A prostate-specific antigen-activated N-(2-hydroxypropyl) methacrylamide copolymer prodrug as dual-targeted therapy for prostate cancer
A prostate-specific antigen-activated N-(2-hydroxypropyl) methacrylamide copolymer prodrug as dual-targeted therapy for prostate cancer
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DOI：
10.1158/1535-7163.mct-07-0392
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发表时间：
2007-11-01
影响因子：
5.7
通讯作者：
Denmeade, Samuel R.
中科院分区：
文献类型：
--
作者：
Chandran, Sachin S.;Nan, Anian;Denmeade, Samuel R.
我们的实验室正在开发由前列腺特异性抗原（PSA）的丝氨酸蛋白酶活性激活的前列腺癌靶向肽前药。为了增强这些前药的递送和溶解度，将由 N-(2-羟丙基)甲基丙烯酰胺 (HPMA) 基共聚物组成的大分子载体与 PSA 激活的肽前药共价偶联。 HPMA 共聚物是水溶性、非免疫原性合成载体，在药物输送应用中表现出良好的前景。这些高分子共聚物通过增强的渗透性和滞留作用进入实体瘤的间质。 PSA 激活的肽底物具有选择性，因为它在前列腺肿瘤部位特异性水解并释放细胞毒素。具有酶活性的 PSA 在肿瘤的细胞外液中大量存在，但 PSA 在血液中通过与血清蛋白酶抑制剂结合而失活。作为概念的初步证明，HPMA 共聚物是用与荧光团 7-氨基-4-甲基香豆素 (AMC) 结合的肽底物 (HSSKLQ) 合成的。观察到 HPMA-HSSKLQ-AMC 共聚物发生 PSA 裂解，从而合成了具有前药 SSKYQ-L12ADT [HPMA-吗啉代羰基-Ser-Ser-Lys-Tyr-Gin-Leu-12-氨基十二酰基毒胡萝卜素 (JHPD)] 的基于 HPMA 的共聚物。 L12ADT 是高细胞毒性天然产物毒胡萝卜素的有效类似物。 HPMA-JHPD 在体外被 PSA 水解，在活性 PSA 存在的情况下对前列腺癌细胞具有毒性。当以500μmol/L L12ADT当量剂量给药时，HPMA-JHPD未产生全身毒性。对用单剂量或多剂量 HPMA-JHPD 共聚物治疗的小鼠的肿瘤组织进行的分析表明，L12ADT 毒素在肿瘤组织内释放和积聚。 [Mol Cancer Ther 2007;6(11):2928-37]。
Prostate cancer targeted peptide prodrugs that are activated by the serine protease activity of prostate-specific antigen (PSA) are under development in our laboratory. To enhance delivery and solubility of these prodrugs, macromolecular carriers consisting of N-(2-hydroxypropyl) methacrylamide (HPMA)-based copolymers were covalently coupled to a PSA-activated peptide prodrug. HPMA copolymers are water-soluble, nonimmunogenic synthetic carriers that exhibit promise for drug delivery applications. These macromolecular copolymers enter the interstitium of solid tumors by the enhanced permeability and retention effect. The PSA-activated peptide substrate imparts selectivity because it is specifically hydrolyzed to release a cytotoxin at the site of prostate tumor. Enzymatically active PSA is present in high amounts in the extracellular fluid of a tumor, but PSA is inactivated in blood by binding to serum protease inhibitors. As an initial proof of concept, the HPMA copolymer was synthesized with a peptide substrate (HSSKLQ) bound to a fluorophore, 7-amino-4-methylcoumarin (AMC). PSA cleavage of the HPMA-HSSKLQ-AMC copolymer was observed, which led to the synthesis of an HPMA-based copolymer with the prodrug SSKYQ-L12ADT [HPMA-morpholinocarbonyi-Ser-Ser-Lys-Tyr-Gin-Leu-12-aminododecanoyl thapsigargin (JHPD)]. L12ADT is a potent analogue of the highly cytotoxic natural product thapsigargin. HPMA-JHPD was hydrolyzed by PSA in vitro and was toxic to prostate cancer cells in the presence of active PSA. The HPMA-JHPD produced no systemic toxicity when given at a 500 mu mol/L L12ADT equivalent dose. Analysis of tumor tissue from mice treated with a single or multiple dose of the HPMA-JHPD copolymer showed release and accumulation of the L12ADT toxin within the tumor tissue. [Mol Cancer Ther 2007;6(11):2928-37].