He Jiang, Liu Guozheng, Zhang Surong, Rusckowski Mary, Hnatowich Donald J
Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.
Cancer Biother Radiopharm. 2003 Dec;18(6):941-7. doi: 10.1089/108497803322702905.
For use in amplification targeting, an oligomer-conjugated polymer must display adaptable chemistry, minimal steric hindrance, low toxicity, and favorable pharmacokinetics. In particular, the polymer must remain in circulation sufficiently long to permit target localization.
To evaluate their properties for amplification targeting, the biodistribution in normal mice was determined for four polymers conjugated with multiple copies of a phosphorodiamidate morpholino (MORF) oligomer.
An amine-derivatized 25-mer MORF oligomer was radiolabeled with 99mTc. Three polymers of succinylated polylysine (PL) with initial weight average molecular weights (Mw) of 30, 100, and 200 KDa, and one poly (methyl vinyl ether-alt-maleic acid) (PA) with initial Mw of 45 KDa polymer, were each conjugated with an amine derivatized 25-mer complementary MORF (i.e., cMORF). The average number of attached cMORF groups on each polymer molecule (i.e., gpm) was estimated by a high performance liquid chromatography (HPLC) shift assay after the addition of trace 99mTc-MORF to the unpurified polymer, while the average number of accessible cMORF on each polymer was determined by adding radiolabeled MORF at increasing concentrations to the purified cMORF polymer solution until saturation. After purification, each polymer was radiolabeled by incubation with trace 99mTc-MORF. The biodistribution was then established in normal CD1 mice at a constant dosage of 2-4 micrograms of cMORF.
The gpm varied from about 12 on 30 KDa PL to 40 on 45 KDa PA. The biodistribution results show that the pharmacokinetics of the radiolabel is a function of both the type of polymer as well as its gpm. Of the four polymers, the 30 KDa PL showed the most favorable pharmacokinetic profile, with the lowest liver accumulation and the highest blood values compared to the remaining three polymers.
The biodistribution of the four polymers showed characteristic differences, with one polymer (30 KDa PL) showing the most favorable properties for amplification targeting.
用于扩增靶向时，寡聚物共轭聚合物必须具备适应性化学性质、最小的空间位阻、低毒性以及良好的药代动力学特性。特别是，聚合物必须在循环中保留足够长的时间以实现靶点定位。
为评估四种与多个磷酰二胺吗啉代（MORF）寡聚物拷贝共轭的聚合物的扩增靶向性质，测定了它们在正常小鼠体内的生物分布。
将一种胺衍生的25聚体MORF寡聚物用99mTc进行放射性标记。三种初始重均分子量（Mw）分别为30、100和200 kDa的琥珀酰化聚赖氨酸（PL）聚合物，以及一种初始Mw为45 kDa的聚（甲基乙烯基醚-alt-马来酸）（PA）聚合物，分别与一种胺衍生的25聚体互补MORF（即cMORF）共轭。在未纯化的聚合物中加入微量99mTc-MORF后，通过高效液相色谱（HPLC）位移测定法估算每个聚合物分子上连接的cMORF基团的平均数（即gpm），而通过向纯化的cMORF聚合物溶液中加入浓度递增的放射性标记MORF直至饱和来确定每个聚合物上可及的cMORF的平均数。纯化后，每种聚合物通过与微量99mTc-MORF孵育进行放射性标记。然后以2-4微克cMORF的恒定剂量在正常CD1小鼠中确定生物分布。
gpm从30 kDa PL上的约12变化到45 kDa PA上的40。生物分布结果表明，放射性标记的药代动力学是聚合物类型及其gpm的函数。在这四种聚合物中，30 kDa PL显示出最有利的药代动力学特征，与其余三种聚合物相比，肝脏蓄积最低且血液值最高。
这四种聚合物的生物分布表现出特征差异，其中一种聚合物（30 kDa PL）显示出最有利于扩增靶向的性质。
