Cyclo-γ-polyglutamic acid-coated dual-responsive nanomicelles loaded with doxorubicin for synergistic chemo-photodynamic therapy.
Cyclo-γ-polyglutamic acid-coated dual-responsive nanomicelles loaded with doxorubicin for synergistic chemo-photodynamic therapy.
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DOI：
10.1039/d1bm00713k
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发表时间：
2021-08
影响因子：
6.6
通讯作者：
Chao Wang;Beilei Wang;Shuaijun Zou;Bo Wang;Guoyan Liu;Fuhai Zhang;Qianqian Wang;Qian He;Liming Zhang
中科院分区：
文献类型：
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作者：
Chao Wang;Beilei Wang;Shuaijun Zou;Bo Wang;Guoyan Liu;Fuhai Zhang;Qianqian Wang;Qian He;Liming Zhang
纳米给药系统在提高肿瘤靶向能力和减少抗癌药物的副作用方面得到了广泛的应用。在本研究中，设计并开发了对双重刺激有反应的纳米胶束作为药物载体，用于递送阿霉素（DOX）。纳米胶束的疏水性基团由光敏剂原卟啉IX （PpIX）和含二硫键的α -硫辛酸（LA）组成；亲水性基团由核定位信号（NLS， CGGGPKKKRKVGG）肽和赖氨酸连接体组成。将阴离子环-γ-聚谷氨酸（cyclo-γ-PGA）包被在阳离子胶束表面，构建多功能给药体系（NLS-LA-PpIX-DOX@cyclo-γ-PGA）。Cyclo-γ-PGA作为一种生物涂层材料，通过减少与阴离子基团的非特异性反应，显著提高了阳离子胶束的稳定性。此外，cyclo-γ-PGA涂层介导活性肿瘤靶向，并通过γ-谷氨酰转肽酶（GGT）途径增强细胞对胶束的摄取。集成胶束不仅通过光活化活性氧（ROS）实现光化学内化（PCI）和光动力治疗（PDT），而且通过谷胱甘肽（GSH）响应的二硫键裂解实现细胞内药物的可控释放。结果，NLS-LA-PpIX-DOX@cyclo-γ-PGA在体外和体内均表现出优异的协同化学光动力抗肿瘤活性，且副作用小于其他治疗方法。综上所述，这种新的双反应给药系统（NLS-LA-PpIX-DOX@cyclo-γ-PGA）具有更好的稳定性和增强的肿瘤靶向能力，可能促进高效低毒纳米治疗方法的发展。
Nanodrug delivery systems have been used extensively to improve the tumor-targeting ability and reduce the side effects of anticancer drugs. In this study, nanomicelles responsive to dual stimuli were designed and developed as drug carriers for delivering doxorubicin (DOX). The hydrophobic group of the nanomicelles was composed of the photosensitizer protoporphyrin IX (PpIX) and the disulfide bond-containing alpha-lipoic acid (LA); the hydrophilic group was made up of the nuclear localization signal (NLS, CGGGPKKKRKVGG) peptide with a lysine linker. Furthermore, anionic cyclo-γ-polyglutamic acid (cyclo-γ-PGA) was coated on the surface of the cationic micelles to construct a multifunctional drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA). Cyclo-γ-PGA, as a biological coating material, notably improved the stability of the cationic micelles by reducing nonspecific reactions with anionic groups. Additionally, the cyclo-γ-PGA coating mediated active tumor targeting and enhanced the cellular uptake of micelles via the γ-glutamyl transpeptidase (GGT) pathway. The integrated micelles not only achieved photochemical internalization (PCI) and photodynamic therapy (PDT) via light-activated reactive oxygen species (ROS) but also realized controlled intracellular drug release via the glutathione (GSH)-responsive disulfide-bond cleavage. As a result, NLS-LA-PpIX-DOX@cyclo-γ-PGA exhibited excellent synergistic chemo-photodynamic antitumor activity and fewer side effects than other therapies both in vitro and in vivo. In conclusion, this new dual-responsive drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA) with improved stability and enhanced tumor-targeting ability may facilitate the development of high-efficiency and low-toxicity nanotherapeutic approaches.