Multi-stimuli responsive hollow MnO2-based drug delivery system for magnetic resonance imaging and combined chemo-chemodynamic cancer therapy
Multi-stimuli responsive hollow MnO2-based drug delivery system for magnetic resonance imaging and combined chemo-chemodynamic cancer therapy
复制标题
用于磁共振成像和化学-化学动力学联合癌症治疗的多刺激响应空心二氧化锰药物递送系统
DOI：
10.1016/j.actbio.2021.03.048
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发表时间：
2021-04-29
影响因子：
9.7
通讯作者：
Li, Cao
中科院分区：
文献类型：
--
作者：
Xu, Xiangyu;Duan, Junlin;Li, Cao
空心二氧化锰纳米粒子（HMDN）在生物传感和生物医学领域的探索和应用在过去的十年中获得了极大的研究关注。本研究制备了一种可生物降解的HMDN，并将其成功负载于盐酸阿霉素（DOX）载体上，用于多刺激响应的肿瘤靶向给药。然后，将载药的HMDN依次用聚乙烯亚胺（PEI）作为看门人，接着用柠康酸酐（cit）官能化的聚L-赖氨酸（PLL（cit））作为电荷反转部分官能化，以产生所得DOX@HMDN-PEI-PLL（cit）纳米颗粒。体外研究表明，DOX@HMDN-PEI-PLL（cit）在生理条件下表现出“隐身”性质，并且由于cit的离开而响应于弱酸性肿瘤微环境而增强细胞摄取活性。体外释药实验表明，HMDN在酸性条件下或高浓度谷胱甘肽（GSH）作用下分解为Mn 2+，引发DOX释放和类Fenton反应，从而提高疗效。Mn ~（2+）也可作为T_1加权磁共振成像（MRI）的对比剂。体内研究进一步证明，DOX@HMDN-PEI-PLL（cit）具有电荷反转和联合治疗特性，显示出良好的肿瘤富集能力和治疗效果，对小鼠的副作用很少。这些结果表明DOX@HMDN-PEIPLL（cit）纳米粒是一种很有前途的肿瘤靶向治疗药物传递系统。我们采用空心二氧化锰纳米粒子（HMDN）负载DOX，并在其表面包覆聚乙烯亚胺，然后用柠康酸酐功能化聚赖氨酸赋予其电荷反转特性，得到了一种多刺激响应的药物传递系统DOX@HMDN-PEI-PLL（cit）。它是“隐形的”，正常细胞的细胞摄取能力低，但可以在肿瘤中被“酸激活”，被癌细胞内吞，以减少副作用。HMDN可在酸性条件/高谷胱甘肽浓度下分解为Mn 2+以在细胞内释放DOX。DOX和Mn 2+催化的类Fenton反应可实现联合化疗动力学治疗。Mn ~（2+）可用于T_1加权磁共振成像。(C)2021 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
The exploration and application of hollow manganese dioxide nanoparticle (HMDN) for biosensing and biomedicine has gained significant research attention in the past decade. In this study, a type of biodegradable HMDN is prepared for multi-stimuli responsive tumor-targeted drug delivery, which was successfully loaded with doxorubicin hydrochloride (DOX). Then, the drug-loaded HMDN is functionalized with polyethyleneimine (PEI) as a gatekeeper followed by citraconic anhydride (cit) functionalized polyL-lysine (PLL(cit)) as a charge reversal moiety successively to yield the resultant DOX@HMDN-PEI-PLL(cit) nanoparticles. In vitro study showed that DOX@HMDN-PEI-PLL(cit) exhibited a "stealthy'' property under physiological conditions and enhanced cellular uptake activity in response to the mild acidic tumor microenvironment due to the departure of cit. In vitro release profiles proved that the decomposition of HMDN to Mn2+ under acidic condition/high glutathione (GSH) concentration triggered the release of DOX and Fenton-like reaction for improved therapeutic effect. And Mn2+ could also act as a T-1-weighted magnetic resonance imaging (MRI) contrast agent. In vivo studies further proved with both the charge reversal and combined therapy properties, DOX@HMDN-PEI-PLL(cit) showed a good tumor enrichment ability and therapeutic effect with few side effects to the mice. These results demonstrate that DOX@HMDN-PEIPLL(cit) nanoparticles are promising drug delivery systems for targeted cancer therapy.Statement of significanceTraditional chemotherapy based on anticancer drugs such as doxorubicin hydrochloride (DOX) shows limited efficacy with serious side effects. We employed hollow manganese dioxide nanoparticle (HMDN) to loaded DOX and coated it with polyethyleneimine and then citraconic anhydride functionalized poly- Llysine to endow it with a charge reversal property to obtain a multi-stimuli responsive drug delivery system named DOX@HMDN-PEI-PLL(cit). It was "stealthy'' with low cellular uptake capability by normal cells, but could be "acid-activated" in tumors for endocytosis by cancer cells to reduce side effects. HMDN could be decomposed to Mn2+ under acidic conditions/high glutathione concentration to release DOX intracellular. DOX and Mn2+ catalyzed Fenton-like reaction could achieve a combined chemochemodynamic therapy. And Mn2+ could be used for T-1-weighted magnetic resonance imaging. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.