College of Chemistry, Chemical Engineering and Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, Soochow University, Suzhou 215123, P. R. China.
Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, P. R. China.
J Mater Chem B. 2023 Oct 11;11(39):9467-9477. doi: 10.1039/d3tb01703f.
Stimuli-responsive cross-linked micelles (SCMs) are ideal nanocarriers for anti-cancer drugs. Compared with non-cross-linked micelles, SCMs exhibit superior structural stability. At the same time, the introduction of an environmentally sensitive crosslinker into a drug delivery system allows SCMs to respond to single or multiple stimuli in the tumor microenvironment, which can minimize drug leakage during the blood circulation process. In this study, curcumin (CUR) was modified as the hydrophobic core crosslinker by utilizing the bisphenol structure, and redox sensitive disulfide bonds were introduced to prepare the glutathione (GSH) stimulated responsive core crosslinker (abbreviated as N--CUR--N). In addition, amphiphilic polymer APEG--PBYP was prepared through the ring opening reaction, and reacted with the crosslinker through the "click" reaction. After being dispersed in the aqueous phase, core cross-linked nanoparticles (CCL NPs) were obtained. Finally, monoclonal antibody CD326 (mAb-CD326) was reduced and coupled to the hydrophilic chain ends to obtain the nanoparticles with surface modified antibodies (R-mAb-CD326@CCL NPs) for further enhancing targeted drug delivery. The structures of the polymer and crosslinker were characterized by H NMR, UV-Vis, FT-IR, and GPC. The morphology, size and stability of CCL NPs and R-mAb-CD326@CCL NPs were investigated by DLS and TEM. The drug release behavior of CCL NPs was also studied. The results showed that the CCL NPs exhibited reduction-responsiveness and were able to release the original drug CUR under 10 mM GSH conditions. Additionally, the CCL NPs exhibited excellent stability in both the simulated body fluid environment and organic solvents. Especially, R-mAb-CD326@CCL NPs can actively target tumor cells and showed better therapeutic efficacy in experiments with a tumor suppression rate of 78.7%. This work provides a new idea for the design of nano-drugs targeting breast cancer.
刺激响应型交联胶束（SCMs）是抗癌药物的理想纳米载体。与非交联胶束相比，SCMs表现出优异的结构稳定性。同时，将环境敏感交联剂引入药物传递系统中，使 SCMs能够响应肿瘤微环境中的单一或多种刺激，从而最大限度地减少药物在血液循环过程中的泄漏。在这项研究中，利用双酚结构将姜黄素（CUR）修饰为疏水性核交联剂，并引入氧化还原敏感的二硫键，制备谷胱甘肽（GSH）刺激响应核交联剂（简称 N--CUR--N）。此外，通过开环反应制备两亲性聚合物 APEG-PBYP，并通过“点击”反应与交联剂反应。在水相分散后，得到核交联纳米粒子（CCL NPs）。最后，将单克隆抗体 CD326（mAb-CD326）还原并偶联到亲水性链末端，得到表面修饰抗体的纳米粒子（R-mAb-CD326@CCL NPs），以进一步增强靶向药物递送。通过 H NMR、UV-Vis、FT-IR 和 GPC 对聚合物和交联剂的结构进行了表征。通过 DLS 和 TEM 研究了 CCL NPs 和 R-mAb-CD326@CCL NPs 的形态、粒径和稳定性。还研究了 CCL NPs 的药物释放行为。结果表明，CCL NPs 表现出还原响应性，并能够在 10 mM GSH 条件下释放原始药物 CUR。此外，CCL NPs 在模拟体液环境和有机溶剂中均表现出优异的稳定性。特别是，R-mAb-CD326@CCL NPs 能够主动靶向肿瘤细胞，在肿瘤抑制率为 78.7%的实验中表现出更好的治疗效果。这项工作为设计针对乳腺癌的纳米药物提供了新的思路。
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