Purpose: Therapy for triple-negative breast cancer (TNBC) is a global problem due to lack of specific targets for treatment selection. Cancer stem cells (CSCs) are responsible for tumor formation and recurrence but also offer a promising target for TNBC-targeted therapy. Here, zirconium-89 (⁸⁹Zr)-labelled multifunctional liposomes (MLPs) surface-decorated with chitosan (CS) were fabricated to specifically target and trace cluster of differentiation 44⁺ (CD44⁺) TNBC CSCs specifically.
Patients and Methods: The biological basis of CS targeting CD44 for cancer therapy was investigated by detecting the expression of CD44 in TNBC CSCs and TNBC tissues. Molecular docking and dynamics simulations were performed to investigate the molecular basis of CS targeting CD44 for cancer therapy. Gambogic acid (GA)-loaded, ⁸⁹Zr@CS-MLPs (⁸⁹Zr-CS-GA-MLPs) were prepared, and their uptake and biodistribution were observed. The anti-tumor efficacy of ⁸⁹Zr@CS-GA-MLPs was investigated in vivo.
Results: CD44 is overexpressed in TNBC CSCs and tissues. Molecular docking and dynamics simulations showed that CS could be stably docked into the active site of CD44 in a reasonable conformation. Furthermore, ⁸⁹Zr@CS-GA-MLPs were able to bind specifically to CD44⁺ TNBC stem-like cells and accumulated in tumors of xenograft-bearing mice with excellent radiochemical stability. ⁸⁹Zr@CS-GA-MLPs loaded with GA showed remarkable anti-tumor efficacy in vivo.
Conclusion: The GA-loaded, ⁸⁹Zr-labelled, CS-decorated MLPs developed in this study represent a novel strategy for TNBC imaging and therapy.

Keywords: radionuclide, PET, CS, CD44, molecular docking, molecular dynamics simulation


中文翻译：

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89Zr 标记的多功能脂质体偶联壳聚糖用于 PET 可追踪的三阴性乳腺癌干细胞靶向治疗

目的：三阴性乳腺癌 (TNBC) 的治疗是一个全球性问题，因为缺乏治疗选择的具体目标。癌症干细胞 (CSC) 负责肿瘤的形成和复发，但也为 TNBC 靶向治疗提供了一个有希望的靶点。在这里，制备了表面装饰有壳聚糖 (CS) 的锆 89 ( ⁸⁹ Zr) 标记的多功能脂质体 (MLP)，以特异性靶向和追踪分化簇 44 ⁺ (CD44 ⁺ ) TNBC CSC。
患者和方法：通过检测 TNBC CSC 和 TNBC 组织中 CD44 的表达，研究了 CS 靶向 CD44 用于癌症治疗的生物学基础。进行分子对接和动力学模拟以研究 CS 靶向 CD44 用于癌症治疗的分子基础。制备了负载藤黄酸（GA）的⁸⁹个 Zr@CS-MLPs（⁸⁹个 Zr-CS-GA-MLPs），并观察了它们的吸收和生物分布。^{在体内研究了89}种Zr@CS-GA-MLPs的抗肿瘤功效。
结果： CD44 在 TNBC CSCs 和组织中过度表达。分子对接和动力学模拟表明，CS可以以合理的构象稳定地与CD44的活性位点对接。此外，⁸⁹Zr@CS-GA-MLPs 能够特异性结合 CD44 ⁺ TNBC 干细胞样细胞，并在异种移植小鼠的肿瘤中积累，具有优异的放射化学稳定性。⁸⁹个载有 GA 的 Zr@CS-GA-MLP 在体内表现出显着的抗肿瘤功效。
结论：本研究开发的载有 GA、⁸⁹ Zr 标记、CS 装饰的 MLP 代表了 TNBC 成像和治疗的新策略。

关键词：放射性核素，PET，CS，CD44，分子对接，分子动力学模拟