In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer.
In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer.
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DOI：
10.1039/b904890a
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发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
Tsien RY
中科院分区：
文献类型：
--
作者：
Olson ES;Aguilera TA;Jiang T;Ellies LG;Nguyen QT;Wong EH;Gross LA;Tsien RY
可激活细胞穿透肽（ACPP）是新型体内靶向剂，由通过可裂解接头连接至中和聚阴离子的聚阳离子细胞穿透肽（CPP）组成（图1A）。细胞的吸附和摄取受到抑制，直到接头被蛋白水解。可在体外被基质金属蛋白酶 2 (MMP-2) 裂解的 ACPP 是第一个被证明可在体内肿瘤模型中发挥作用的 ACPP，但仅测试了 HT-1080 异种移植物和切除的人类鳞状细胞癌。对于其他癌症类型的普遍性、ACPP 对 MMP 的体内选择性以及空间分辨率需要进一步表征。我们现在表明，ACPP 可以针对来自不同癌症部位的许多异种移植肿瘤模型，以及经过充分研究的自发性乳腺癌转基因模型（驱动多瘤中 T 抗原的小鼠乳腺肿瘤病毒启动子，MMTV-PyMT）。药理学抑制剂和基因敲除表明，当前的 ACPP 在上述体内模型中对 MMP-2 和 MMP-9 具有选择性。根据 MMP 活性的已知局部分布，在原发性肿瘤和相关转移瘤的肿瘤-基质界面处积聚最强，表明比目前可用的其他 MMP 可裂解探针具有更好的空间分辨率（<50 µm）。我们还发现，通过将 30-50 KDa 的惰性大分子添加到聚阴离子抑制结构域，可以减少 ACPP 进入正常组织（例如肝脏和肾脏）的背景摄取。我们的结果验证了一种通常应将显像剂和化疗药物递送至侵袭、促进肿瘤的炎症和转移部位的方法。
Activatable cell penetrating peptides (ACPPs) are novel in vivo targeting agents comprised of a polycationic cell penetrating peptide (CPP) connected via a cleavable linker to a neutralizing polyanion (Fig. 1A). Adsorption and uptake into cells are inhibited until the linker is proteolyzed. An ACPP cleavable by matrix metalloproteinase-2 (MMP-2) in vitro was the first one demonstrated to work in a tumor model in vivo, but only HT-1080 xenografts and resected human squamous cell carcinomas were tested. Generality to other cancer types, in vivo selectivity of ACPPs for MMPs, and spatial resolution require further characterization. We now show that ACPPs can target many xenograft tumor models from different cancer sites, as well as a well thoroughly studied transgenic model of spontaneous breast cancer (mouse mammary tumor virus promoter driving polyoma middle T antigen, MMTV-PyMT). Pharmacological inhibitors and genetic knockouts indicate that current ACPPs are selective for MMP-2 and MMP-9 in the above in vivo models. In accord with the known local distribution of MMP activity, accumulation is strongest at the tumor-stromal interface in primary tumors and associated metastases, indicating better spatial resolution (<50 µm) than other currently available MMP-cleavable probes. We also find that background uptake of ACPPs into normal tissues such as liver and kidney can be decreased by appending inert macromolecules of 30–50 KDa to the polyanionic inhibitory domain. Our results validate an approach that should generally deliver imaging agents and chemotherapeutics to sites of invasion, tumor-promoting inflammation, and metastasis.
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影响因子：
3.4
作者：
Shalinsky, DR;Brekken, J;Appelt, K
通讯作者：
Appelt, K
影响因子：
82.9
作者：
Bremer, C;Tung, CH;Weissleder, R
通讯作者：
Weissleder, R
影响因子：
4.1
作者：
McIntyre, JO;Fingleton, B;Matrisian, LM
通讯作者：
Matrisian, LM
影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
通讯作者：
MULLER, WJ
影响因子：
6
作者：
Lin, EY;Jones, JG;Pollard, JW
通讯作者：
Pollard, JW