Pharmacokinetics in mice of four oligomer-conjugated polymers for amplification targeting.
Pharmacokinetics in mice of four oligomer-conjugated polymers for amplification targeting.
复制标题
用于放大靶向的四种低聚物缀合聚合物在小鼠中的药代动力学。
DOI：
10.1089/108497803322702905
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Hnatowich,DonaldJ
中科院分区：
文献类型：
--
作者：
He,Jiang;Liu,Guozheng;Zhang,Surong;Rusckowski,Mary;Hnatowich,DonaldJ
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.ObjectivesTo 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.MethodsAn amine-derivatized 25-mer MORF oligomer was radiolabeled with99mTc. 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 trace99mTc-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 trace99mTc-MORF. The biodistribution was then established in normal CD1 mice at a constant dosage of 2-4 μg of cMORF.ResultsThe 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.ConclusionThe biodistribution of the four polymers showed characteristic differences, with one polymer (30 KDa PL) showing the most favorable properties for amplification targeting.
