查找使用阿拉丁产品的科研文献

Isoginkgetin synergizes with doxorubicin for robust co-delivery to induce autophagic cell death in hepatocellular carcinoma

Yang Wang,Yunfei Yi,Jie Yao,Haoqiang Wan,Mian Yu,Lanlan Ge,Xiaobin Zeng,Meiying Wu,Lin Mei

Doxorubicin (DOX) widely used in hepatocellular carcinoma (HCC) can induce serious side effects and drug resistance. Herein, we aimed to seek a strategy to improve the efficacy and reduce the side effects of DOX in HCC based on an autophagy inducer drug called isoginkgetin (ISO). The design of multifunctional nanocarriers based on hyaluronic acid-conjugated and manganese-doped mesoporous silica nanoparticles (HM) for the co-delivery of antitumor drugs against HCC provided an effective and promising antitumor strategy. Our results showed that [email protected] @DOX could efficiently inhibit HCC cell proliferation through activating autophagy through AMPKa-ULK1 pathway. Moreover, intravenous injection of [email protected] @DOX significantly suppressed HCC tumor progression in nude mouse HCC model. Collectively, our findings revealed an anti-HCC mechanism of [email protected] @DOX through autophagy and provide an effective therapeutic strategy for HCC. Statement of significance In our study, we constructed a co-delivery system by loading ISO and DOX in the mesoporous channels of manganese-doped mesoporous silica nanoparticles, which could be further conjugated with hyaluronic acid to obtain [email protected] @DOX. The nanocarriers had been demonstrated to be biodegradable under the acidic and reducing tumor microenvironment, as well as to possess the tumor targeting capability via the conjugated hyaluronic acid. In addition, [email protected] @DOX enhanced the therapeutic efficacy against human HCC tumor through the combinatorial therapies of chemotherapeutics, Mn 2+ -mediated chemodynamic therapeutics and autophagic cell death, which might be achieved through AMPK-ULK1 signaling. This work revealed that such a nanomedicine exhibited superior tumor accumulation and antitumor efficiency against HCC with extremely low systemic toxicity in an autophagy-boosted manner.

Synthesis of Doxorubicin-Loaded Nanobubble and Its Effect on Targeted Therapy for Patients with Ovarian Cancer

Jiang Ning,Cao Fang

Nanomedicine has developed rapidly for improving the solubility of anti-cancer drugs, prolonging the circulation time in the body, and enhancing the accumulation in the lesion through the enhanced permeability and retention (EPR) effect. First, a new type of dithiolane trimethylene carbonate (MGN) was synthesized, and an amphiphilic polymer PEG-P (ERF-MGN) was synthesized based on MGN and trimethylene carbonate (ERF). Then, N-hydroxysuccinimide (NHS)-PEG-P (ERF-MGN) was prepared by further polymerizing NHS, which was amidated with polypeptide to obtain CC11-PEG-P (ERF-MGN). Finally, it was reacted with PEG-P (ERF-MGN) (mass ratio was 1:4), and CC11-PS was made by solvent exchange method. Through pH gradient method, doxorubicin (Dox) was loaded to prepare Dox nanobubble (CC11-PS-Dox). The prepared nanobubble was compared with the commonly utilized polyethylene glycol liposome Dox (Lipo-Dox) for tumor suppression, and CC11-PS-Dox had a relatively higher tolerated dose. After intravenous administration at a dose of 150 mg/kg, tumor growth in ovarian cancer mice bearing SKOV-3 was effectively inhibited, toxic and side effects were reduced, and the survival time of mice was dramatically increased (P < 0.05). In addition, CC11-PS-Dox was configured as a solution injected into patients with ovarian cancer, phosphate buffer saline (PBS) was injected as a control, and the tumor was irradiated with near-infrared laser (NIR). The tumor’s warming range was detected, and the tumor tissue was removed and stained with hematoxylin-eosin (HE) to observe the growth of the tumor. The results showed that CC11-PS-Dox + NIR can promote the tumor to heat up to 55 °C or more, while PBS + NIR can only promote the tumor to heat up to 37 °C. HE staining results showed that CC11-PS-Dox + NIR can promote tumor loss and cause cell damage. Therefore, it was verified that CC11-PS-Dox can be adopted for photothermal treatment of ovarian cancer.

