富含整合素的膜纳米载体用于特异性递送 RGD 修饰的松弛素类似物以通过逆转肝星状细胞激活来抑制胰腺癌肝转移,Advanced Functional Materials

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富含整合素的膜纳米载体用于特异性递送 RGD 修饰的松弛素类似物以通过逆转肝星状细胞激活来抑制胰腺癌肝转移
Advanced Functional Materials ( IF 18.5 ) Pub Date : 2022-09-16 , DOI: 10.1002/adfm.202208404
Lijing Zhang ₁ , Zian Li _{1,

2} , Fazhan Wang ₁ , Qiang Chen ₁ , Mali Zu _{3,

4} , Xingfan Li _{3,

4} , Jiajia Wan ₁ , Xiaohan Yao ₁ , Xiaohan Lou ₁ , Yupeng Shi ₁ , Yuqiao Sheng ₁ , Ming Wang ₁ , Jinjian Yang ₁ , Xinjun Wang ₂ , Zhihai Qin ₁ , Tianjiao Ji _{1,

3,

4}

Affiliation

肝转移在胰腺癌 (PC) 患者中很常见，并且是与 PC 相关的主要死亡原因。由活化的肝星状细胞 (HSC) 诱导的肝纤维化创造了促进转移生长的有利转移微环境。B7-33 是一种治疗性肽（松弛素类似物），靶向活化 HSC 上的松弛素家族肽受体，抑制 pSMAD2/3 信号通路并削弱活化 HSC 的纤维化特性。然而，B7-33 序列的短半衰期和高度保守的性质限制了其在体内的应用。_{在这里，B7-33 用 cRGD 序列修饰，这不影响 B7-33 的功效，并允许 B7-33 通过与整合素 α v} β特异性相互作用组装成血管内皮细胞膜衍生的囊泡₃ . 这些合理设计的囊泡 (B7-33-HNPs) 能够延长 B7-33 在体内的半衰期，并在肝脏中积累以逆转 HSCs 的激活。此外，B7-33-HNP 可防止转移性 PC 小鼠模型中肝转移的形成和生长。本研究提出了通过特异性相互作用构建治疗性肽递送系统的可行策略，为通过调控HSCs预防PC肝转移提供了参考。

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Integrin-Enriched Membrane Nanocarrier for the Specific Delivery of RGD-modified Relaxin Analog to Inhibit Pancreatic Cancer Liver Metastasis through Reversing Hepatic Stellate Cell Activation

Liver metastasis is common in patients with pancreatic cancer (PC) and is the leading cause of death associated with PC. Liver fibrosis induced by activated hepatic stellate cells (HSCs) creates a favorable metastatic microenvironment that promotes metastasis growth. B7-33, a therapeutic peptide (relaxin analog) that targets relaxin family peptide receptors on activated HSCs, inhibits the pSMAD2/3 signaling pathway and weakens the fibrogenic properties of activated HSCs. However, the short half-life and highly conserved nature of the B7-33 sequence limit its application in vivo. Here, B7-33 is modified with the cRGD sequence, which does not affect the efficacy of B7-33 and allows B7-33 to assemble into vascular endothelial cell membrane-derived vesicles by specifically interacting with integrin α_vβ₃. These rationally designed vesicles (B7-33-HNPs) are able to prolong the half-life of B7-33 in vivo and accumulate in the liver to reverse HSCs activation. Moreover, B7-33-HNPs prevent the formation and growth of liver metastases in a mouse model of metastatic PC. This study proposes a feasible strategy for building a therapeutic peptide delivery system through specific interactions, serving as a reference for preventing liver metastasis of PC through the regulation of HSCs.

更新日期：2022-09-16

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