Julyan P J, Seymour L W, Ferry D R, Daryani S, Boivin C M, Doran J, David M, Anderson D, Christodoulou C, Young A M, Hesslewood S, Kerr D J
Department of Nuclear Medicine, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham B15 2TH, UK.
J Control Release. 1999 Feb 22;57(3):281-90. doi: 10.1016/s0168-3659(98)00124-2.
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 123I-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/m2 doxorubicin as PK2, however the therapeutic usefulness of this targeted drug has yet to be established.
尽管在人体中尚未证实，但将大分子和药物偶联物以半乳糖为靶点递送至去唾液酸糖蛋白受体（ASGPR）阳性细胞在动物研究中已有广泛报道。在本研究中，我们报告了首例参与聚[N-(2-羟丙基)甲基丙烯酰胺]共聚物（携带阿霉素和半乳糖胺，即PK2）I期临床研究患者的药代动力学及成像结果。通过梯度高效液相色谱（HPLC）对血浆和尿液进行评估，并结合基于123I的成像技术，结果显示药物从血浆中的清除呈双相性（半衰期分别为78±1和990±15），且通过24小时全身平面成像测定，约30%的药物被递送至肝脏区域。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，在24小时时肿瘤组织与正常肝脏摄取率之比约为1:3。基于该患者的情况，静脉注射20 mg/m2阿霉素（以PK2形式）后可实现有效的肝脏靶向，但这种靶向药物的治疗效果尚未确定。
