INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2025
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IF 5.2
Huihui Li,Kang Liu,Zexin Yang,Quanwei Sun,Wencui Shang,Yunlong Li,Mingjing Wang,Ye Yang,Hanmeng Liu,Dengke Yin,Wei Shen
Although vascular disrupting agents (VDAs) can induce shutdown of blood flow and necrosis in the tumor core, eradicating tumor rim cells remains a significant challenge. Recently, researchers have developed various combination treatment strategies to improve the efficacy of VDAs. However, the aggravated hypoxic tumor microenvironment following vascular disruption limits the effectiveness of conventional therapeutic approaches. Here, we developed an ε-polylysine-derived oncolytic polymer (named OPAA) with membrane lytic activity. Its cytotoxic effect on tumor cells is largely unaffected by hypoxic conditions, as evidenced by the ratio of its IC50 value for 4 T1 cells under normoxic conditions to that under hypoxic conditions, which is 0.98. Subsequently, a pH-responsive combretastatin A4 phosphate disodium salt (CA4P)-loaded nanoparticle (OPAA@CA4P NPs) has been designed to efficiently deliver OPAA and CA4P to solid tumors. OPAA@CA4P NPs exhibited a prolonged serum half-life (t 1/2 = 3.15 h) compared to CA4P (t 1/2 = 0.31 h) and an enhanced tumor accumulation. In addition, CA4P can be responsively released within the tumor microenvironment, leading to necrosis in the tumor center. Concurrently, OPAA released from the nanoparticles eradicated the surviving cancer cells at the tumor periphery, thereby improving the overall therapeutic effect. Notably, compared to the CA4P + doxorubicin group (tumor suppression rates, TSR = 36.17 %), the OPAA@CA4P NPs group demonstrated superior therapeutic outcomes (TSR = 60.30 %). Overall, the introduction of oncolytic polymers provides new insights into the potential future applications of VDAs.
研究领域:
药理学
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肿瘤学
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生物材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2018
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IF 3.466
Ali Fan,Jiali Wei,Mengru Yang,Qing Zhang,Yaliang Zhang,Qingwang Liu,Ning Li,Di Zhao,Yang Lu,Junxiu Li,Jie Zhao,Shuhua Deng,Bingjie Zhang,Hailiang Zhu,Xijing Chen
YMR-65, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a potential tubulin inhibitor exhibiting good anticancer activity. In our study, we illustrated the biological activities in HepG2 cells and the pharmacodynamic and pharmacokinetic profiles were evaluated in murine H22 hepatoma-bearing mice. Molecular docking assay and colchicine competition assay indicated that YMR-65 could bind tightly to the colchicine binding site of tubulin. Further investigation demonstrated that YMR-65 arrested cells in the G2/M phase of cell cycle and induced apoptosis in HepG2 cells. Compared with control group, the tumor growth inhibition determined by final relative volume of tumor/the initial tumor volume were 32.57%, 24.00% and 34.95%, respectively, for YMR-65 (10 mg/kg), YMR-65 (20 mg/kg) and CA4P (10 m/kg) groups. Besides there were no obvious body change or tissue damage (enhanced by histopathology study). YMR-65 administration at 10 and 20 mg/kg in H22 tumor-bearing mice resulted in 1.87- and 1.80-fold longer half time (t 1/2 ) and 0.36- and 0.78-fold lower area under concentration-time curve (AUC 0–∞ ) in plasma in contrast with normal mice at 10 mg/kg. Furthermore, YMR-65 showed a wide distribution to various tissues or tumor and the highest distribution index (the ratio of AUC tissue or tumor /AUC plasma ) was found in tumor, which implied that it might accumulate in tumor after administration. In brief, our results indicated that YMR-65 was a promising candidate with high antitumor efficacy and low tissue damage.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Research
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2025
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IF 10.7
Xuan Wei,Jiamin Cheng,Meijuan Geng,Siyu Chen,Liyang Gong,Siyu Meng,Keying Chen,Ziyan Wang,Zhang Yuan,Kaiyong Cai,Liangliang Dai
The inhibition of dependent glutamine metabolism is an effective treatment for triple-negative breast cancer (TNBC) starvation, but it is limited by compensatory glycolysis and inadequate delivery efficiency. Herein, we construct a pH-responsive size/charge-reprogrammed micelle with hierarchical delivery characteristics for TNBC suppression with glutamine depletion and vessel blockade. It consists of a positively charged prodrug micelle chemically grafted with the glutamine transport inhibitor V9302 as the inner core layer, the neovascular disruptor CA4P adsorbed in the middle layer, and a pH-responsive peelable polymer as the outer shell. The nanosystem PPD/PPQV@C could effectively reduce size and reverse charge in response to the tumor acidic microenvironment by removing the outer polymer PPD, as accompanying the release of CA4P. Furthermore, the remaining PPQV could responsively release V9302 in the cytoplasm of tumor cells, improving the bioavailability of cargoes and overcoming permeability barrier through precise hierarchical release strategy. Importantly, V9302 and CA4P localized in the tumor intracellular and extracellular matrix could effectively block TNBC-dependent glutamine metabolism and inhibit compensatory nutrient by blocking angiogenesis, achieving the desired tumor suppression with prolonged survival time. This work exhibits a smart nanoplatform for efficient TNBC treatment via dual blockade of the dependent glutamine metabolism and angiogenesis.
研究领域:
癌症生物学
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纳米医学
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药学
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生物化学
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分子生物学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
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2023
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IF 15.1
Youqiang Fang,Xing Luo,Yanteng Xu,Zheng Liu,Rachel L. Mintz,Haiyang Yu,Xuan Yu,Kai Li,Enguo Ju,Haixia Wang,Zhaohui Tang,Yu Tao,Mingqiang Li
As a currently common strategy to treat cancer, surgical resection may cause tumor recurrence and metastasis due to residual postoperative tumors. Herein, an implantable sandwich-structured dual-drug depot is developed to trigger a self-intensified starvation therapy and hypoxia-induced chemotherapy sequentially. The two outer layers are 3D-printed using a calcium-crosslinked mixture ink containing soy protein isolate, polyvinyl alcohol, sodium alginate, and combretastatin A4 phosphate (CA4P). The inner layer is one patch of poly (lactic- co -glycolic acid)-based electrospun fibers loaded with tirapazamine (TPZ). The preferentially released CA4P destroys the preexisting blood vessels and prevents neovascularization, which obstructs the external energy supply to cancer cells but aggravates hypoxic condition. The subsequently released TPZ is bioreduced to cytotoxic benzotriazinyl under hypoxia, further damaging DNA, generating reactive oxygen species, disrupting mitochondria, and downregulating hypoxia-inducible factor 1 α , vascular endothelial growth factor, and matrix metalloproteinase 9. Together these processes induce apoptosis, block the intracellular energy supply, counteract the disadvantage of CA4P in favoring intratumor angiogenesis, and suppress tumor metastasis. The in vivo and in vitro results and the transcriptome analysis demonstrate that the postsurgical adjuvant treatment with the dual-drug-loaded sandwich-like implants efficiently inhibits tumor recurrence and metastasis, showing great potential for clinical translation.
研究领域:
肿瘤学
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药学
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生物医学工程
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外科手术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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