Intracellular cargo delivery by an octaarginine transporter adapted to target prostate cancer cells through cell surface protease activation
Intracellular cargo delivery by an octaarginine transporter adapted to target prostate cancer cells through cell surface protease activation
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DOI：
10.1021/bc0503216
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发表时间：
2006-05-17
影响因子：
4.7
通讯作者：
Franc, Benjamin L.
中科院分区：
文献类型：
--
作者：
Goun, Elena A.;Shinde, Rajesh;Franc, Benjamin L.
将治疗剂和成像剂递送至靶组织需要具有分子特异性的定位和激活策略。细胞相关蛋白酶可在许多病理条件下用于这些目的，并且它们的酶活性可用于活化策略。在此，基于D-精氨酸八聚体（r（8））蛋白转导结构域（PTD，也称为分子转运蛋白）的分子已经被改造成仅在通过前列腺特异性抗原（PSA）（与某些前列腺癌细胞的表面和微环境相关的细胞外蛋白酶）蛋白水解裂解PTD衰减序列之后才被选择性摄取到细胞中。这些可激活的PTDs（APTD）的收敛合成进行了描述，并确定了最有效的r8 PTD衰减序列。显示缀合物在血清中稳定，被PSA切割，并且仅在被PSA切割后被摄取到Jurkat（人T细胞）和PC 3 M前列腺癌细胞系中。这些基于APTD肽的分子可以促进治疗剂或成像剂向表达PSA的前列腺癌的靶向递送。
Delivery of therapeutics and imaging agents to target tissues requires localization and activation strategies with molecular specificity. Cell-associated proteases can be used for these purposes in a number of pathologic conditions, and their enzymatic activities can be exploited for activation strategies. Here, molecules based on the D-arginine octamer (r(8)) protein-transduction domain (PTD, also referred to as molecular transporters) have been adapted for selective uptake into cells only after proteolytic cleavage of a PTD-attenuating sequence by the prostate-specific antigen (PSA), an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. Convergent syntheses of these activatable PTDs (APTDs) are described, and the most effective r8 PTD-attenuating sequence is identified. The conjugates are shown to be stable in serum, cleaved by PSA, and taken up into Jurkat ( human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA. These APTD peptide-based molecules may facilitate targeted delivery of therapeutics or imaging agents to PSA-expressing prostate cancers.