肿瘤细胞治疗研究
英文原题：Human Mesenchymal Stem Cell-Derived Exosomes as Engineering Vehicles of Daunorubicin for Targeted c-Mpl+ AML Therapy.
我们的结果表明，工程化 Exos 可作为高效的靶向药物递送载体，用于清除 c-Mpl⁺ AML 细胞，同时保持良好的安全性。
背景：急性髓系白血病（AML）高度异质，治疗结局和总体预后较差，c-Mpl阳性AML尤为如此。原癌基因c-Mpl在AML中的表达显著高于正常人组织细胞。本研究旨在开发一种靶向外泌体（Exos），将抗癌药物直接递送至c-Mpl阳性AML细胞。方法：分离人脐带间充质干细胞（hUCMSC）作为外泌体来源。通过生物工程改造，使带有不同数量血小板生成素（TPO）模拟肽的融合CD63蛋白表达于hUCMSC及其来源外泌体膜上，以靶向c-Mpl。采用DUAL膜系统、荧光共振能量转移效率及内吞实验评估融合蛋白靶向能力。装载抗癌药柔红霉素（DNR）后，评估靶向外泌体清除c-Mpl阳性AML细胞的能力，并在小鼠AML模型中进一步测试安全性和疗效。结果：工程化hUCMSC来源外泌体可有效靶向c-Mpl，且易被c-Mpl阳性AML细胞内吞。在工程化外泌体中，含3条TPO模拟肽的融合蛋白（CD63-mTPO3，命名为m3Exos）对c-Mpl结合亲和力最高。装载DNR后，m3Exos@DNR在体内外均可有效清除c-Mpl阳性AML细胞。安全性评估显示，治疗相关毒性处于可接受范围，副作用可管理。结论：工程化外泌体可作为高效靶向递送载体清除c-Mpl阳性AML细胞，并保持良好安全性。这些发现也为AML及其他具有特定膜蛋白表达的肿瘤治疗策略开发提供了参考。
BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous disease with poor therapeutic outcomes and overall prognosis, particularly in c-Mpl+ AML. c-Mpl , a proto-oncogene, is expressed at significantly higher levels in AML compared to normal human tissue cells. This study aimed to develop a type of targeted exosomes (Exos) capable of delivering anticancer drugs directly to c-Mpl+ AML cells. METHODS: Human umbilical cord mesenchymal stem cells (hUCMSCs) were isolated as the source of Exos. Fusion CD63 proteins with varying numbers of thrombopoietin (TPO)-mimic peptides, designed to target c-Mpl, were bioengineered to be expressed on the membranes of hUCMSCs and their derived Exos. The targeting capability of the fusion proteins was assessed using the DUAL membrane system, fluorescence resonance energy transfer efficiency, and endocytosis assays. After encapsulating the anticancer drug daunorubicin (DNR), these targeted Exos were evaluated for their ability to eliminate c-Mpl+ AML cells. Safety and efficacy were further tested in a mouse AML model. RESULTS: Our findings showed that the engineered hUCMSCs-derived Exos demonstrated excellent targeting ability to c-Mpl and a strong propensity for endocytic uptake by c-Mpl+ AML cells. Among the engineered Exos, those with the fusion protein containing three TPO-mimic peptides (CD63-mTPO 3 ), named as m 3 Exos, exhibited the highest binding affinity for c-Mpl. When loaded with DNR, these engineered Exos (m 3 Exos@DNR) effectively eliminated c-Mpl+ AML cells in both in vitro and in vivo experiments. Furthermore, safety assessments revealed that therapy-related toxicities were within acceptable limits and associated with manageable side effects. CONCLUSION: In summary, our results suggest engineered Exos as a highly effective targeted drug delivery vehicle for eliminating c-Mpl+ AML cells while maintaining a favorable safety profile. These findings also provide valuable insights for developing therapeutic strategies for AML and other tumors characterized by specific membrane protein expression.
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