Department of Gastroenterology and Hepatology, The First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, People's Republic of China.
J Nanobiotechnology. 2022 May 18;20(1):233. doi: 10.1186/s12951-022-01431-8.
Gastric cancer (GC) is a highly heterogeneous disease with many different histological and molecular subtypes. Due to their reduced systemic adverse effects, nanoformulation agents have attracted increasing attention for use in the treatment of GC patients in the clinic. To improve therapeutic outcomes, it is vitally necessary to provide individual medication references and guidance for use of these nanoformulations, and patient-derived organoids (PDOs) are promising models through which to achieve this goal.
Using an improved enzymatic digestion process, we succeeded in constructing GC PDOs from surgically resected tumor tissues and endoscopic biopsies from GC patients; these PDOs closely recapitulated the histopathological and genomic features of the corresponding primary tumors. Next, we chose two representative paclitaxel (PTX) nanoformulations for comparative study and found that liposomal PTX outperformed albumin-bound PTX in killing GC PDOs at both the transcriptome and cellular levels. Our results further showed that the different distributions of liposomal PTX and albumin-bound PTX in PDOs played an essential role in the distinct mechanisms through which they kill PDOs. Finally, we constructed patient-derived xenografts model in which we verified the above distinct therapeutic outcomes via an intratumoral administration route.
This study demonstrates that GC PDOs are reliable tools for predicting nanoformulation efficacy.
胃癌（GC）是一种高度异质性疾病，具有许多不同的组织学和分子亚型。由于其全身不良反应减少，纳米制剂已引起越来越多的关注，并在临床上用于治疗 GC 患者。为了提高治疗效果，迫切需要为这些纳米制剂的使用提供个体化的药物参考和指导，而患者来源的类器官（PDO）是实现这一目标的有前途的模型。
我们使用改良的酶消化工艺，成功地从 GC 患者手术切除的肿瘤组织和内镜活检中构建了 GC PDO；这些 PDO 紧密重现了相应原发性肿瘤的组织病理学和基因组特征。接下来，我们选择了两种代表性的紫杉醇（PTX）纳米制剂进行比较研究，发现脂质体 PTX 在转录组和细胞水平上均比白蛋白结合型 PTX 更能杀死 GC PDO。我们的结果进一步表明，脂质体 PTX 和白蛋白结合型 PTX 在 PDO 中的不同分布在它们杀死 PDO 的不同机制中起着重要作用。最后，我们构建了患者来源的异种移植模型，通过瘤内给药途径验证了上述不同的治疗效果。
本研究表明，GC PDO 是预测纳米制剂疗效的可靠工具。