Quantitative subcellular study of transferrin receptor-targeted doxorubicin and its metabolite in human breast cancer cells

Xu Jinhui,Sheng Yuan,Xu Feifei,Yu Ying,Chen Yun

The extended use of doxorubicin (DOX) could be limited due to the emergence of drug resistance and cardiotoxicity associated with its treatment. Conjugates of DOX with transferrin (DOX–TRF) can effectively alleviate these side effects, thereby leading to a better treatment. The effectiveness of DOX–TRF could result from the enhancement of transferrin receptor (TfR)-mediated transportation. However, detailed TfR-mediated DOX delivery has not been fully elucidated thus far, which may rely on the quantitative subcellular study of DOX distribution and metabolism. In this study, an immunoisolation assay was developed to isolate the organelles with high purity, yield and integrity. Using this immunoisolation assay together with liquid chromatography–tandem mass spectrometry (LC/MS/MS), the subcellular distribution profiles of DOX and its main metabolite doxorubicinol (DOXol) in human breast cancer cells MCF-7/WT and MCF-7/ADR were determined and compared after the treatment of DOX and DOX–TRF. As expected, DOX–TRF treated cells have a higher drug accumulation compared to DOX treated cells. DOX–TRF was predominantly cytoplasmic. In addition, TfR-mediated transportation had a significant impact on the transformation of DOX to DOXol in the cells. This study provided the evidence that immunoisolation together with LC/MS/MS is an effective technique in subcellular investigations.

Double-loop hairpin probe and doxorubicin-loaded gold nanoparticles for the ultrasensitive electrochemical sensing of microRNA

Yiyi Tao,Dan Yin,Mingchao Jin,Jie Fang,Tao Dai,Yi Li,Yuxia Li,Qinli Pu,Guoming Xie

An electrochemical microRNA (miRNA) analysis platform by combining double-loop hairpin probe (DHP) and doxorubicin-loaded gold nanoparticles ( [email protected] ) for ultrasensitive miRNA detection is proposed. Firstly, we here report a DHP that is simultaneously engineered to incorporate a miRNA recognition sequence, an output segment and output's complementary fragment. The important aspect of this hairpin probe is that it would not be degraded by duplex specific nuclease (DSN) and circumvents elaborately chemical modification disadvantages encountered by classic molecular beacon . For the DHP-based DSN signal amplification system, DHP hybridizes with target miRNA to form DNA-miRNA heteroduplexes , and the DSN can hydrolyze the DNA in the heteroduplexes structure selectively, while released target miRNA strand can initiate another cycle resulting in a significant signal amplification and the accumulated output segments could be responsible for strand displacement on the electrode directly. Furthermore, a great deal of doxorubicin (Dox) are loaded on the gold nanoparticles (AuNPs) to fabricate the [email protected] biocomposites that could magnify the electrochemical signal and enable the ultrasensitive analysis of miRNA. As a result, the miRNA was capable of being detected in a limit of 0.17   pM and other kinds of miRNA were discriminated facilely by this method. The described DHP as a toolbox and the nano-biocomposites as a novel signal material would not only promote the design of electrochemical biosensors but also open a good way to promote the establishment of test method in malignant tumors.

Modification-Driven Nanocarriers: Ovarian Cancer Cell Membrane– Camouflaged Indoximod/Doxorubicin Co-Delivery Systems for Synergistic Immunochemotherapy

