JOURNAL OF PHARMACEUTICAL SCIENCES
·
2015
·
IF 2.59
Wei-Liang Ye,Yi-Pu Zhao,Ren Na,Fei Li,Qi-Bing Mei,Ming-Gao Zhao,Si-Yuan Zhou
ABSTRACT Alendronate-monoethyl adipate-(hydrazone)-doxorubicin conjugate (ALN-MA-hyd-DOX) was synthesized to specifically deliver doxorubicin (DOX) to bone tumor tissue. The binding kinetics of ALN-MA-hyd-DOX with hydroxyapatite (HA) and natural bone were detected by using spectrophotometer. Cytotoxicity of ALN-MA-hyd-DOX on tumor cells was determined by MTT [3-(4,5-dimethylthiaol-2-yl)-2,5-diphenyl-tetrazolium bromide] method. The cellular uptake of ALN-MA-hyd-DOX was observed by using fluorescence microscopy . The in vivo antitumor activity of ALN-MA-hyd-DOX was investigated by using tumor-bearing nude mice model. The results indicated that ALN-MA-hyd-DOX was able to quickly bind with HA and natural bone. ALN-MA-hyd-DOX immobilized on the natural bone released more DOX in pH 5.0 medium than that in pH 6.0 or 7.4 medium. The cytotoxicity of ALN-MA-hyd-DOX toward A549 cells and MDA-MB-231/ADR cells was greater than DOX. ALN-MA-hyd-DOX was rapidly uptaken by A549 cells and MDA-MB-231/ADR cells. Compared with the same dose of free DOX, ALN-MA-hyd-DOX significantly decreased tumor volume of tumor-bearing nude mice. DOX mainly distributed in bone tumor tissue after ALN-MA-hyd-DOX was intravenously administered to tumor-bearing nude mice, whereas DOX distributed through the whole body after DOX was intravenously administered to tumor-bearing nude mice. These findings implied that the ALN-MA-hyd-DOX was a promising bone-targeted conjugate for treating bone neoplasms.
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JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
·
2019
·Vol. 19
·期 9
·5456-5462
·
IF 1.093
Jie Liyong,Lang Dan,Kang Xuqi,Yang Zhixin,Du Yongzhong,Ying Xiaoying
The magnetic resonance imaging diagnosis and high-efficiency tumor targeting treatment are of notable importance for cancer therapy. In this study, starch-octanoic acid (ST-OA) micelles were successfully prepared to co-encapsulate the anti-tumor drug doxorubicin (DOX) and superparamagnetic
iron oxide nanoparticles (SPIONs), taking advantage of the hydrophobic core of the core–shell micellar structure. Size distribution, morphology and in vitro release behaviors of micelles were investigated. In addition, magnetic properties and the anti-tumor theranostic performance
were confirmed by conducting the cellular uptake, in vivo imaging and anti-tumor activity experiments. Therefore, co-encapsulation and specific delivery of the chemotherapeutic drug and contrast agent into tumor cells can realize the diagnosis and treatment of malignant tumor at the
same time.
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Nanoscale
·
2016
·Vol. 8
·期 12
·6801-6809
·
IF 7.76
Lei Yang,Zheran Wang,Ju Wang,Weihua Jiang,Xuewei Jiang,Zhaoshi Bai,Yunpeng He,Jianqi Jiang,Dongkai Wang,Li Yang
Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared with free DOX. Thus, the DOX-CD conjugates may be exploited as promising drug delivery vehicles in cancer therapy.
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CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Mei Zhang,Sajid Asghar,Cihui Tian,Ziyi Hu,Qineng Ping,Zhipeng Chen,Feng Shao,Yanyu Xiao
Herein, lactoferrin (Lf)/phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels crosslinked with disulfide-bond crosslinker was developed as a reduction-sensitive dual-targeting glioma therapeutic platform for doxorubicin hydrochloride (DOX) delivery (Lf-DOX/PBNG). Spherical Lf-DOX/PBNG with optimized physicochemical properties was obtained, and it could rapidly release the encapsulated DOX under high glutathione concentration. Moreover, enhanced cytotoxicity, superior cellular uptake efficiency, and significantly improved brain permeability of Lf-DOX/PBNG were observed in cytological studies compared with those of DOX solution, DOX-loaded PBA functionalized nanogels (DOX/PBNG), and Lf modified DOX-loaded nanogels (Lf-DOX/NG). The pharmacokinetic study exhibited that the area under the curve of DOX/PBNG, Lf-DOX/NG, and Lf-DOX/PBNG increased by 8.12, 4.20 and 4.32 times compared with that of DOX solution, respectively. The brain accumulation of Lf-DOX/PBNG was verified in biodistribution study to be 12.37 and 4.67 times of DOX solution and DOX/PBNG, respectively. These findings suggest that Lf-DOX/PBNG is an excellent candidate for achieving effective glioma targeting.
