A CD326 monoclonal antibody modified core cross-linked curcumin-polyphosphoester prodrug for targeted delivery and cancer treatment
A CD326 monoclonal antibody modified core cross-linked curcumin-polyphosphoester prodrug for targeted delivery and cancer treatment
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DOI：
10.1039/d3tb01703f
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发表时间：
2023-09-12
影响因子：
7
通讯作者：
Ni，Peihong
中科院分区：
文献类型：
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作者：
Li，Haijiao;Zhang，Mingzu;Ni，Peihong
刺激响应型交联胶束是理想的抗癌药物纳米载体。与非交联胶束相比，超临界胶束具有上级的结构稳定性。同时，将环境敏感的交联剂引入药物递送系统中，允许SCM对肿瘤微环境中的单一或多种刺激做出反应，这可以最大限度地减少血液循环过程中的药物泄漏。利用姜黄素（CUR）的双酚结构，将其修饰为疏水性核交联剂，并引入氧化还原敏感的二硫键，制备了谷胱甘肽（GSH）刺激响应型核交联剂（N3-ss-CUR-ss-N3）。此外，通过开环反应制备了两亲性聚合物APEG-b-PBYP，并与交联剂通过“点击”反应进行反应。在分散于水相中之后，获得核交联纳米颗粒（CCL NPs）。最后，将单克隆抗体CD 326（mAb-CD 326）还原并偶联到亲水链末端，以获得具有表面修饰抗体的纳米颗粒（R-mAb-CD326@CCL NPs），用于进一步增强靶向药物递送。用1H 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CCL NPs和R-mAb-CD326@CCL NPs的形态、大小和稳定性。并对纳米粒的体外释药行为进行了研究。结果表明，CCL纳米粒表现出还原响应性，并能够在10 mM GSH条件下释放原始药物CUR。此外，CCL NP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纳米粒能够主动靶向肿瘤细胞，在体内实验中显示出更好的治疗效果，肿瘤抑制率为78.7%。这项工作为针对乳腺癌的纳米药物设计提供了新的思路。
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 N3-ss-CUR-ss-N3). In addition, amphiphilic polymer APEG-b-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 1H 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 in vitro 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 in vivo experiments with a tumor suppression rate of 78.7%. This work provides a new idea for the design of nano-drugs targeting breast cancer.