Sequential Targeting TGF-β Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer
Sequential Targeting TGF-β Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer
复制标题
连续靶向 TGF-β 信号传导和 KRAS 突变可提高胰腺癌的治疗效果
DOI：
10.1002/smll.201900631
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发表时间：
2019-06-01
期刊：
影响因子：
13.3
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Pei, Yuanyuan;Chen, Liang;Chen, Jun
胰腺癌是一种高度侵袭性的恶性肿瘤，对现有的治疗方法有强烈的抵抗力。现有疗法的失败主要归因于恶劣的肿瘤微环境（TME）限制了药物的获取以及肿瘤细胞的不可成药靶点。抑制性 TME 的形成受到转化生长因子 β (TGF-β) 信号传导的调节，而近 90% 的胰腺癌患者的反应不佳和生存期短是由于致癌 KRAS 突变造成的。因此，同时针对 TGF-β 和 KRAS 通路可能会消除胰腺癌治疗的障碍。在此，开发了一种新颖的顺序靶向策略，其中构建抗纤维化的fraxinellone负载CGKRK修饰纳米颗粒（Frax-NP-CGKRK）来调节TGF-β信号传导，并应用负载siRNA的脂质包被磷酸钙（LCP）仿生纳米颗粒（siKras-LCP-ApoE3）来干扰致癌KRAS。 Frax-NP-CGKRK 通过识别过度表达的硫酸乙酰肝素蛋白聚糖成功靶向肿瘤部位，逆转激活的癌症相关成纤维细胞 (CAF)，削弱致密基质屏障，并增强肿瘤血液灌注。随后，siKras-LCP-ApoE3 通过巨胞饮作用和特异性沉默 KRAS 突变被肿瘤细胞有效内化。与吉西他滨相比，这种序贯靶向策略显着延长了胰腺肿瘤动物的寿命，从而为胰腺癌治疗提供了一种有前景的方法。
Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF-beta) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF-beta and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential-targeting strategy is developed, in which antifibrotic fraxinellone-loaded CGKRK-modified nanoparticles (Frax-NP-CGKRK) are constructed to regulate TGF-beta signaling and siRNA-loaded lipid-coated calcium phosphate (LCP) biomimetic nanoparticles (siKras-LCP-ApoE3) are applied to interfere with the oncogenic KRAS. Frax-NP-CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer-associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras-LCP-ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential-targeting strategy significantly elongates the lifespans of pancreatic tumor-bearing animals, hence providing a promising approach for pancreatic cancer therapy.