Yiyin Ruan,Huijie Han,Xin Guan,Weiwei Feng,Xiaojuan Cui

Among the three primary gynecological malignancies, ovarian cancer has the highest mortality rate, and its onset is often insidious. Despite standard treatments, relapse and drug resistance remain major challenges. Doxorubicin (DOX) is known to induce immunogenic cell death (ICD); however, some patients still experience tumor resistance and recurrence owing to tumor-driven immunosuppression. Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in tumor tissues, impairs T-cell function and differentiation, thereby promoting immunosuppression. Consequently, combining the IDO inhibitor indoximod (IND) with DOX may reverse immunosuppression and enhance both T-cell–mediated and ICD-driven anticancer effects. However, both drugs are limited by high systemic toxicity and poor tumor targeting, necessitating the use of nanocarriers to improve delivery efficiency and minimize toxicity. This study aims to develop novel cell membrane–camouflaged liposomes capable of co-delivering IND and DOX (DOX/IND@cmLPs) for ovarian cancer therapy and to evaluate its anticancer effects in vitro and in vivo. The particle size of DOX/IND@cmLPs is measured as 111.7 ± 2.7 nm using a Malvern Zetasizer Pro, with a zeta potential of −22.4 ± 4.00 mV. Entrapment efficiency (EE) is assessed using ultra-high performance liquid chromatography and ultraviolet spectrophotometry, yielding EE values of 85.1% ± 3.4% for DOX and 23.9% ± 1.3% for IND. At both pH 7.4 and pH 5.5, DOX release from DOX/IND@cmLPs is rapid during the first 24 hours, followed by a slower, more sustained release. Coomassie Brilliant Blue staining and Western Blot analysis confirmed successful encapsulation of the cell membrane in the liposomes. The potent antitumor effect of DOX/IND@cmLPs is demonstrated via CellTiter-Glo assays in vitro. Flow cytometry and immunofluorescence staining revealed an increased ratio of CD8 + T cells to Treg cells in tumor tissues, suggesting that DOX/IND@cmLPs may partially reverse local tumor-induced immunosuppression. Reduced Ki-67 expression and increased TdT-mediated dUTP nick-end labeling positive cell ratios in tumor sections indicated that DOX/IND@cmLPs treatment suppressed tumor proliferation and promoted apoptosis. Immunohistochemistry showed alterations in mammalian target of rapamycin (mTOR)-related pathway proteins in tumors. Furthermore, DOX/IND@cmLPs could induce an abscopal effect and provide long-lasting tumor suppression in a subcutaneous mouse model. In this study, a formulation of DOX/IND-loaded liposomes camouflaged with ovarian cancer cell membranes is successfully developed, and their stable physicochemical properties are confirmed. As an effective nanodrug delivery system, DOX/IND@cmLPs exhibited enhanced tumor-targeting and immune-mediated anticancer activity both in vitro and in vivo, indicating their potential as a platform for future combined chemotherapy and immunotherapy.

A comparative study of the in vitro antitumor effect of mannose-doxorubicin conjugates with different linkers

Xinxin Cui,Kunda Du,Xiaoyin Yuan,Wen Xiao,Yayu Tao,Defeng Xu,Hang Hu

In this work, five Man-DOX conjugates with different linkers were developed for targeted DOX delivery. The five Man-DOX conjugates with different linkers were characterized by 1 H NMR, HRMS, HPLC, UV–vis, and fluorescence spectroscopy. Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX can self-assemble into near-spherical nanoparticles with hydrodynamic diameters of 150–200 nm and negative zeta potentials in deionized water, whereas Man-SS-DOX and Man-SeSe-DOX are hardly dispersed in deionized water. The self-assembly behaviors of Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX were studied by dissipative particle dynamics simulation and the results show that Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX all self-assemble into spherical particles with Man and linkers on the surfaces and DOX in the interiors. The in vitro drug release study shows that Man-Suc-DOX, Man-TDG-DOX, and Man-DG-DOX exhibit limited drug release, while Man-SS-DOX and Man-SeSe-DOX exhibit glutathione-responsive drug release. The cellular uptake study shows that Man-DG-DOX exhibits the highest cellular uptake amount on HepG2 cells. Finally, Man-DG-DOX exhibits the best in vitro antitumor effect against HepG2 cells among the five Man-DOX conjugates with different linkers. Although the in vitro antitumor activity of Man-DG-DOX is still lower than free DOX, Man-DG-DOX shows significant selectivity toward HepG2 cells. Man-DG-DOX might achieve selective DOX delivery for mannose receptor overexpressed tumors.

