Modulating paclitaxel bioavailability for targeting prostate cancer
Modulating paclitaxel bioavailability for targeting prostate cancer
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DOI：
10.1016/j.bmc.2007.04.029
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发表时间：
2007-07-15
影响因子：
3.5
通讯作者：
Khan, Saeed R.
中科院分区：
文献类型：
--
作者：
Kumar, Srinivas K.;Williams, Simon A.;Khan, Saeed R.
设计并合成了四种新型的水溶性肽-紫杉醇偶联物，作为前列腺特异性抗原（PSA）活化的前列腺癌治疗前药。这些前药由肽HSSKLQ或SSKYQ组成，其中的每一个可被PSA选择性裂解;自分解接头，对氨基苯甲醇（PABS）或乙二胺（EDA）;和母体药物紫杉醇。在前药2-5中的肽和紫杉醇之间引入PABA或EDA接头导致产物具有增加的PSA水解速率。由于PABA和紫杉醇之间的弱碳酸酯键，具有PABA接头的前药2和3在含血清介质中的稳定性差;然而，通过在前药4和5中使用EDA接头引入氨基甲酸酯键克服了该缺点。因此，EDA接头的掺入增加了这些前药的稳定性和PSA介导的活化。与紫杉醇相比，每种前药的细胞毒性针对多种细胞系，包括PSA分泌型CWR 22 Rv 1前列腺癌细胞系进行测定。紫杉醇5的EDA衍生的前药是稳定的，并且能够有效地转化为在PSA存在下特异性杀死细胞的活性药物，这表明该前药和类似设计的PSA可裂解的前药可能具有作为前列腺癌特异性治疗剂的潜力。(c)2007年由Elsevier Ltd.出版
Four novel water-soluble peptide-paclitaxel conjugates were designed and synthesized as prostate-specific antigen (PSA)-activated prodrugs for prostate cancer therapy. These prodrugs were composed of a peptide, HSSKLQ or SSKYQ, each of which is selectively cleavable by PSA; a self-immolative linker, either para-aminobenzyl alcohol (PABS) or ethylene diamine (EDA); and the parent drug, paclitaxel. Introduction of a PABA or EDA linker between the peptide and paclitaxel in prodrugs 2-5 resulted in products with an increased rate of hydrolysis by PSA. The stability of prodrugs 2 and 3, with the PABA linker, was poor in the serum-containing medium because of the weak carbonate bond between the PABA and paclitaxel; however, this disadvantage was overcome by introducing a carbamate bond using an EDA linker in prodrugs 4 and 5. Thus, the incorporation of an EDA linker increased both the stability and PSA-mediated activation of these prodrugs. The cytotoxicity of each prodrug, as compared to paclitaxel, was determined against a variety of cell lines, including the PSA-secreting CWR22Rv1 prostate cancer cell line. The EDA-derived prodrug of paclitaxel 5 was stable and capable of being efficiently converted to an active drug that killed cells specifically in the presence of PSA, suggesting that this prodrug and similarly designed PSA-cleavable prodrugs may have potential as prostate cancer-specific therapeutic agents. (c) 2007 Published by Elsevier Ltd.