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BIOMACROMOLECULES
·
2016
·
IF 5.583
Yanjuan Wu,Dongfang Zhou,Qingfei Zhang,Zhigang Xie,Xuesi Chen,Xiabin Jing,Yubin Huang
A tumor is a complicated system, and tumor cells are typically heterogeneous in many aspects. Polymeric drug delivery nanocarriers sensitive to a single type of biosignals may not release cargos effectively in all tumor cells, leading to low therapeutic efficacy. To address the challenges, here, we demonstrated a pH/reduction dual-sensitive charge-conversional polymeric prodrug strategy for efficient codelivery. Reduction-sensitive disulfide group and acid-labile anticancer drug (demethylcantharidin, DMC)-conjugated β-carboxylic amide group were repeatedly and regularly introduced into copolymer chain simultaneously via facile CuAAC click polymerization. The obtained multifunctional polymeric prodrug P(DMC), mPEG-b-poly(disulfide-alt-demethylcantharidin)-b-mPEG was further utilized for DOX encapsulation. Under tumor tissue/cell microenvironments (pH 6.5 and 10 mM GSH), the DOX-loaded polymeric prodrug nanoparticles (P(DMC)@DOX NPs) performed surface negative-to-positive charge conversion and accelerated/sufficient release of DMC and DOX. The remarkably enhanced cellular internalization and cytotoxicity in vitro, especially against DOX-resistant SMMC-7721 cells, were demonstrated. P(DMC)@DOX NPs in vivo also exhibited higher tumor accumulation and improved antitumor efficiency compared to P(SA)@DOX NPs with one drug and without charge-conversion ability. The desired multifunctional polymeric prodrug strategy brings a new opportunity for cancer chemotherapy.
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ACS Applied Nano Materials
·
2018
·
IF 0
Jie Wang,Dajun Xu,Tao Deng,Yunyan Li,Le Xue,Tong Yan,Dechun Huang,Dawei Deng
Concerns associated with the nondegradability of silica (SiO2)-based nanoplatforms have hindered their potential clinical translation as drug carriers. Hence, in this work, by embedding drug (doxorubicin (DOX) or methylene blue (MB), etc.) molecules into SiO2 nanoparticles (NPs), self-decomposable drug-embedded SiO2 NPs were prepared. Importantly, we found that the intermediate morphology during the decomposition depends on the type of the embedded drug molecules, (e.g., DOX results in mesoporous nanostructures; MB results in center-hollowed nanoshells). Second, different from previous studies, the intermediate mesoporous DOX-embedded SiO2 (mDOX@SiO2) NPs with radial mesopores were modified with nuclear localization signal peptides to achieve nuclear targeted DOX delivery upon the fragmentation of NPs. Meanwhile, MB (a widely used photosensitizer) was further uploaded into the mesopores to realize chemo-photodynamic combination therapy. At last, in vitro and in vivo antitumor efficacy and toxicity of the as-designed drug-delivery system were evaluated. The results showed that compared with the nontargeting and chemotherapy-only systems, the self-decomposable NPs with nuclear targeting capability and MB loading exhibited enhanced therapeutic efficacy, and no noticeable systemic toxicity was observed, indicating that the present system should be a promising paradigm in the design of SiO2-based drug carriers.
