug release at pH 6.5 versus less than 40% at pH 7.4. Biomimetic coating enabled homologous targeting, enhancing cellular uptake and synergistic cytotoxicity in SK-BR-3 cells (7.89% apoptosis). In vivo, the system prolonged the circulation half-life to nearly 6 h, effectively suppressed tumor growth, and demonstrated excellent biocompatibility with no significant toxicity or body weight loss. In conclusion, mem(DTX&Met@MSNs) integrates homologous targeting with dual-drug synergism, offering a safe and effective strategy for the treatment of HER2-positive breast cancer.

Extracellular Matrix Stiffness Enhancement Promotes Docetaxel Resistance in Prostate Cancer via Inhibition of Apoptosis Mediated by Upregulation of PRRX1

Chen Jiahao,Chen Mengting,Xie Zhiwen,Shen Luheng,Jiang Juntao,Xia Shujie

Background: Prostate cancer (PCa) poses a significant health burden for men, with docetaxel constituting the primary therapeutic option for patients with metastatic PCa. However, the mechanisms governing docetaxel resistance remain incompletely understood. Several studies have implicated the role of the extracellular matrix (ECM) stiffness in cancer drug resistance, yet the precise role of ECM stiffness in docetaxel resistance in PCa remains elusive. The aim of this study was to explore the influence of ECM stiffness on docetaxel resistance in PCa and elucidate the underlying molecular mechanisms, thereby providing novel insights into PCa treatment.Methods: Polyacrylamide gels of varying stiffness were utilized to mimic different ECM stiffness conditions. The sensitivity of PCa cells to docetaxel was evaluated using CCK-8, TUNEL staining, flow cytometry, and western blotting. RNA-seq was employed to analyze the transcriptomic effects of different ECM stiffness on PC-3 cells. Western blotting, qPCR, and siRNA were utilized to validate the regulatory role of the key gene in the sensitivity of PCa cells to docetaxel under varying stiffness conditions.Results: Our findings indicate that high ECM stiffness enhances docetaxel resistance in PCa cells by inhibiting docetaxel-induced apoptosis. This process is mediated through the integrin-related mechanotransduction pathway. Specifically, high ECM stiffness upregulates the expression of PRRX1, thereby promoting docetaxel resistance in PCa cells.Conclusions: High ECM stiffness promotes docetaxel resistance in PCa, with PRRX1 identified as a pivotal gene in this process. These findings contribute to a deeper understanding of the mechanisms underlying docetaxel resistance in PCa and may inform the development of novel therapeutic strategies.

Polysaccharide dextran-based conjugate for selective co-delivery of two synergistic drugs docetaxel and docosahexaenoic acid to tumor cells

Peng Dong,Hongshuai Lv,Weiping Jia,Jiaojiao Liu,Si Wang,Xiaohai Li,Jinghua Hu,Ling Zhao,Yikang Shi

Polymeric complex micelles based on the double-hydrazone linkage and dual drug-loading strategy for pH-sensitive docetaxel delivery

Zhihui Su,Yanchao Liang,Yao Yao,Tianqi Wang,Na Zhang

Stimuli-triggered drug release and improved drug loading are two key prerequisites in the preparation of nano-drug delivery systems. Herein, we constructed the first pluronic P123-double (d)–hydrazone bond (hyd)–docetaxel (DTX)/DTX complex micelles (P123-d–hyd–DTX/DTX) which integrated the highly pH-sensitive strategy and the dual drug-loading pattern in one platform. We synthesized pluronic P123-double (d)–hydrazone bond (hyd)–docetaxel (DTX) conjugates (P123-d–hyd–DTX) by conjugating DTX to the PEO chains of P123 via two hydrazone linkages in the backbone for the first time. An increase in the number of hydrazone linkages within the unimolecular conjugate was conducive to improve the pH sensitivity of conjugated-based micelles. Besides, aiming at improving drug loading, the dual drug-loading strategy (chemical conjugation and physical encapsulation) was adopted. Namely, pH-sensitive P123-d–hyd–DTX was used as a vehicle to further encapsulate DTX for preparing P123-d–hyd–DTX/DTX complex micelles. The resulting P123-d–hyd–DTX/DTX micelles exhibited intact spherical shape, uniform particle size distribution (110.37 nm) and higher drug loading (12.64%). The release study in vitro confirmed that P123-d–hyd–DTX/DTX micelles and P123-d–hyd–DTX micelles (as a control) showed highly pH-responsive release properties. In particular at pH 6.5, almost 90.9% and 75% of DTX was released within 48 h, respectively. Compared to P123-d–hyd–DTX micelles, P123-d–hyd–DTX/DTX complex micelles exhibited higher proliferation inhibition effects on B16F10 cells (p < 0.01), while the cytotoxicity of P123-d–hyd–DTX/DTX complex micelles was slightly inferior to that of free DTX (p < 0.05). In the xenograft B16F10 melanoma model, P123-d–hyd–DTX/DTX complex micelles suppressed tumor growth more effectively than Duopafei® (p < 0.01) and P123-d–hyd–DTX micelles (p < 0.05), without causing obvious adverse effects. Overall, the novel polymeric complex micelle based on double-hydrazone bond and dual drug-loading strategies was a promising delivery platform to improve therapeutic efficiency and decrease side effects in cancer treatments.