Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Department of Radiology and Nuclear Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, PR China.
Colloids Surf B Biointerfaces. 2020 Apr;188:110772. doi: 10.1016/j.colsurfb.2020.110772. Epub 2020 Jan 20.
This study aimed to develop sheddable polyethylene glycol (PEG) shells with TAT-modified core cross-linked nanomicelles as drug-delivery carriers of doxorubicin (DOX) to establish a programmed response against the tumor microenvironment, enhanced endocytosis, and lysosomal pH-triggered DOX release. First, poly(L-succinimide) (PSI) underwent a ring-opening reaction with ethylenediamine to generate poly(N-(2-aminoethyl)-l-aspartamide) (P(ae-Asp)). Next, the thiolytic cleavable PEG, 3,4-dihydroxyphenylacetic acid, and TAT were grafted onto P(ae-Asp) to synthesize the amphiphilic graft copolymer of mPEG-SS-g-P(ae-Asp)-MCA-DA-TAT. In aqueous solution, the amphiphilic polymer self-assembled into nanomicelles, encapsulating DOX into the hydrophobic core of micelles. TAT was shielded by the PEG corona during circulation to avoid non-specific transmembrane interaction with normal cells, while the tumor redox environment-responsive shedding of PEG could expose TAT to promote internalization of tumor cells. In order to improve the stability of nanomicelles and achieve pH-triggered drug release, a core cross-linking strategy based on the coordination of catechol and Fe was adopted. In vitro studies demonstrated that core cross-linked nanomicelles maintained the nanostructure in 100 times dilution in pH 7.4 phosphate-buffered saline (PBS). Moreover, DOX release from DOX-loaded core cross-linked nanomicelles (DOX-TAT-CCLMs) was favored at simulated lysosomal conditions over simulated plasma conditions, indicating that these nanomicelles demonstrate characteristics of pH-triggered DOX release. The TAT modification considerably enhanced the mean fluorescence intensity of the nanomicelles endocytosed by MCF-7/ADR cells by 8 times, compared with DOX·HCl after 8 h of incubation. Notably, the IC value of nanomicelles (11.61 ± 0.95 μg/mL) was nearly 4 times lower than that of DOX·HCl against MCF-7/ADR cells, implying that the nanomicelles could overcome drug resistance observed in MCF-7/ADR cells. Furthermore, the DOX-TAT-CCLMs reported superior tumor growth suppression in a 4T1 tumor-bearing mouse model. Thus, the redox- and pH- stimuli stepwise-responsive novel nanomicelles fabricated from the mPEG-SS-g-P(ae-Asp)-MCA-DA-TAT graft copolymer exhibited multifunctionality and displayed great potential for drug delivery.
本研究旨在开发具有 TAT 修饰核交联纳米胶束的可脱落聚乙二醇（PEG）壳作为阿霉素（DOX）的药物递送载体，以建立针对肿瘤微环境的程序性响应，增强内吞作用和溶酶体 pH 触发的 DOX 释放。首先，聚（L-琥珀酰亚胺）（PSI）与乙二胺进行开环反应，生成聚（N-（2-氨基乙基）-L-天冬酰胺）（P（ae-Asp））。接下来，将硫解可切割的 PEG、3,4-二羟基苯乙酸和 TAT 接枝到 P（ae-Asp）上，合成两性嵌段共聚物 mPEG-SS-g-P（ae-Asp）-MCA-DA-TAT。在水溶液中，两亲性聚合物自组装成纳米胶束，将 DOX 包封在胶束的疏水性核心内。TAT 在循环过程中被 PEG 冠屏蔽，以避免与正常细胞发生非特异性跨膜相互作用，而 PEG 的肿瘤氧化还原环境响应性脱落可以暴露 TAT，从而促进肿瘤细胞的内化。为了提高纳米胶束的稳定性并实现 pH 触发的药物释放，采用了基于儿茶酚和 Fe 配位的核交联策略。体外研究表明，在 pH 7.4 磷酸盐缓冲盐水（PBS）中稀释 100 倍时，核交联纳米胶束仍保持纳米结构。此外，与模拟血浆条件相比，载 DOX 的核交联纳米胶束（DOX-TAT-CCLMs）中的 DOX 释放更有利于模拟溶酶体条件，表明这些纳米胶束具有 pH 触发的 DOX 释放特征。与孵育 8 小时后的 DOX·HCl 相比，TAT 修饰使 MCF-7/ADR 细胞内吞的纳米胶束的平均荧光强度增加了 8 倍。值得注意的是，纳米胶束的 IC 值（11.61±0.95μg/mL）比 DOX·HCl 对 MCF-7/ADR 细胞的 IC 值低近 4 倍，这表明纳米胶束可以克服 MCF-7/ADR 细胞中观察到的耐药性。此外，在 4T1 荷瘤小鼠模型中，报告的 DOX-TAT-CCLMs 具有优异的肿瘤生长抑制作用。因此，由 mPEG-SS-g-P（ae-Asp）-MCA-DA-TAT 接枝共聚物制备的具有氧化还原和 pH 刺激逐步响应的新型纳米胶束表现出多功能性，并显示出在药物递送方面的巨大潜力。
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