Purpose

Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis due to recurrence from highly resistant GBM cancer stem cells (CSCs), for which the current standard of treatment with temozolomide (TMZ) alone will unlikely produce a viable cure. In addition, CSCs regenerate rapidly and overexpress methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to resistance. The objective of this research was to apply the concepts of nanotechnology to develop a multi-drug therapy, TMZ and idasanutlin (RG7388, a potent mouse double minute 2 (MDM2) antagonist), loaded in functionalized nanoparticles (NPs) that target the GBM CSC subpopulation, reduce the cell viability and provide possibility of in vivo preclinical imaging.

Methods

Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed by a double emulsion technique loading TMZ and/or RG7388. The NPs were covalently bound to a 15-nucleotide base-pair CD133 aptamer to target the CD133 antigen expressed on the surfaces of GBM CSCs. For diagnostic functionality, the NPs were labelled with radiotracer Zirconium-89 (⁸⁹Zr).

Results

NPs maintained size range less than 100 nm, a low negative charge and exhibited the ability to target and kill the CSC subpopulation when TMZ and RG7388 were used in combination. The targeting function of CD133 aptamer promoted killing in GBM CSCs providing impetus for further development of targeted nanosystems for localized therapy in future in vivo models.

Conclusions

This work has provided a potential clinical application for targeting GBM CSCs with simultaneous diagnostic imaging.

中文翻译：

---

用于胶质母细胞瘤的 CD133 靶向多药聚合物胶束纳米颗粒的开发 - 胶质母细胞瘤干细胞的体外评估

目的

胶质母细胞瘤 (GBM) 是一种恶性脑肿瘤，由于高耐药性 GBM 癌症干细胞 (CSC) 的复发，长期预后较差，目前单独使用替莫唑胺 (TMZ) 的治疗标准不太可能产生可行的治愈方法。此外，CSCs 快速再生并过度表达甲基转移酶，这会覆盖 TMZ 的 DNA 烷基化机制，导致抗性。本研究的目的是应用纳米技术的概念来开发多药疗法，TMZ 和 idasanutlin（RG7388，一种有效的小鼠双分钟 2 (MDM2) 拮抗剂），加载在靶向 GBM CSC 的功能化纳米粒子 (NPs) 中亚群，降低细胞活力并提供体内临床前成像的可能性。

方法

由聚（苯乙烯-b-环氧乙烷）（PS- b - PEO）和聚（乳酸-共-乙醇酸）（PLGA）组成的聚合物胶束纳米颗粒是通过加载 TMZ 和/或 RG7388 的双乳液技术开发的。NPs 与 15 个核苷酸碱基对的 CD133 适体共价结合，以靶向表达在 GBM CSCs 表面上的 CD133 抗原。对于诊断功能，NPs 用放射性示踪剂 Zirconium-89 ( ⁸⁹ Zr)标记。

结果

当 TMZ 和 RG7388 组合使用时，NPs 保持小于 100 nm 的尺寸范围、低负电荷并表现出靶向和杀死 CSC 亚群的能力。CD133 适体的靶向功能促进了 GBM CSCs 的杀伤作用，为未来体内模型中局部治疗的靶向纳米系统的进一步开发提供了动力。

结论

这项工作为通过同步诊断成像靶向 GBM CSCs 提供了潜在的临床应用。