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JOURNAL OF NANOPARTICLE RESEARCH
·
2012
·Vol. 14
·期 4
·1-9
·
IF 3.287
Duan Jinghua,Liu Mujun,Zhang Yangde,Zhao Jinfeng,Pan Yifeng,Yang Xiyun
A novel chitosan coated poly(butyl cyanoacrylate) (PBCA) nanoparticles loaded doxorubicin (DOX) were synthesized and then conjugated with folic acid to produce a folate-targeted drug carrier for tumor-specific drug delivery. Prepared nanoparticles were surface modified by folate for targeting cancer cells, which is confirmed by FTIR spectroscopy and characterized for shape, size, and zeta potential measurements. The size and zeta potential of prepared DOX-PBCA nanoparticles (DOX-PBCA NPs) were almost 174 ± 8.23 nm and +23.14 ± 4.25 mV, respectively with 46.8 ± 3.32% encapsulation capacity. The transmission electron microscopy study revealed that preparation allowed the formation of spherical nanometric and homogeneous. Fluorescent microscopy imaging and flow cytometry analysis revealed that DOX-PBCA NPs were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells. The results demonstrate that folate-conjugated DOX-PBCA NPs drug delivery system could provide increased therapeutic benefit by delivering the encapsulated drug to the folate receptor positive cancer cells.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 24
·e71369
·
IF 4.2
Mengxin Li,Xuanzhong Wang,Jinghui Hong,Xin Guan,Yichang Chen,Hongxu zhou,Xin Wang,Baoling Liang,Xiaochuan Gao,Yuheng Wu,Dong Song
Breast cancer (BC) continues to be a representative malignancy globally, with its inherent heterogeneity and chemotherapy resistance posing significant therapeutic obstacles. Doxorubicin (Dox), a commonly utilized chemotherapeutic agent, is often constrained by dose-dependent toxicities and acquired resistance, which ultimately lead to suboptimal clinical outcomes in numerous BC patients. Co-treatment of Dox with RSL3, a small-molecule compound that inactivates glutathione peroxidase 4 (GPX4), was shown in this study to synergistically inhibit BC cell viability and proliferation at low doses in vitro and in vivo. In vitro tests showed that RSL3 exacerbated Dox-induced cell cycle arrest and apoptosis, markedly potentiating the cytotoxicity of Dox against BC cells. Mechanistically, RSL3 triggered ferroptosis-dependent ROS accumulation, leading to glycolytic impairment characterized by reduced intracellular ATP and pyruvate concentrations levels and downregulation of HKII, PFKP, and PKM2. Supplementation with exogenous sodium pyruvate ameliorated RSL3-induced glycolytic dysfunction, restored the changes in apoptosis-related protein expression caused by RSL3/Dox co-treatment, and reduced RSL3/Dox-induced cell apoptosis. Besides, according to in vivo studies, the combination of RSL3 and Dox further suppressed BC tumor growth without inducing significant adverse effects. On these accounts, RSL3 makes BC cells more sensitive to Dox by inducing glycolytic dysfunction, implying that RSL3/Dox co-treatment could be a viable therapeutic approach for BC patients. Graphical RSL3 Mitigates Doxorubicin Resistance in Breast Cancer via Targeted Disruption of Glycolytic Flux. Co-treatment with RSL3 and doxorubicin (Dox) synergistically inhibits breast cancer growth in vitro and in vivo. RSL3 sensitizes BC cells to Dox by inducing ferroptosis and ROS accumulation, which impairs glycolysis (reducing ATP/pyruvate and downregulating HK2/PFKP/PKM2). This metabolic disruption exacerbates Dox-induced cell cycle arrest and apoptosis. The combination therapy offers enhanced efficacy without significant toxicity, presenting a promising low-dose therapeutic strategy.
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INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
·
2024
·
IF 3.4
Jiawen Chen,Xiaozhi Xu,Yuru Shao,Xiaohong Bian,Ruiyan Li,Yubin Zhang,Yibei Xiao,Meiling Lu,Qizhou jiang,Yuan Zeng,Fangrong Yan,Junmei Ye,Zhe Li
Doxorubicin (DOX), a widely used chemotherapy agent in cancer treatment, encounters limitations in clinical efficacy due to associated cardiotoxicity. This study aims to explore the role of AKT serine/threonine kinase 2 (AKT2) in mitigating DOX-induced oxidative stress within the heart through both intracellular and extracellular signaling pathways. Utilizing AKT2 knockout (KO) and NRF2 KO murine models, alongside neonatal rat cardiomyocytes (NRCMs), we systematically investigate the impact of AKT2 deficiency on DOX-induced cardiac injury. Our findings reveal that DOX administration induces significant oxidative stress, a primary contributor to cardiac injury. Importantly, Akt2 deficiency exhibits a protective effect by alleviating DOX-induced oxidative stress. Mechanistically, Akt2 deficiency facilitates nuclear translocation of NRF2, thereby suppressing intracellular oxidative stress by promoting the expression of antioxidant genes. Furthermore, We also observed that AKT2 inhibition facilitates superoxide dismutase 2 (SOD2) expression both inside macrophages and SOD2 secretion to the extracellular matrix, which is involved in lowering oxidative stress in cardiomyocytes upon DOX stimulation. The present study underscores the important role of AKT2 in mitigating DOX-induced oxidative stress through both intracellular and extracellular signaling pathways. Additionally, our findings propose promising therapeutic strategies for addressing DOX-induced cardiomyopathy in clinic.
