PHARMAZIE
·
2020
·Vol. 75
·期 5
·186-190
·
IF 1.198
Qin Yanjie,Wang Nanxi,Chen Fen,Han Xuemei,Zhu Ying,Rang Ying,Zhai Xuejia,Lu Yongning
Irinotecan (CPT-11) is a broad spectrum agent for the treatment of solid tumor malignancies, despite severe diarrhea is limiting its widespread usage. The local effects of SN-38 in the small intestine were considered to be responsible for the irinotecan-induced delayed diarrhea. It
was proposed that cyclosporin A (CsA) inhibiting biliary excretion could attenuate this side effect, but in fact, it could not improve the therapeutic index of irinotecan. At present, most studies focused on the inhibition of bile excretion by cyclosporin A through the transporters MRP2 and
MDR1 and its effect the irinotecan treatment in vivo. However, UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1) was related to a significantly altered disposition of irinotecan and its metabolites, and was therefore associated with irinotecan-induced toxicity. This study focused
on UGT1A1-mediated conversion of SN-38 to SN-38G, and systematically investigated the CsA-irinotecan interactions in vitro and in vivo. After treatment with 10 mg·kg-1 CsA for 7 days, the bile excretion of irinotecan and its metabolites decreased and AUC0-∞
increased significantly. The AUC0-∞ (SN-38G)/AUC0-∞ (SN-38) was significantly reduced when compared with that in vehicle-treated rats. In the liver microsome incubation system, the IC50 of CsA for UGT1A1 enzyme was 9.4 μM. Furthermore, the UGT1A1
mRNA and protein expression levels were significantly reduced. The present study indicated that CsA treatment could enhance the systemic exposure and toxicity of SN-38 by inhibiting the UGT1A1 enzyme. The inhibition of UGT1A1 enzyme might be a critical factor in the failure of CsA improving
irinotecan's treatment index.
研究领域:
药理学
·
肿瘤学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Xinyue Zang,Peigen Wei,Chunxia Xu,Jiuyang Sun,Xiuling Yu,Deyin Wang,Zaixiang Zhang,Chang Liu,Feng Feng,Ruoping Wang,Yang Yang
The design of multimechanistic conjugates based on 10-hydroxycamptothecin (10-HCPT) offers a promising approach to reduce toxicity and enhance antitumor efficacy. We designed and synthesized a novel series of conjugates by linking melampomagnolide B (MMB) to 10-HCPT/SN-38 via diverse linkers. Among them, 6i1/6i2 exhibited remarkable anticolorectal cancer potency and minimal cytotoxicity toward normal THLE-2 cells. Mechanistic studies indicated that 6i1/6i2 could inhibit IκB kinase β (IKKβ), leading to the inhibition of p65 and IκBα phosphorylation, suppression of p65 nuclear translocation, and subsequent regulation of genes controlled by nuclear factor kappa-B (NF-κB). Additionally, they targeted topoisomerase I (Topo I), inducing DNA damage, reactive oxygen species (ROS) accumulation, mitochondrial membrane potential loss, and S-phase arrest. In a CT-26 xenograft model, 6i1 and 6i2 (5 mg/kg) potently suppressed tumor growth, achieving TGI rates of 89.9% and 95.4% without observable toxicity.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MATERIALS RESEARCH
·
2024
·
IF 2.7
Deng Jianhua,Li Daosheng,Wang Yifei,Chen Rui,Liu Denghui,Peng Jindi
We constructed an iron (Fe 2+ ) metal–organic framework (MOF) in this study. We loaded SN-38 into the MOF before coating the MOF's surface with hyaluronic acid (SN-38@HA@MOF) to improve its ability to target cancer cells. SN-38@HA@MOF can specifically target cancer tissues, has a high loading efficiency, is biocompatible, has a good monodispersity, has a robust cell absorption capacity, and produces significant intracellular reactive oxygen species levels. The in vitro cytotoxicity of the nanocomposites was investigated in different neuroblastoma cancer cells (SH-SY5Y and IMR 32). Even at a 200 µg/mL dosage, the IC 50 range was as high as 85%, indicating that MOF and HA@MOF are non-cytotoxic to non-cancerous cells and have outstanding biocompatibility and low toxicity. Flow cytometric analyses investigated the cell death morphological investigation and mechanism. The adaptive multifunctional SN-38@HA@MOF has the potential to treat targeted neuroblastoma cancer. Graphical abstract
研究领域:
药学
·
纳米技术
·
癌症生物学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2015
·Vol. 25
·期 31
·4956-4965
·
IF 11.805
Hangxiang Wang,Haiyang Xie,Jianguo Wang,Jiaping Wu,Xueji Ma,Lingling Li,Xuyong Wei,Qi Ling,Penghong Song,Lin Zhou,Xiao Xu,Shusen Zheng
The availability of precisely modulated chemical modifications dramatically affects the physicochemical properties of pristine drugs and should facilitate the amphiphilic self-assembly of prodrugs into supramolecular nanoprodrugs (SNPs). However, rationally designing such prodrugs to achieve favorable clinical outcomes still remains a challenge. Here, a library of prodrugs through site-specific attachment of a variety of lipophilic moieties to the antitumor agent SN-38 (7-ethyl-10-hydroxycamptothecin) is constructed. Taking advantage of the role of hydroxyl groups as solvophilic moieties, these prodrugs exhibit self-assembly in aqueous environments, allowing for the identification of five prodrugs capable of self-assembling into SNPs at high drug concentrations. Importantly, in vivo studies demonstrate that the antitumor activity of the SNPs correlates well with their stability and long-term circulation. In addition, the modular feature of this SNP design strategy offers the opportunity to readily incorporate additional valuable functionalities (e.g., tumor-specific targeting ligands) to the particle surface, which is further exploited to improve antitumor efficacy in mouse xenograft models. Thus, this structure-based reconstruction of SN-38 molecules significantly improves the potency of SNPs for clinical use. These results also provide novel mechanistic insights into the rational design of prodrugs.
研究领域:
药学
·
纳米技术
·
癌症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）