Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer-drug conjugates
Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer-drug conjugates
复制标题
DOI：
10.1016/j.jconrel.2015.08.029
复制
发表时间：
2015-11-10
影响因子：
10.8
通讯作者：
David, Ayelet
中科院分区：
文献类型：
--
作者：
Shamay, Yosi;Raviv, Lior;David, Ayelet
目前还没有有效的手段来预防或控制癌细胞的转移性扩散。E-选择素是一种仅在炎症和血管生成血管上表达的粘附分子，在癌症转移的几个限速步骤中起重要作用。在这项研究中，我们评估了N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物与E-选择素结合肽（Esbp，DITWDQLWDLMK）缀合并配备化疗药物阿霉素（P-（Esbp）-DOX）或促凋亡肽（D）（KLAKLAK）（2）（P-（Esbp）-KLAK）的体内抗肿瘤疗效。单次静脉注射后，P-（Esbp）-DOX降低肿瘤生长速率并延长荷原发性刘易斯肺癌（3LL）肿瘤的小鼠的存活率，显著超过用非靶向共聚物（P-DOX）或用游离DOX的治疗。在实验性B16-F10肺转移模型中，单次静脉内剂量的P-（Esbp）-DOX或P-（Esbp）-KLAK比非靶向共聚物或游离药物显著延长小鼠存活时间，并且完全肿瘤消退的百分比随着剂量的增加和给药频率而增加。此外，与未治疗的小鼠相比，用E-选择素靶向的“无药物”共聚物（P-（Esbp）-FITC）预处理的小鼠在肺中表现出显著更少的B16-F10肿瘤病灶，证明了共聚物的抗转移特性及其通过E-选择素介导的相互作用控制癌症扩散的能力。生物分布分析进一步证实了E-选择素靶向的近红外荧光标记的共聚物P-（Esbp）-IR 783在B16-F10肺转移瘤中的优先积累。总之，本研究首次证明了E-选择素靶向共聚物-药物缀合物可以抑制原发性肿瘤生长并预防体内转移。(c)2015 Elsevier B. V.版权所有。
There is currently no effective means to prevent or control metastatic dissemination of cancer cells. E-selectin, an adhesion molecule expressed exclusively on inflamed and angiogenic blood vessels, plays an important role in several rate-limiting steps of cancer metastasis. In this study, we assessed the in vivo antitumor efficacy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers conjugated to an E-selectin binding peptide (Esbp, DITWDQLWDLMK) and equipped with the chemotherapeutic drug doxorubicin (P-(Esbp)-DOX) or with the proapoptotic peptide (D)(KLAKLAK)(2) (P-(Esbp)-KLAK). Following a single intravenous injection, P-(Esbp)-DOX reduced tumor growth rate and prolonged the survival of mice bearing primary Lewis lung carcinoma (3LL) tumors significantly more than treatment with a non-targeted copolymer (P-DOX) or with free DOX. In an experimental B16-F10 lung metastasis model, a single intravenous dose of P-(Esbp)-DOX or P-(Esbp)-KLAK prolonged mice survival time significantly more than the non-targeted copolymers or the free drugs, and the percentage of complete tumor regression increased with increasing doses and with dosing frequency. In addition, mice pretreated with an E-selectin-targeted "drug-free" copolymer (P-(Esbp)-FITC) exhibited significantly fewer B16-F10 tumor foci in the lungs as compared with non-treatedmice, demonstrating the anti-metastatic properties of the copolymer and its ability to control cancer spread through E-selectin-mediated interactions. Biodistribution analysis further confirmed the preferential accumulation of the E-selectin-targeted near-infrared fluorescently-labeled copolymer P-(Esbp)-IR783 in B16-F10 lung metastases. Taken together, this study demonstrates, for the first time, that the E-selectin targeted copolymer-drug conjugates can inhibit primary tumor growth and prevent metastases in vivo. (c) 2015 Elsevier B.V. All rights reserved.