EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2024
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IF 4.4
Kangyuan Hu,Xiuhua Li,Zhaodan Tan,Yan Shi
Ovarian cancer is the most common malignant tumor in women. Shikonin (SHK), an herbal extract from Chinese medicine, shows promise in treating ovarian cancer by inducing reactive oxygen species (ROS). However, its clinical use is limited by poor tumor targeting and low bioavailability, and its therapeutic potential is further compromised by the elevated levels of antioxidants such as glutathione (GSH) within tumor cells. In this study, a novel formulation of ROS-responsive micelles loaded with SHK was developed using hyaluronic acid-phenylboronic acid pinacol ester conjugation (HA-PBAP) for targeted therapy of ovarian cancer through disruption of intracellular redox homeostasis. The SHK@HA-PBAP exhibits targeted delivery to ovarian cancer cells through the interaction between HA and CD44 receptors. Upon internalization by cancer cells, the high levels of intracellular ROS triggered the degradation of SHK@HA-PBAP and simultaneously released SHK and generated GSH scavenger quinone methide (QM). The SHK and QM released from the SHK@HA-PBAP effectively induce the production of ROS and deplete intracellular GSH, leading to the disruption of intracellular redox homeostasis and subsequent induction of cell death. These characteristics collectively inhibit the growth of ovarian cancer. In vitro and in vivo studies have demonstrated that SHK@HA-PBAP micelles exhibit superior antitumor efficacy compared to free SHK in both A2780 cells and A2780 tumor-bearing mice. The ROS-responsive SHK@HA-PBA presents a promising therapeutic approach for the treatment of ovarian cancer.
研究领域:
药学
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癌症生物学
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纳米技术
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
WATER RESEARCH
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2020
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IF 9.13
Hangbo Xu,Yupan Zhu,Mengru Du,Yuqi Wang,Siyao Ju,Ruonan Ma,Zhen Jiao
Although the identification of effective reactive oxygen species (ROS) generated by plasma has been extensively studied, yet the subcellular mechanism of microbial inactivation has never been clearly elucidated in plasma disinfection processes. In this study, subcellular mechanism of yeast cell inactivation during plasma-liquid interaction was revealed in terms of comprehensive factors including cell morphology, membrane permeability, lipid peroxidation, membrane potential, intracellular redox homeostasis (intracellular ROS and H 2 O 2 , and antioxidant system (SOD, CAT and GSH)), intracellular ionic equilibrium (intracellular H + and K + ) and energy metabolism (mitochondrial membrane potential, intracellular Ca 2+ and ATP level). The ROS analysis show that ·OH, 1 O 2 , ·O 2 − and H 2 O 2 were generated in this plasma-liquid interaction system and ·O 2 − served as the precursor of 1 O 2 . Additionally, the solution pH was reduced. Plasma can effectively inactivate yeast cells mainly via apoptosis by damaging cell membrane, intracellular redox and ion homeostasis and energy metabolism as well as causing DNA fragmentation. ROS scavengers ( l -His, d -Man and SOD) and pH buffer (phosphate buffer solution, PBS) were employed to investigate the role of five antimicrobial factors (·OH, 1 O 2 , ·O 2 − , H 2 O 2 and low pH) in plasma sterilization. Results show that they have different influences on the aforementioned cell physiological activities. The ·OH and 1 O 2 contributed most to the yeast inactivation. The ·OH mainly attacked cell membrane and increased cell membrane permeability. The disturb of cell energy metabolism was mainly attributed to 1 O 2 . The damage of cell membrane as well as extracellular low pH could break the intracellular ionic equilibrium and further reduce cell membrane potential. The remarkable increase of intracellular H 2 O 2 was mainly due to the influx of extracellular H 2 O 2 via destroyed cell membrane, which played a little role in yeast inactivation during 10-min plasma treatment. These findings provide comprehensive insights into the antimicrobial mechanism of plasma, which can promote the development of plasma as an alternative water disinfection strategy.
