Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy
Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy
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DOI：
10.1016/j.jconrel.2012.06.019
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发表时间：
2012-08-20
影响因子：
10.8
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Takara, Kazuhiro;Hatakeyama, Hiroto;Harashima, Hideyoshi
抗血管生成治疗是治疗耐药癌症的潜在化疗策略。然而，用于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治疗成功的主要障碍。我们设计了直径控制在300 nm左右的脂质体（LP），并用特异性配体和细胞穿透肽（CPP）（双配体LP）对其进行修饰，用于靶向肾细胞癌（RCC）中表达CD 13的新生血管。我们修饰的脂蛋白与NGR基序肽的顶部聚（乙二醇）和四精氨酸（R4）的脂质体膜表面上的特异性和CPP配体，分别。大尺寸防止了双配体LP的外渗，这使其能够与靶血管系统结合。虽然用特异性配体或CPP配体的单一修饰显示靶向性没有增加，但双配体在全身施用至OS-RC-2异种移植小鼠后增加了递送的脂质体的量。评价包封阿霉素的双配体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（R）进行比较。尽管Doxil没有显示出抗肿瘤活性，但双配体LP抑制了肿瘤生长，因为有效地诱导了肿瘤血管的破坏。结果表明，肿瘤内皮细胞对阿霉素的敏感性比肾细胞癌高2个数量级，并能有效地诱导肿瘤血管破裂。总之，双配体LP是通过破坏TEC来治疗耐药RCC的有希望的载体。(C)2012年爱思唯尔B。V.保留所有权利。
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 (R), 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. (C) 2012 Elsevier B. V. All rights reserved.