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Small Methods
·
2025
·
IF 9.1
Wenbo Yin,Zonghang Liu,Shangjie An,Tao Song,Yue Wang,Xiue Jiang
Doxorubicin (DOX) is a clinically approved chemotherapeutic agent that exerts its cytotoxicity through DNA intercalation and topoisomerase II inhibition. However, its redox-based mechanism remains underexplored. Here, it is revealed that DOX specifically binds to the heme center of cytochrome P450 (CYP450) enzymes via its quinone moiety, enabling electron transfer that catalyzes molecular oxygen into superoxide anions (O 2 •− ). To enhance this process, mesoporous polydopamine (mPDA) is introduced as an electron-rich scaffold, amplifying electron flow to DOX. Furthermore, L-arginine (L-Arg) is co-delivered to supply nitric oxide (NO), which reacts with O 2 •− to generate peroxynitrite (ONOO − ), a stable, highly cytotoxic ROS. ONOO − further activates matrix metalloproteinase (MMP), promoting extracellular matrix degradation and facilitating drug/oxygen penetration. Moreover, the system enables multimodal tumor therapy by integrating DOX-based chemotherapy, nitric oxide (NO) gas therapy, and mPDA-mediated photothermal therapy. This work unveils a novel DOX-CYP450 electron transfer mechanism and establishes a synergistic therapeutic paradigm to overcome tumor microenvironmental barriers and enhance treatment efficacy.
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Biomaterials Science
·
2017
·Vol. 5
·期 10
·2169-2178
·
IF 4.21
Shengcai Yang,Zhaohui Tang,Dawei Zhang,Mingxiao Deng,Xuesi Chen
A pH and redox dual-sensitive biodegradable polysaccharide, succinic acid-decorated dextran-g-phenylalanine ethyl ester-g-cysteine ethyl ester (Dex-SA-L-Phe-L-Cys), was synthesized to load doxorubicin hydrochloride (DOX·HCl). The DOX-loaded nanoparticles, which were prepared in aqueous solution and free of organic solvent, could spontaneously self-assemble into uniform sizes. When loading DOX·HCl, mercapto Dex-SA-L-Phe-L-Cys was oxidized into a crosslinked disulfide linkage to form pH and redox dual-sensitive nanoparticles (DOX-S-NPs). The amphiphilic polymer loaded DOX·HCl into the core through electrostatic and hydrophobic interactions, meanwhile the crosslinked disulfide bond could stabilize the drug loaded nanoparticles. As a control with similar polymer structure, succinic acid decorated dextran-g-phenylalanine ethyl ester (Dex-SA-L-Phe) was prepared to obtain pH-sensitive DOX-loaded micelles (DOX-N-NPs). The controlled pH and redox-dependent release profiles of the DOX-S-NPs in vitro were certified in different releasing mediums. Furthermore, the cellular uptake of the DOX-S-NPs was comparable with that of free DOX·HCl, determined by confocal laser scanning microscopy (CLSM) and flow cytometry. Cytotoxicity assay in vitro showed that the DOX-S-NPs and free DOX·HCl were similar in inhibiting the proliferation of non-small cell lung carcinoma A549 and breast cancer MCF-7 cell lines. DOX-S-NPs displayed similar antitumor efficiency compared with free DOX·HCl, but lower toxicity by body weight. These dual-sensitive DOX-S-NPs provide a useful strategy for anti-tumor therapy.
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RSC Advances
·
2016
·Vol. 6
·期 31
·26280-26287
·
IF 3.289
Binbin Li,Heng Liu,Chuanbin Sun,Zeeshan Ahmad,Zhaohui Ren,Xiang Li,Gaorong Han
The investigation of nano-carriers with controllable and trackable drug release kinetics has attracted worldwide attention for new tumor theranostic strategies with catabatic side effects. Herein, a range of monodispersed core–shell structured photoluminescent SrTiO3:Yb3+,Er3+@mSiO2 nanoparticles were designed and synthesized. The surfactant cetyltrimethylammonium bromide (CTAB) was used to vary the microstructure of the mesoporous SiO2 shell. The specific surface area and pore volume increase proportionally with the content of CTAB. Consequently, the doxorubicin (DOX) loading capacity increases, and the drug release kinetics possesses a sustained behaviour. More importantly, the DOX release kinetics was found to correspond well to the evolution of the up-conversion luminescence (UCL) phenomenon. More rapid drug release induces more rapid photoluminescence enhancement, and vice versa. This study has therefore been anticipated to suggest another promising multifunctional drug delivery platform for advanced chemotherapies.
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