通过微环境响应 BAPTA-AM/BAC 共递送纳米系统快速阻断钙过载/ROS 产生反馈回路以减轻急性肾损伤,Small

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通过微环境响应 BAPTA-AM/BAC 共递送纳米系统快速阻断钙过载/ROS 产生反馈回路以减轻急性肾损伤
Small ( IF 13.0 ) Pub Date : 2023-01-31 , DOI: 10.1002/smll.202206936
Jiahui Yan _{1,

2} , Yanan Wang _{1,

2} , Jingwen Zhang _{1,

2} , Xiaohu Liu _{1,

2} , Liangmin Yu _{1,

2} , Zhiyu He _{1,

2}

Affiliation

钙过载和 ROS 过量产生是急性肾损伤 (AKI) 的两个主要诱因，它们会自我放大并相互增强，形成一个复杂的级联反馈回路，导致肾细胞“自杀”并最终导致肾功能衰竭。目前临床上尚无治疗AKI有效的药物，不包括辅助治疗。在这项研究中，开发了一种富含二硫键骨架（<50 nm）的多孔硅基纳米载体，其外层由肾小管靶向肽 PEG-LTH。一旦靶向肾脏损伤部位，纳米载体结构就会在 AKI 早期的高谷胱甘肽环境中崩溃，释放药物。²⁺，阻断内质网/线粒体凋亡通路（ATF4-CHOP-Bax 轴、Casp-12-Casp-3 轴、Cyt-C-Casp-3 轴）和炎症通路（TNF-α-NF-κB 轴）来自源，从而挽救处于“生存临界”状态的肾细胞，进一步恢复肾功能。总的来说，这种纳米颗粒作为 I/R 损伤相关疾病的潜在治疗策略显示出巨大的临床前景。

"点击查看英文标题和摘要"

Rapidly Blocking the Calcium Overload/ROS Production Feedback Loop to Alleviate Acute Kidney Injury via Microenvironment-Responsive BAPTA-AM/BAC Co-Delivery Nanosystem

Calcium overload and ROS overproduction, two major triggers of acute kidney injury (AKI), are self-amplifying and mutually reinforcing, forming a complicated cascading feedback loop that induces kidney cell “suicide” and ultimately renal failure. There are currently no clinically effective drugs for the treatment of AKI, excluding adjuvant therapy. In this study, a porous silicon-based nanocarrier rich in disulfide bond skeleton (<50 nm) is developed that enables efficient co-loading of the hydrophilic drug borane amino complex and the hydrophobic drug BAPTA-AM, with its outer layer sealed by the renal tubule-targeting peptide PEG-LTH. Once targeted to the kidney injured site, the nanocarrier structure collapses in the high glutathione environment of the early stage of AKI, releasing the drugs. Under the action of the slightly acidic inflammatory environment and intracellular esterase, the released drugs produce hydrogen and BAPTA, which can rapidly eliminate the excess ROS and overloaded Ca²⁺, blocking endoplasmic reticulum/mitochondrial apoptosis pathway (ATF4-CHOP-Bax axis, Casp-12-Casp-3 axis, Cyt-C-Casp-3 axis) and inflammatory pathway (TNF-α-NF-κB axis) from the source, thus rescuing the renal cells in the “critical survival” state and further restoring the kidney function. Overall, this nanoparticle shows substantial clinical promise as a potential therapeutic strategy for I/R injury-related diseases.

更新日期：2023-01-31

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