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Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy

机译:靶向肿瘤血管的大小可控的双配体修饰脂质体有望用于耐药性癌症治疗

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摘要

Anti-angiogenic therapy is a potential chemotherapeutic strategy for the treatment of drug resistant cancers. However, a method for delivering such drugs to tumor endothelial cells remains to be a major impediment to the success of anti-angiogenesis therapy. We designed liposomes (LPs) with controlled diameter of around 300 nm, and modified them with a specific ligand and a cell penetrating peptide (CPP) (a dual-ligand LP) for targeting CD13-expressing neovasculature in a renal cell carcinoma (RCC). We modified the LPs with an NGR motif peptide on the top of poly(ethylene glycol) and tetra-arginine (R4) on the surface of the liposome membrane as a specific and CPP ligand, respectively. The large size prevented extravasation of the dual-ligand LP, which allowed it to associate with target vasculature. While a single modification with either the specific or CPP ligand showed no increase in targetability, the dual-ligand enhanced the amount of delivered liposomes after systemic administration to OS-RC-2 xenograft mice. The anti-tumor activity of a dual-ligand LP encapsulating doxorubicin was evaluated and the results were compared with Doxil®, which is clinically used to target tumor cells. Even though Doxil showed no anti-tumor activity, the dual-ligand LP suppressed tumor growth because the disruption of tumor vessels was efficiently induced. The comparison showed that tumor endothelial cells (TECs) were more sensitive to doxorubicin by 2 orders than RCC tumor cells, and the disruption of tumor vessels was efficiently induced. Collectively, the dual-ligand LP is promising carrier for the treatment of drug resistant RCC via the disruption of TECs.
机译:抗血管生成疗法是用于治疗抗药性癌症的潜在化疗策略。然而,将此类药物递送至肿瘤内皮细胞的方法仍然是抗血管生成疗法成功的主要障碍。我们设计了直径约300 nm的脂质体(LP),并用特异性配体和细胞穿透肽(CPP)(双配体LP)修饰了脂质体,以靶向肾细胞癌(RCC)中表达CD13的新脉管系统。我们用脂质体膜表面的聚乙二醇和四精氨酸(R4)顶部的NGR基序肽修饰了LP,分别作为特异性配体和CPP配体。大尺寸阻止了双配体LP的外渗,使其与靶脉管系统相关联。尽管使用特异性配体或CPP配体进行的单次修饰均未显示出可靶向性,但在对OS-RC-2异种移植小鼠进行全身给药后,双配体增加了脂质体的递送量。评估了封装有阿霉素的双配体LP的抗肿瘤活性,并将结果与​​临床上用于靶向肿瘤细胞的Doxil®进行了比较。即使Doxil没有显示抗肿瘤活性,双配体LP也抑制了肿瘤生长,因为有效诱导了肿瘤血管的破坏。比较表明,肿瘤内皮细胞(TECs)对阿霉素的敏感性比RCC肿瘤细胞高2倍,并且可以有效地诱导肿瘤血管的破坏。总体而言,双配体LP是有望通过破坏TECs来治疗耐药RCC的载体。

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