MOLECULAR PHARMACEUTICS
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2019
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IF 4.396
Ying Li,Jing Luo,Meng-Ting Lin,Pei Zhi,Wang-Wei Guo,Min Han,Jian You,Jian-Qing Gao
Doxorubicin (DOX) is a first-line chemo drug for cancer therapy, yet it fails to treat multi-drug-resistant tumors. Hypoxia is a major causative factor leading to chemotherapy failure. Particularly, hypoxia up-regulates its responsive transcription factor—hypoxia-inducible factors (HIF)—to induce the overexpression of drug resistant genes. Metformin (MET) is recently found to cooperate with DOX against multiple tumors. As a mitochondrial inhibitor, MET could suppress tumor oxygen consumption, and thereby modulate the hypoxic tumor microenvironment. In this study, we used cationic liposomes to codeliver both DOX and MET for treating multi-drug-resistant breast cancer cells—MCF7/ADR. Faster release of MET enhanced the cytotoxicity of DOX through attenuating hypoxic stress both in vivo and in vitro. MET diminished the cellular oxygen consumption and inhibited HIF1α and P-glycoprotein (Pgp) expression in vitro. In addition, the dual-drug-loaded liposomes increased tumor targeting and intratumoral blood oxygen saturation, which suggested that the tumor reoxygenation effect of MET facilitated the exertion of its synergistic activity with DOX against MCF7/ADR xenografts. In general, our study represents a feasible strategy to boost the therapeutic effect in treating multi-drug-resistant cancer by improving the hypoxic tumor microenvironment.
研究领域:
肿瘤学
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Chuang Yang,Zheng Chen,Min Wei,Shen Hu,Mengyuan Cai,Nan Wang,Yunan Guan,Fangyuan Li,Qiang Ding,Daishun Ling
Ferroptosis has recently become an attractive strategy to combat the chemoresistance of cancer cells, but the intracellular ferroptosis defense system greatly challenges the efficient ferroptosis induction. Herein, we report a ferrous metal-organic framework-based nanoagent (FMN) that inhibits the intracellular upstream glutathione synthesis and induces self-amplified ferroptosis of cancer cells, for reversing chemoresistance and boosting chemotherapy. The FMN is loaded with SLC7A11 siRNA (siSLC7A11) and chemotherapeutic doxorubicin (DOX), which shows enhanced tumor cell uptake and retention, thus ensuring the effective DOX delivery and tumor intracellular iron accumulation. Importantly, the FMN simultaneously catalyzes the iron-dependent Fenton reaction and triggers the siSLC7A11-mediated suppression of upstream glutathione synthesis for intracellularly self-amplified ferroptosis, which further inhibits P-glycoprotein activity for DOX retention, and regulates the expression of Bcl-2/Bax to reverse the apoptotic resistance state of tumor cells. The FMN-mediated ferroptosis is also demonstrated in ex vivo patient-derived tumor fragment platform. Consequently, FMN successfully reverses cancer chemoresistance and achieves a highly efficient in vivo therapeutic efficacy in MCF7/ADR tumor-bearing mice. Our study provides a self-amplified ferroptosis strategy via inhibiting intracellular upstream glutathione synthesis, which is effective to reverse cancer chemoresistance.
研究领域:
肿瘤学
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纳米技术
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2019
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IF 10.273
Jia Liu,Zhilan Ye,Mengxi Xiang,Bingcheng Chang,Jinyuan Cui,Tiantian Ji,Lei Zhao,Qilin Li,Yan Deng,Luming Xu,Guobin Wang,Lin Wang,Zheng Wang
Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers' complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity . Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. The EVs isolated from noncancerous HEK293T cells (hEVs) reduce P-glycoprotein (P-gp) expression in drug resistant MCF7/ADR cells. To acquire tumor-targeting capability, hEVs are modified with lipidomimetic chains-grafted HA (lipHA) by a simple incubation. Owing to CD44-mediated cancer-specific targeting and P-gp suppressive capability, the HA-functionalized hEVs (lipHA-hEVs) remarkably promote the intracellular DOX accumulation in drug resistant breast cancer cells. In preclinical MDR tumor models, lipHA-hEVs deeply penetrate into tumor tissue and effectively transport DOX into tumor local, while eliminating DOX's systemic toxicity. Importantly, [email protected] inhibited MDR tumor growth by 89% and extend animal survival time by approximately 50%. Thus, our engineered tumor-targeting hEVs are promising natural carriers for overcoming cancer MDR.
研究领域:
药学
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癌症研究
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纳米技术
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2018
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IF 3.862
Weixia Xu,Xiaofeng Gao,Pengjin Ge,Fuquan Jiang,Xiaokun Zhang,Jingjing Xie
Multidrug resistance (MDR), as a major obstacle in cancer therapy, has resulted in over 90% of cancer chemotherapeutic failure. Mesoporous silica nanospheres (MSNs) have been demonstrated to be tuned with large pore sizes, mediating the MDR-reversal effects. However, the study that surface functionality of the large pore sized-MSNs affects the MDR-overcoming effects hasn’t been extensively studied. In this study, we developed a new dendrimer-like MSNs delivery system based on a rational synthesis strategy and further modified MSNs with various surface functionalities to evaluate their roles in overcoming cancer MDR. Our results showed that the small particle sized-MSNs could be fabricated with dendrimer-like internal structure, resulting in the large pore size of 9 nm. Surface functionality of MSNs, especially hydroxylation and carboxylation, largely improved the intra-nuclear delivery and therapeutic efficiency of DOX for MCF7/ADR cells, which was not up to inhibiting P-gp expression but significantly increasing the intracellular drug accumulation of over 90% even under the strong drug efflux. This study indicates that surface functionality design strategy may display the potential of the large pore sized-MSNs as the efficient chemotherapeutic carriers to combat MDR.
研究领域:
纳米技术
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药学
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癌症治疗
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材料科学
✓ 已验证
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）