通过 saracatinib/capivasertib 共递送纳米颗粒同时失活Src 和 AKT，以提高头颈部鳞状细胞癌抗Src 治疗的疗效。

Simultaneously inactivating Src and AKT by saracatinib/capivasertib co-delivery nanoparticles to improve the efficacy of anti-Src therapy in head and neck squamous cell carcinoma.

机构信息

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.

Department of Pediatrics, Emory Children's Center, Emory University, Atlanta, GA, USA.

出版信息

J Hematol Oncol. 2019 Dec 5;12(1):132. doi: 10.1186/s13045-019-0827-1.

DOI:10.1186/s13045-019-0827-1

PMID:31805962

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6896687/

Abstract

BACKGROUND

Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical benefit of targeting Src is significantly dampened in HNSCC patients, because the cytotoxic effects of anti-Src therapy and tumor resistance to it are less predictable. Thus, understanding the mechanism of tumor resistance to Src inhibition and seeking a way to overcome it are warranted.

METHODS

Dual drug-loaded nanoparticles (NPs) were developed to co-deliver Src inhibitor saracatinib (AZD0530) and AKT inhibitor capivasertib (AZD5363) into the same population of tumor cells. An orthotopic tongue tumor model was generated to evaluate the in vivo therapeutic effects. Cell growth was determined by CellTiter-Glo® Luminescent Cell Viability Kit, colony formation, and 3D culture, and tumor growth was determined by bioluminescence and tumor size. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry.

RESULTS

Capivasertib inactivated the AKT-S6 signaling and re-sensitized saracatinib-resistant HNSCC cells to saracatinib. Combination of capivasertib with saracatinib suppressed HNSCC growth more efficiently than either drug alone. Cathepsin B-sensitive NPs for co-delivering saracatinib and capivasertib significantly improved the efficacy of tumor repression without increasing side effects, which were due to highly specific tumor-targeting drug delivery system and synergistic anticancer effects by co-inactivation of AKT and Src in HNSCC cells.

CONCLUSIONS

Addition of AKT blockade improves anti-HNSCC efficacy of anti-Src therapy, and co-delivery of capivasertib and saracatinib by tumor-targeting NPs has the potential to achieve better treatment outcomes than the free drug combination.

摘要

背景

Src 是一种致癌蛋白，可促进头颈部鳞状细胞癌（HNSCC）的进展，在这种疾病中通常过度活跃。不幸的是，针对 Src 的临床获益在 HNSCC 患者中显著降低，因为抗 Src 治疗的细胞毒性作用及其对肿瘤的耐药性不太可预测。因此，了解肿瘤对 Src 抑制的耐药机制并寻求克服耐药性的方法是有必要的。

方法

开发了载双药纳米颗粒（NPs），以将 Src 抑制剂 saracatinib（AZD0530）和 AKT 抑制剂 capivasertib（AZD5363）共同递送至同一群肿瘤细胞中。建立了原位舌肿瘤模型以评估体内治疗效果。通过 CellTiter-Glo®发光细胞活力试剂盒、集落形成和 3D 培养来确定细胞生长，通过生物发光和肿瘤大小来确定肿瘤生长。通过 Western blot 和免疫组化评估治疗引起的分子变化。

结果

Capivasertib 使 AKT-S6 信号失活，并使 saracatinib 耐药的 HNSCC 细胞重新对 saracatinib 敏感。与单独使用任何一种药物相比，capivasertib 与 saracatinib 的联合使用更有效地抑制了 HNSCC 的生长。共递送 saracatinib 和 capivasertib 的组织蛋白酶 B 敏感 NPs 显著提高了肿瘤抑制的疗效，而没有增加副作用，这是由于高度特异性的肿瘤靶向药物递送系统和在 HNSCC 细胞中共同失活 AKT 和 Src 的协同抗癌作用。