Development of a peptide-drug conjugate for prostate cancer therapy.
Development of a peptide-drug conjugate for prostate cancer therapy.
复制标题
开发用于前列腺癌疗法的肽 - 药物结合物。
DOI：
10.1021/mp200007b
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发表时间：
2011-06-06
影响因子：
4.9
通讯作者：
Cheng K
中科院分区：
文献类型：
--
作者：
Tai W;Shukla RS;Qin B;Li B;Cheng K
TGX-221是一种高效的磷脂酰肌醇3-激酶β（PI 3 K β）抑制剂，有望成为治疗前列腺癌的新型化疗药物。然而，溶解性差和缺乏靶向性限制了其治疗应用。本研究的目的是开发一种肽-药物缀合物，以特异性地将TGX-221递送至HER 2过表达的前列腺癌细胞。合成了四种添加羟基的TGX-221衍生物用于肽缀合。其中，TGX-D1表现出与TGX-221相似的生物活性，并且其被选择用于与含有HER 2靶向配体和前列腺特异性抗原（PSA）底物连接的肽前体结合。由此选择，证实肽-药物缀合物被PSA逐渐切割以释放TGX-D1。与母体药物相比，肽-药物缀合物的细胞摄取在前列腺癌细胞中显著更高。此外，肽-药物偶联物及其裂解产物均表现出与母体药物TGX-D1相当的活性。我们的结果表明，这种肽-药物缀合物可能为前列腺癌患者提供一种有希望的化疗。
TGX-221 is a highly potent phosphoinositide 3-kinases β (PI3Kβ) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate to specifically deliver TGX-221 to HER2 over-expressing prostate cancer cells. Four TGX-221 derivatives with added hydroxyl groups were synthesized for peptide conjugation. Among them, TGX-D1 exhibited a similar bioactivity to TGX-221, and it was selected for conjugation with a peptide promoiety containing a HER2-targeting ligand and a prostate specific antigen (PSA) substrate linkage. From this selection, the peptide-drug conjugate was proven to be gradually cleaved by PSA to release TGX-D1. Cellular uptake of the peptide-drug conjugate was significantly higher in prostate cancer cells compared to the parent drug. Moreover, both the peptide-drug conjugate and its cleaved products demonstrated comparable activities as the parent drug TGX-D1. Our results suggest that this peptide-drug conjugate may provide a promising chemotherapy for prostate cancer patients.
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DOI：
10.1023/a:1019749504418
发表时间：
2002-05-01
期刊：
JOURNAL OF PROTEIN CHEMISTRY
影响因子：
--
作者：
Karasseva, NG;Glinsky, VV;Quinn, TP
通讯作者：
Quinn, TP
影响因子：
3.5
作者：
Kumar, Srinivas K.;Williams, Simon A.;Khan, Saeed R.
通讯作者：
Khan, Saeed R.
影响因子：
7.3
作者：
Garsky, VM;Lumma, PK;Freidinger, RM
通讯作者：
Freidinger, RM
DOI：
10.1016/j.bbapap.2007.10.003
发表时间：
2008-01-01
影响因子：
3.2
作者：
Marone, Romina;Cmijanovic, Vladimir;Wymann, Matthias P.
通讯作者：
Wymann, Matthias P.
影响因子：
20.3
作者：
Canobbio, Ilaria;Stefanini, Lucia;Torti, Mauro
通讯作者：
Torti, Mauro