Cascade polymeric MRI contrast media derived from poly(ethylene glycol) cores: Initial syntheses and characterizations
Cascade polymeric MRI contrast media derived from poly(ethylene glycol) cores: Initial syntheses and characterizations
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DOI：
10.1021/bm061141h
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发表时间：
2007-05-01
影响因子：
6.2
通讯作者：
Brasch, Robert C.
中科院分区：
文献类型：
--
作者：
Fu, Yanjun;Raatschen, Hans-Juergen;Brasch, Robert C.
磁共振成像(MRI)的诊断性造影剂通常用于增强血液信号，以便定量定义血管功能特征，包括组织血容量、流量和渗漏。目前正在寻找耐受性良好和安全的大分子制剂，这些制剂在血液中保留相对较长的时间，并选择性地从病变血管，特别是癌症血管渗漏。我们合成了一类新的大分子水溶性磁共振造影剂，方法是在聚乙二醇链的两端各引入两个不同的聚赖氨酸级联放大器，然后用Gd-DTPA螯合物取代末端的赖氨酸氨基。本文报道了四种候选的聚乙二醇级联偶联物，PEG3400-Gen4-(Gd-DTPA)(8)，PEG6000-Gen4-(Gd-DTPA)(8)，PEG12000-Gen4-(Gd-DTPA)(8)和PEG3400-Gen5-(Gd-DTPA)(13)，描述了它们的基本物理、生物学和动力学性质，包括真实和有效的分子尺寸，质子T1在水和血浆中的松弛程度，分配系数，分子量，螯合稳定性，在血浆中的稳定性，对高压灭菌的稳定性，某些体内药代动力学(血液半衰期，血液清除性，体积分布)，以及正常啮齿动物的全身消除曲线。这些候选的聚乙二醇级联核磁共振造影剂显示了一系列有效的分子大小，类似于重达74-132 kDa的蛋白质，尽管它们的实际分子量小得多，为12-20 kDa。所有化合物都表现出较窄的尺寸分散性和相对较高的T1驰豫系数(约为2T和37℃时未共轭Gd-DTPA的3倍)。具有代表性的化合物也表现出高度的亲水性，在溶液缓冲液和血浆中稳定，缺乏与蛋白质的结合。有效分子尺寸最大的两个候选化合物PEG12000-Gen4-(Gd-DTPA)(8)和PEG3400-Gen5-(Gd-DTPA)(13)具有较长的血半衰期，分别为36和73min(两者均为单指数动力学)，并显示出强烈的、延长的血管MRI增强。结果还表明，通过选择聚乙二醇核的分子尺寸和级联多赖氨酸簇的放大程度，可以调整体内药代动力学和体内消除曲线。来自这种新型造影剂的初步评估化合物在许多方面(但不是所有方面)显示出可接受的、理想的特性。进一步的努力指向具有更高的热力学稳定性、更高的Gd螯合物取代度和更快的体内消除的候选大分子。
Diagnostic contrast media for magnetic resonance imaging (MRI) are often applied to enhance the signal of blood allowing for quantitative definition of vascular functional characteristics including tissue blood volume, flow, and leakiness. Well-tolerated and safe macromolecular formulations are currently being sought that remain in the blood for a relatively long period and that leak selectively from diseased vessels, particularly cancer vessels. We synthesized a new class of macromolecular, water-soluble MRI contrast media by introducing two diverging polylysine cascade amplifiers at each end of a poly(ethylene glycol) (PEG) backbone, followed by substitution of terminal lysine amino groups with Gd-DTPA chelates. Four candidate PEG cascade conjugates are reported here, PEG3400-Gen4-(Gd-DTPA)(8), PEG6000-Gen4-(Gd-DTPA)(8), PEG12000-Gen4-(Gd-DTPA)(8), and PEG3400-Gen5-(Gd-DTPA)(13) with descriptions of their basic physical, biological, and kinetic properties, including real and effective molecular sizes, proton T1 relaxivities in water and plasma, partition coefficients, osmolalities, chelate stability, stability in plasma, stability to autoclaving, certain in vivo pharmacokinetics (blood half-life, blood clearance, volume of distribution), and whole body elimination profiles in normal rodents. These candidate PEG-core cascade MRI contrast media showed a range of effective molecular sizes similar to proteins weighing 74-132 kDa, although their actual molecular weights were much smaller, 12-20 kDa. All compounds exhibited a narrow range of size dispersity and relatively high T1 relaxivities (approximately 3 times the value for unconjugated Gd-DTPA at 2 T and 37 degrees C). Representative compounds also showed a high degree of hydrophilicity, stability in solution buffer and plasma, and lack of binding to proteins. The two candidate compounds with the largest effective molecular sizes, PEG12000-Gen4-(Gd-DTPA)(8) and PEG3400-Gen5-(Gd-DTPA)(13), had longer blood half-lives, 36 and 73 min, respectively (monoexponential kinetics for both), and showed strong, prolonged MRI enhancement of vessels. Results also indicate that in vivo pharmacokinetics and bodily elimination profiles can be adjusted by the selection of molecular size for the PEG core and the selection of the amplification degree of the cascade polylysine clusters. The initially evaluated compounds from this new class of contrast media show acceptable, desirable characteristics in many, but not all, respects. Further efforts are directed toward candidate macromolecules having higher thermodynamic stability, higher degree of substitution by gadolinium chelates, and more rapid bodily elimination.