Reduction-sensitive mixed micelles based on mPEG-SS-PzLL /TPGS to enhance anticancer efficiency of doxorubicin

Guoguang Chen,Qiqi Zheng,Jie Dai,Jia Liu,Jun Yin,Xiaoqing Xu,Aiping Chen,Lili Ren

Currently, the drawbacks of the chemotherapy drugs are still demonstrated poor water solubility, systemic toxicity and even multidrug resistance (MDR) in clinical applications. To address these problems, an amphiphilic block polymer self-assembled reduction sensitive micelle , mPEG-SS-PzLL/TPGS/DOX, was synthesized for efficient anticancer therapy. The polymer had a biodegradable backbone and disulfide bond can be cleaved by reduced glutathione (GHS) in tumor cells, which led to fast release of the DOX . TPGS was designed for an increaseing drug accumulation and a reduction in drug efflux. In follow-up research, we found that mPEG-SS-PzLL/TPGS/DOX micelles achieved a high encapsulation efficiency of 96.1%. Photomicrographs gotten by TEM showed homogeneous and spherical-shaped particles with the particl size of 83.7 ± 3.2 nm. The in vitro release in high reducing conditions reached 96% within 48 h. Furthermore, the mPEG-SS-PzLL/TPGS/DOX micelles caused stronger cytotoxicity to 4 T1 cells and promising therapeutic efficacy for BALB/c mice bearing 4 T1 tumors. Therefore, an excellent drug delivery system was created by combing restore sensitivity with multidrug resistance strategy while maximize drug accumulation in tumor cells. Alternatively, this study offers a bright perspective for cancer therapy with chemotherapeutics.

Direct electrochemistry of doxorubicin and its ultra-sensitive detection using a novel porous thorny carbon dodecahedron

Yongchang Ouyang,Miao Liang,Fangzhen Wang,Songqing Mei,Guangquan Mo

Herein, supported by the attractive structure of zeolitic imidazolate frameworks (ZIFs), novel porous thorny carbon dodecahedron implanted with hollow cobalt oxide nanospheres (PCD-HC) was prepared by the two-step pyrolysis of ZIFs. Morphology and structure investigations showed that PCD-HC was a highly porous rhombic dodecahedron embedded with hollow nanospheres. Elemental mapping revealed that the main dodecahedral structure of PCD-HC was a carbonized framework doped with N species. Besides, well-defined hollow Co3O4 nanospheres with abundant O vacancies were implanted. Due to the highly porous structure, embedded active species, and graphite-like structure, PCD-HC displayed distinguished electrocatalysis towards doxorubicin (DOX) with a pair of highly symmetric redox peaks and fast direct electron transfer of anthracycline. The direct electrochemistry and catalytic mechanism of the DOX redox reaction at PCD-HC were elucidated, and a PCD-HC based electrochemical sensor was developed for the DOX sensing with a broad linear range from 1.0 nM to 1.0 μM. The limit of detection was obtained as 0.15 nM (S/N = 3). Besides, PCD-HC sensor also displayed a wide detection range at a high concentration from 2.0 to 12.0 μM. Moreover, PCD-HC sensor presented a high selectivity with strong anti-interference capability towards common inorganic ions and small biomolecules. The reproducibility, repeatability, and stability were examined with satisfactory results. Significantly, a PCD-HC sensor was applied in the monitoring of DOX in HeLa cells inhibiting process, indicating a substantial detection platform for DOX sensing.

Sequential therapy with redox-responsive glucolipid nanocarrier separately delivering siRNA and doxorubicin to overcome multidrug resistance

Tingting Meng,Binbin Lu,Shihong Shao,Ming Yuan,Xuan Liu,Hong Yuan,Xuan Huang,Fuqiang Hu