研究领域:
微生物学
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等离子体物理
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环境科学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
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2020
·Vol. 8
·期 21
·5955-5968
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IF 6.183
Fangying Yu,Yun Zhu,Yupeng Liu,Guoxi Qiu,Xuwei Shang,Tingting Meng,Hong Yuan,Fuqiang Hu
The active targeting strategy has achieved inspiring progress for drug accumulation in tumor therapy; however, the insufficient expression level of many potential receptors poses challenges for drug delivery. Poly-γ-glutamic acid (γ-pGluA), a naturally occurring anionic biopolymer, showed high affinity with tumor-associated gamma-glutamyl transpeptidase (GGT), which localized on the cell surface and exhibited intracellular redox homeostasis-dependent expression pattern; thus, GGT was utilized for mediating endocytosis of nanoparticles. Herein, GGT-targeting nanopolyplexes (γ-pGluA-CSO@Fe3+, PCFN) consisting of cationic chitosan and GGT-targeting γ-pGluA blended with iron ion were constructed to load reactive oxygen species-induced menadione (MA) and doxorubicin, which were utilized to investigate the mechanism of GGT up-regulation. Briefly, the pretreated PCFN/MA induced an intracellular oxidative stress environment, which facilitated adjusted up-regulated GGT expression and boosted tumor targeting. Subsequently, the destroyed redox homeostasis sensitized tumors for synergistic therapy. The innovative strategy of augmenting active targeting by disturbing intracellular redox homeostasis offers insight for the application of γ-pGluA-derived nanopolyplexes.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
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2024
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IF 13
Wanyue Lu,Weidong Wang,Yimin Gong,Jianing Li,Yaming Zhou,Yannan Yang
Intracellular delivery of proteins has largely been relying on cationic nanoparticles to induce efficient endosome escape, which, however, poses serious concerns on the inflammatory and cytotoxic effects. Herein, a versatile noncationic nano biohybrid platform is introduced for efficient cytosolic protein delivery by utilizing a nano-confined biocatalytic reaction. This platform is constructed by co-immobilizing glucose oxidase (GOx) and the target protein into nanoscale hydrogen-bonded organic frameworks (HOFs). The biocatalytic reaction of nano-confined GOx is leveraged to induce controlled perturbation of intracellular redox homeostasis by sustained hydrogen peroxide (H 2 O 2 ) production and diminishing the flux of the pentose phosphate pathway (PPP). This in turn induces the endosome escape of nanobiohybrids. Concomitantly, GOx-mediated hypoxia leads to overexpression of azo reductase that initiated the materials' self-destruction for releasing target proteins. These biological effects collectively induce highly efficient cytosolic protein delivery. The versatility of this delivery platform is further demonstrated for various types of proteins, different protein loading approaches (in situ immobilization or post-adsorption), and in multiple cell lines. Finally, the protein delivery efficiency and biosafety are demonstrated in a tumor-bearing mouse model. This nanohybrid system opens up new avenues for intracellular protein delivery and is expected to be extensively applicable for a broad range of biomolecuels.
研究领域:
纳米技术
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生物医学工程
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药学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2022
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IF 15.304
Yongwei Hu,Yanteng Xu,Rachel L. Mintz,Xing Luo,Youqiang Fang,Yeh-Hsing Lao,Hon Fai Chan,Kai Li,Shixian Lv,Guojun Chen,Yu Tao,Yun Luo,Mingqiang Li
Tumor-positive resection margins after surgery can result in tumor recurrence and metastasis. Although adjuvant postoperative radiotherapy and chemotherapy have been adopted in clinical practice, they lack efficacy and result in unavoidable side effects. Herein, a self-intensified in-situ therapy approach using electrospun fibers loaded with a biomimetic nanozyme and doxorubicin (DOX) is developed. The fabricated PEG-coated zeolite imidazole framework-67 (PZIF67) is demonstrated as a versatile nanozyme triggering reactions in cancer cells based on endogenous H 2 O 2 and •O 2 − . The PZIF67-generated •OH induces reactive oxygen species (ROS) overload, implementing chemodynamic therapy (CDT). The O 2 produced by PZIF67 inhibits the expression of hypoxia-up-regulated proteins, thereby suppressing tumor progression. PZIF67 also catalyzes the degradation of glutathione , further disturbing the intracellular redox homeostasis and enhancing CDT. Furthermore, the introduced DOX not only kills cancer cells individually, but also replenishes the continuously consumed substrates for PZIF67-catalyzed reactions. The PZIF67-weakened drug resistance strengthens the cytotoxicity of DOX. The combined application of PZIF67 and DOX also suppresses metastasis-associated genes. Both in vitro and in vivo results demonstrate that the self-intensified synergy of PZIF67 and DOX on electrospun fibers efficiently prevents postsurgical tumor recurrence and metastasis, offering a feasible therapeutic regimen for operable malignant tumors.
研究领域:
生物医学工程
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纳米技术
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癌症研究
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材料科学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）