Hepatocellular carcinoma (HCC) is one of the most fatal cancer types worldwide. HCC cells were proved to overexpress c-Src and Sgk1, a tyrosine and a serine-threonine kinase, respectively, whose role is crucial for the development and progression of the tumor. Pyrazolo[3,4-d]pyrimidine derivatives are a class of tyrosine kinase inhibitors that have shown good activity against HepG2. HCC cells were also proved to overexpress plasmin, which is localized on the cell surface bound to its receptors. In this study, a tripeptide with sequence d-Ala-Phe-Lys, which binds a specific reactive site of plasmin, was synthesized and characterized. This tripeptide was used to decorate liposomes encapsulating three selected pyrazolo[3,4-d]pyrimidines. Liposomes bearing tripeptide have been characterized, not showing remarkable differences with respect to the corresponding tripeptide-free liposomes. In vitro HepG2 cell uptake profiles and cytotoxicities showed that the presence of the tripeptide on the liposomal membrane surface improves the cell-penetrating ability of liposomes and increases the activity of two of the three tested compounds.

中文翻译：

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载有吡唑并[3,4- d ]嘧啶的纤溶酶结合三肽修饰的脂质体靶向肝细胞癌

肝细胞癌（HCC）是世界上最致命的癌症类型之一。事实证明，HCC细胞过表达c-Src和Sgk1，酪氨酸和丝氨酸-苏氨酸激酶，它们的作用对于肿瘤的发生和发展至关重要。吡唑并[3,4- d ]嘧啶衍生物是一类酪氨酸激酶抑制剂，已显示出对HepG2的良好活性。HCC细胞也被证明过表达纤溶酶，纤溶酶位于结合其受体的细胞表面。在这项研究中，合成并鉴定了具有结合纤溶酶特异性反应位点的序列d -Ala-Phe-Lys的三肽。该三肽用于修饰脂质体，该脂质体包封了三个选定的吡唑并[3,4- d]嘧啶。已经表征了带有三肽的脂质体，相对于相应的不含三肽的脂质体没有显示出显着差异。体外HepG2细胞摄取概况和细胞毒性表明，脂质体膜表面上三肽的存在改善了脂质体的细胞穿透能力，并增加了三种测试化合物中两种化合物的活性。