HPMA Copolymer-Aminohexylgeldanamycin Conjugates Targeting Cell Surface Expressed GRP78 in Prostate Cancer
HPMA Copolymer-Aminohexylgeldanamycin Conjugates Targeting Cell Surface Expressed GRP78 in Prostate Cancer
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DOI：
10.1007/s11095-010-0267-7
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发表时间：
2010-12-01
影响因子：
3.7
通讯作者：
Ghandehari, Hamidreza
中科院分区：
文献类型：
--
作者：
Larson, Nate;Ray, Abhijit;Ghandehari, Hamidreza
本研究主要研究了用于格尔达霉素递送前列腺癌肿瘤的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物偶联物的合成和体外表征。偶联物经修饰后加入了与细胞表面表达的葡萄糖调节蛋白78结合的WIFPWIQL肽。合成了含氨己基格尔达霉素的HPMA共聚物，并对其进行了表征，并对其在pH 7.4和pH 5.0缓冲液、全细胞培养基和胎牛血清中的稳定性进行了评价。比较了GRP78在DU145和PC3细胞株细胞表面的表达，并评估了GRP78与细胞表面的竞争性结合。结合物抑制细胞生长的能力也在体外进行了评估。HPMA共聚物-氨基已基格尔达霉素偶联物是稳定的，在37A℃的胎牛血清中观察到72小时内最大释放量约为10%。携带WIFPWIQL肽的HPMA共聚物与细胞表面结合，表达GRP78，其亲和力与游离的WIFPWIQL肽相当，并且与非靶向偶联物相比，显示出更高的细胞毒性。含有WIFPWIQL肽的HPMA共聚物氨基己基格尔达霉素偶联物能够与细胞表面表达的GRP78结合，抑制人前列腺癌细胞的生长，提示该偶联物具有靶向实体前列腺癌肿瘤的潜力。
This study focused on the synthesis and in vitro characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates for the delivery of geldanamycin to prostate cancer tumors. Conjugates were modified to incorporate WIFPWIQL peptide, which binds to cell-surface-expressed Glucose-regulated protein 78.HPMA copolymers containing aminohexylgeldanamycin with and without WIFPWIQL peptide were synthesized and characterized, and stability in pH 7.4 and pH 5.0 buffers, complete cell culture medium, and fetal bovine serum was evaluated. The comparative cell surface expression of GRP78 in DU145 and PC3 cell lines was assessed and competitive binding to cell surface expressed GRP78 evaluated. The ability of the conjugates to inhibit cell growth was also evaluated in vitro.HPMA copolymer-aminohexylgeldanamycin conjugates were stable with maximal release observed in fetal bovine serum at 37A degrees C of approximately 10% in 72 h. HPMA copolymers bearing WIFPWIQL peptide bound to cell surface expressed GRP78 with affinities comparable to free WIFPWIQL peptide and demonstrated increased cytotoxicity as compared to untargeted conjugates.HPMA copolymer aminohexylgeldanamycin conjugates bearing WIFPWIQL peptide have the ability to bind to cell-surface-expressed GRP78 and inhibit the growth of human prostate cancer cells, suggesting that the conjugates have the potential to target solid prostate cancer tumors.