HPMA copolymer platinates as novel antitumour agents:: In vitro properties, pharmacokinetics and antitumour activity in vivo
HPMA copolymer platinates as novel antitumour agents:: In vitro properties, pharmacokinetics and antitumour activity in vivo
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DOI：
10.1016/s0959-8049(99)00030-1
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发表时间：
1999-06-01
影响因子：
8.4
通讯作者：
Duncan, R
中科院分区：
文献类型：
--
作者：
Gianasi, E;Wasil, M;Duncan, R
本研究的目的是比较在体外和体内HPMA共聚物铂与顺铂的铂释放，毒性和抗肿瘤活性。制备了N-（2-羟丙基）甲基丙烯酰胺（HPMA）缀合物，其含有以羧酸或氨基物质终止的肽基侧链（Gly-Gly或Gly-Phe-Leu-Gly）。使羧酸酯聚合物中间体与顺铂反应，并使聚合物二胺与四氯铂酸钾反应，以产生具有3- 7wt%的铂负载量的Mw为25 000-31 000道尔顿的HPMA共聚物铂酸盐。选择二甘氨酰间隔区是因为它是不可生物降解的，而已知四肽间隔区被溶酶体硫醇依赖性蛋白酶切割。在体外，HPMA共聚物铂酸盐在pH 7.4和5.5下显示出一定范围的铂释放速率;从需要酶促活化的二氨基物质的情况下的< 5%/24 h到羧酸盐的情况下的> 80%/24 h。顺铂和快速释放的羧酸盐物质在体外对B16 F10细胞显示出10 μ g/ml Pt当量的IC 50值，而缓慢释放的缀合物在所研究的剂量范围内没有细胞毒性。HPMA共聚物铂酸盐的抗肿瘤活性首先针对腹膜内（i. p.）接种的L1210和B16 F10肿瘤进行评价。当偶联物腹膜内给药时，观察到的对L1210肿瘤的抗肿瘤活性在游离顺铂的范围内（治疗动物的平均存活率与对照动物的平均存活率之比，T/C，1.20-1.70）。然而，当缀合物静脉内（i. v.）以治疗皮下（s.c.）B16 F10肿瘤生长到可触知的大小，游离顺铂仍然没有活性，但带有羧酸盐和二胺铂酸盐的HPMA共聚物铂酸盐显示出显著的抗肿瘤活性（TI C > 1.35）。在这些研究中，聚合物铂酸盐的体内毒性比顺铂低5-15倍。静脉内给药后，HPMA共聚物铂酸盐的血液清除率（t（1/2 α）与10 h相似）显著低于游离顺铂（t（1/2 α）< 5 min）。HPMA共聚物铂酸盐（15 mg/kg Pt当量）使B16 F10肿瘤组织中的Pt AUC比以其最大耐受剂量（MTD）（1 mg/kg）给予顺铂后增加约60倍。(C)1999爱思唯尔科技有限公司。保留所有权利。
The aim of this study was to compare in vitro and in vivo HPMA copolymer platinates with cisplatin in terms of platinum release, toxicity and antitumour activity. N-(2-hydroxypropyl) methacrylamide (HPMA) conjugates containing peptidyl side-chains (Gly-Gly or Gly-Phe-Leu-Gly) terminating in either carboxylate or amino species were prepared. The carboxylate polymeric intermediate was reacted with cisplatin, and the polymeric diamine with potassium tetrachloroplatinate to produce HPMA copolymer platinates of Mw 25 000-31 000 Daltons with a platinum loading of 3-7wt%. The diglycyl spacer was selected because it is non-biodegradable, whereas the tetrapeptide spacer is known to be cleaved by the lysosomal thiol-dependent proteases. In vitro the HPMA copolymer platinates displayed a range of platinum release rates at pH 7.4 and 5.5; from < 5%/24 h in the case of the diamino species which require enzymatic activation, to > 80%/24 h in the case of the carboxylate. Cisplatin and the fast releasing carboxylate species displayed IC50 values of 10 mu g/ml Pt-equivalent against B16F10 cells in vitro, whereas the slow releasing conjugates were not cytotoxic over the dose range studied. Antitumour activity of HPMA copolymer platinates was first evaluated against L1210 and B16F10 tumours inoculated intraperitoneally (i.p.). When conjugates were administered i.p., the antitumour activity observed against L1210 tumours was within the range seen for free cisplatin (ratio of mean survival of treated animals to mean survival of controls, T/C, 1.20-1.70), Neither cisplatin nor HPMA copolymer platinates were active against intraperitoneal (i.p.) B16F10 tumours when administered i.p. However, when conjugates were administered intravenously (i.v.) to treat subcutaneous (s.c.) B16F10 tumours grown to palpable size, free cisplatin was still not active but the HPMA copolymer platinates bearing carboxylate and diamine platinates showed significant antitumour activity (TI C > 1.35). Throughout these studies, the polymer platinates were 5-15-fold less toxic than cisplatin in vivo. After i.v. administration, the blood clearance of HPMA copolymer platinate was considerably slower (t(1/2 alpha)similar to 10 h) than seen for free cisplatin (t(1/2 alpha) < 5 min). HPMA copolymer platinates (15 mg/kg Pt-equivalent) gave rise to an approximately 60-fold increase in Pt AUC in B16F10 tumour tissue than was achieved after administration of cisplatin at its maximum tolerated dose (MTD) (1 mg/kg). (C) 1999 Elsevier Science Ltd. All rights reserved.