Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine
Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine
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DOI：
10.1016/s0168-3659(98)00124-2
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发表时间：
1999-02-22
影响因子：
10.8
通讯作者：
Kerr, DJ
中科院分区：
文献类型：
--
作者：
Julyan, PJ;Seymour, LW;Kerr, DJ
大分子和药物缀合物的半乳糖靶向递送至脱唾液酸糖蛋白受体（ASGPR）阳性细胞已在动物中被广泛记录，尽管在人类中的靶向从未被证实。在这项研究中，我们报告的药代动力学和成像确定的第一个病人参加了第一阶段的临床研究的聚[N-（2-羟丙基）甲基丙烯酰胺]共聚物轴承阿霉素和半乳糖胺，称为PK 2。血浆和尿液的梯度高效液相色谱法（HPLC）评价与基于I-123的成像相结合，显示药物从血浆中的双相清除（半衰期为78+/-1和990+/-15），约30%的药物递送至肝脏区域，如24小时平面全身成像所测定。该患者患有多灶性肝癌，单光子发射计算机断层扫描（SPECT）分析显示24小时肿瘤组织与正常肝脏摄取的比例约为1：3。在该患者的基础上，静脉注射20 mg/m2多柔比星（PK 2）后可实现有效的肝靶向，但该靶向药物的治疗有效性尚未确定。(C)1999 Elsevier Science B. V.保留所有权利。
Galactose-targeted delivery of macromolecules and drug conjugates to asialoglycoprotein receptor (ASGPR) positive cells has been widely documented in animals, although targeting in humans has never been demonstrated. In this study we report the pharmacokinetics and imaging determined in the first patient enrolled in a phase I clinical study of the poly[N-(2-hydroxypropyl)methacrylamide] copolymer bearing doxorubicin and galactosamine, known as PK2. Gradient high performance liquid chromatography (HPLC) evaluation of plasma and urine has been combined with I-123-based imaging to show biphasic clearance of the drug from the plasma (half-lives of 78+/-1 and 990+/-15), and approximately 30% delivery of the drug to the hepatic region, as determined by planar whole body imaging at 24 h. This patient has a multifocal hepatoma, and single photon emission computed tomography (SPECT) analysis showed a ratio of tumour tissue to normal liver uptake of approximately 1:3, at 24 h. On the basis of this patient, effective hepatic targeting can be achieved following an intravenous dose of 20 mg/m(2) doxorubicin as PK2, however the therapeutic usefulness of this targeted drug has yet to be established. (C) 1999 Elsevier Science B.V. All rights reserved.