Protease-activated pore-forming peptides for the treatment and imaging of prostate cancer.
Protease-activated pore-forming peptides for the treatment and imaging of prostate cancer.
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用于前列腺癌的治疗和成像的蛋白酶激活的成孔肽。
DOI：
10.1158/1535-7163.mct-14-0744
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发表时间：
2015
影响因子：
5.7
通讯作者：
Denmeade,SamuelR
中科院分区：
文献类型：
--
作者：
LeBeau,AaronM;Denmeade,SamuelR
具有高度侵袭性表型的癌症的共同标志是肿瘤和周围微环境中的蛋白水解增加。前列腺癌有许多蛋白酶独特地与它相关，可能在疾病进展中发挥各种重要作用。在这份报告中，我们利用前列腺癌的瘤周蛋白水解活性来激活工程肽结构，用于前列腺癌的治疗和非侵入性成像。使用模块化“前肽”方法，将阳离子非对映体成孔肽结构域连接至失活酸性肽结构域。失活酸性肽结构域被工程化为分泌的丝氨酸蛋白酶前列腺特异性抗原（PSA）或跨膜金属蛋白酶前列腺特异性膜抗原（PSMA）的可裂解底物。然后在直接比较研究中评价前肽。PSA和PSMA激活的前肽在体外对前列腺癌细胞都有细胞毒性作用，而在体内，用PSMA前肽处理LNCaP和CWR 22 Rv 1异种移植物，与单独用PSA前肽或阳离子非对映体肽处理的异种移植物相比，产生了明显的细胞抑制作用。PSMA激活的前肽也被证明是一种有效的光学成像探针在体内时，标记的近红外荧光团。这些数据表明，蛋白酶活化的孔形成肽可潜在地用于成像和治疗前列腺癌。Mol Cancer Ther; 14（3）; 659-68。©2014 AACR.
A common hallmark of cancers with highly aggressive phenotypes is increased proteolysis in the tumor and the surrounding microenvironment. Prostate cancer has a number of proteases uniquely associated with it that may play various important roles in disease progression. In this report, we utilize the peritumoral proteolytic activity of prostate cancer to activate engineered peptide constructs for the treatment and noninvasive imaging of prostate cancer. Using a modular “propeptide” approach, a cationic diastereomeric pore-forming peptide domain was linked to an inactivating acidic peptide domain. The inactivating acidic peptide domain was engineered to be a cleavable substrate for the secreted serine protease prostate-specific antigen (PSA) or the transmembrane metalloprotease prostate-specific membrane antigen (PSMA). The propeptides were then evaluated in a direct comparison study. Both the PSA and PSMA activated propeptides were found to be cytotoxic to prostate cancer cellsin vitro.In vivo, however, treatment of LNCaP and CWR22Rv1 xenografts with the PSMA propeptide resulted in a pronounced cytostatic effect when compared with xenografts treated with the PSA propeptide or the cationic diastereomeric peptide alone. The PSMA activated propeptide also proved to be an effective optical imaging probein vivowhen labeled with a near-infrared fluorophore. These data suggest that protease-activated pore-forming peptides could potentially be used for both imaging and treating prostate cancer.Mol Cancer Ther; 14(3); 659–68. ©2014 AACR.