P-glycoprotein (P-gp) is a major efflux transporter overexpressed on multidrug resistant tumor cells and responsible for pumping drugs out. If anti-tumor drugs are given when P-gp level is low, satisfactory treatment efficiency may be achieved. Thus, a P-gp down-regulating siRNA (siMDR1) and doxorubicin (DOX) were applied to eliminate multidrug resistant breast cancer cells (MCF-7/ADR). A redox-responsive glucolipid conjugate (CSO-ss-SA) was used to condense siRNA (CSO-ss-SA/siRNA) and encapsulate DOX (CSO-ss-SA/DOX) separately. They responded to the high reducing environment of tumor cells and fast released the payload. CSO-ss-SA/siMDR1 silenced MDR1 gene and resulted in a transient decrease of P-gp. Sequentially, DOX formulation (CSO-ss-SA/DOX or DOX·HCl) was delivered when P-gp was reduced to the lowest level. After pretreatment by CSO-ss-SA/siMDR1, cytotoxicity of CSO-ss-SA/DOX and DOX·HCl against MCF-7/ADR cells were 6.4 or 3.4-fold respectively of that treated by DOX·HCl alone, which exhibited increased cytotoxin sensitivity of drug resistant cells and maximized therapeutic outcomes. These results revealed that the sequential treatment strategy of CSO-ss-SA/siRNA and CSO-ss-SA/DOX hold potential in achieving an optimal overcoming multidrug resistance efficiency.

Mitigating Doxorubicin-Induced Cardiotoxicity and Enhancing Anti-Tumor Efficacy with a Metformin-Integrated Self-Assembled Nanomedicine

Jiaxin Huang,Jieru Yang,Yuanying Yang,Xiaofeng Lu,Juan Xu,Shan Lu,Hong Pan,Wenhu Zhou,Wenqun Li,Songwen Chen

Doxorubicin (Dox) is a potent chemotherapeutic agent commonly used in cancer treatment. However, cardiotoxicity severely limited its clinical application. To address this challenge, a novel self-assembled nanomedicine platform, PMDDH, is developed for the co-delivery of Dox and metformin, an antidiabetic drug with cardioprotective and anti-tumor properties. PMDDH integrates metformin into a polyethyleneimine-based bioactive excipient (PMet), with Dox intercalated into double-stranded DNA and a hyaluronic acid (HA) coating to enhance tumor targeting. The PMDDH significantly improves the pharmacokinetics and tumor-targeting capabilities of Dox, while metformin enhances the drug's anti-tumor activity by downregulating programmed cell death ligand 1 (PD-L1) and activating the AMP-activated protein kinase (AMPK) signaling pathway. Additionally, the DNA component stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which synergizes with Dox-induced immunogenic cell death (ICD) to promote a robust anti-tumor immune response. PMDDH markedly reduces Dox-induced cardiotoxicity by preserving mitochondrial function, reducing reactive oxygen species (ROS) production, and inducing protective autophagy in cardiomyocytes. These findings position PMDDH as a promising dual-function nanomedicine that enhances the anti-tumor efficacy of Dox while minimizing its systemic toxicity, offering a safer and more effective alternative for cancer therapy.

Facile preparation of pH/reduction dual-stimuli responsive dextran nanogel as environment-sensitive carrier of doxorubicin

Kun Yu,Xiyao Yang,Lihua He,Rong Zheng,Jie Min,Hongying Su,Shaoyun Shan,Qingming Jia

Dual and multi-stimuli responsive polymeric nanoparticles that can respond to two or more signals have been demonstrated as prospective drug carriers with enhanced tumor accumulation and on-demand drug release profiles. In this study, dextran-based (Dex-SS) nanogels were developed via a facile method based on the disulfide containing Schiff base formation between polyaldehyde dextran and cystamine in water-in-oil inverse microemulsion . Acidic and reductive (GSH) environment sensitive degradation behaviors of the resulted nanogels were investigated by morphology analysis of the treated nanogels using SEM imaging. Doxorubicin (DOX) was covalently conjugated into the dextran nanogels via Schiff base linkages, and pH/GSH dual sensitive drug release profiles were demonstrated. Effective cell uptake of the DOX-loaded nanogels was finally identified by human cancer cell line of H1299. Take advantage of the acidic and reductive tumor microenvironment, the dual-stimuli responsive Dex-SS nanogels can serve as microenvironment-sensitive drug delivery systems for tumor therapy.

Fabrication of doxorubicin-gated mesoporous polydopamine nanoplatforms for multimode imaging-guided synergistic chemophotothermal therapy of tumors

Min Yang,Ningnan Zhang,Tao Zhang,Xian Yin,Jie Shen