Division of Biomedical Science and Biochemistry, Research School of Biology, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia.
J Drug Target. 2011 Sep;19(8):681-9. doi: 10.3109/1061186X.2010.536984. Epub 2010 Dec 9.
The therapeutic efficacy of anticancer drugs like doxorubicin can be significantly increased by their incorporation into liposomes, but an ability to actively target the drug-containing liposomes to tumors could well provide an even greater curative effect. In this work, a commercial preparation of doxorubicin-loaded liposomes (Caelyx) was modified by incorporation of the metal chelator lipid 3(nitrilotriacetic acid)-ditetradecylamine (NTA(3)-DTDA) to enable engraftment of histidine-tagged targeting molecules. Our results show that when engrafted with p15-RGR, a His-tagged peptide containing a sequence purported to bind platelet-derived growth factor receptor β (PDGFRβ), NTA(3)-DTDA-containing Caelyx (3NTA-Caelyx) can be targeted to NIH-3T3 cells in vitro, leading to increased cytotoxicity compared with non-targeted 3NTA-Caelyx. PDGFRβ is known to be expressed on pericytes in the tumor vasculature; however, when radiolabeled p15-RGR liposomes were administered to mice bearing subcutaneous B16-F1 tumors, minimal accumulation into tumors was observed. In contrast, an alternative targeting peptide, p46-RGD, was found to actively direct liposomes to tumors (4.7 %ID/g). Importantly, when injected into tumor-bearing mice, p46-RGD-engrafted 3NTA-Caelyx significantly decreased the tumor growth rate compared with controls. These results indicate that the incorporation of NTA(3)-DTDA into liposomal drugs could represent a simple modification to the drug to allow engraftment of targeting molecules and to increase its efficacy.
抗癌药物阿霉素（doxorubicin）的治疗效果可以通过将其纳入脂质体显著提高，但使载药脂质体主动靶向肿瘤的能力很可能提供更好的治疗效果。在这项工作中，通过掺入金属螯合剂脂质 3(nitrilotriacetic acid)-ditetradecylamine（NTA(3)-DTDA）对商业阿霉素载药脂质体（Caelyx）进行修饰，使组氨酸标记的靶向分子能够连接到脂质体上。我们的结果表明，当连接到含有据称能结合血小板衍生生长因子受体β（PDGFRβ）的序列的 His 标记肽 p15-RGR 时，含有 NTA(3)-DTDA 的 Caelyx（3NTA-Caelyx）可以在体外靶向 NIH-3T3 细胞，导致与非靶向 3NTA-Caelyx 相比细胞毒性增加。PDGFRβ 已知在肿瘤血管中的周细胞上表达；然而，当放射性标记的 p15-RGR 脂质体施用于皮下 B16-F1 肿瘤的小鼠时，观察到很少有脂质体进入肿瘤。相比之下，另一种靶向肽 p46-RGD 被发现能主动将脂质体导向肿瘤（4.7 %ID/g）。重要的是，当注射到荷瘤小鼠中时，与对照组相比，p46-RGD 连接的 3NTA-Caelyx 显著降低了肿瘤生长速度。这些结果表明，将 NTA(3)-DTDA 掺入脂质体药物中可能是一种简单的修饰药物的方法，可以使靶向分子连接并提高其疗效。
