Targeting and Cytotoxicity of SapC-DOPS Nanovesicles in Pancreatic Cancer
Targeting and Cytotoxicity of SapC-DOPS Nanovesicles in Pancreatic Cancer
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DOI：
10.1371/journal.pone.0075507
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发表时间：
2013-10-04
期刊：
影响因子：
3.7
通讯作者：
Qi, Xiaoyang
中科院分区：
文献类型：
--
作者：
Chu, Zhengtao;Abu-Baker, Shadi;Qi, Xiaoyang
只有少数有前景的药物针对胰腺癌，胰腺癌是癌症死亡的第四大原因，其 5 年生存率低于 5%。我们的目标是开发一种新的生物治疗剂，其中溶酶体蛋白（saposin C，SapC）和磷脂（二油酰磷脂酰丝氨酸，DOPS）被组装成纳米囊泡（SapC-DOPS）来治疗胰腺癌。 SapC-DOPS 纳米囊泡的一个显着特征是它们对富含磷脂酰丝氨酸（PS）的微结构域具有高亲和力，这些微结构域异常暴露在人胰腺肿瘤细胞的膜表面。为了评估外部细胞 PS 的作用，使用体外测定来关联 PS 暴露与 SapC-DOPS 在人类肿瘤和非致瘤性胰腺细胞中的细胞毒性作用。接下来，胰腺肿瘤异种移植物（原位和皮下模型）用于全身 SapC-DOPS 治疗的肿瘤靶向和治疗效果研究。我们观察到纳米囊泡通过诱导细胞凋亡在体外选择性杀死人胰腺癌细胞，而未转化的细胞则不受影响。这种体外细胞毒性作用与肿瘤细胞上 PS 的表面暴露水平相关。使用异种移植物，用 SapC-DOPS 治疗的动物显示出明显的生存益处，并且它们的肿瘤缩小或消失。此外，在活体小鼠中使用双追踪方法，我们发现纳米囊泡专门针对原位植入的生物发光胰腺肿瘤。这些数据表明，酸性磷脂 PS 是胰腺癌的生物标志物，可以有效地利用癌症选择性 SapC-DOPS 纳米囊泡进行治疗。这项研究为支持开发胰腺癌新治疗方法提供了令人信服的证据。
Only a small number of promising drugs target pancreatic cancer, which is the fourth leading cause of cancer deaths with a 5-year survival of less than 5%. Our goal is to develop a new biotherapeutic agent in which a lysosomal protein (saposin C, SapC) and a phospholipid (dioleoylphosphatidylserine, DOPS) are assembled into nanovesicles (SapC-DOPS) for treating pancreatic cancer. A distinguishing feature of SapC-DOPS nanovesicles is their high affinity for phosphatidylserine (PS) rich microdomains, which are abnormally exposed on the membrane surface of human pancreatic tumor cells. To evaluate the role of external cell PS, in vitro assays were used to correlate PS exposure and the cytotoxic effect of SapC-DOPS in human tumor and nontumorigenic pancreatic cells. Next, pancreatic tumor xenografts (orthotopic and subcutaneous models) were used for tumor targeting and therapeutic efficacy studies with systemic SapC-DOPS treatment. We observed that the nanovesicles selectively killed human pancreatic cancer cells in vitro by inducing apoptotic death, whereas untransformed cells remained unaffected. This in vitro cytotoxic effect correlated to the surface exposure level of PS on the tumor cells. Using xenografts, animals treated with SapC-DOPS showed clear survival benefits and their tumors shrank or disappeared. Furthermore, using a double-tracking method in live mice, we showed that the nanovesicles were specifically targeted to orthotopically-implanted, bioluminescent pancreatic tumors. These data suggest that the acidic phospholipid PS is a biomarker for pancreatic cancer that can be effectively targeted for therapy utilizing cancer-selective SapC-DOPS nanovesicles. This study provides convincing evidence in support of developing a new therapeutic approach to pancreatic cancer.