Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, and National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610041, China.
Biomater Sci. 2019 Apr 23;7(5):1919-1932. doi: 10.1039/c8bm01103f.
Accumulation of nano-scale contrast agents in body tissues potentially induces adverse effects associated with free Gd(iii) ion release from the nano-scale system, such as nephrogenic systemic fibrosis and gadolinium deposition in the brain tissue. A novel formulation strategy was proposed herein for Gd-based macromolecular MRI contrast agents (Gd-mCAs), which may significantly reduce Gd(iii) retention but maintain sufficient imaging contrast. Biodegradable poly[N-(1,3-dihydroxypropyl)methacrylamide] copolymers (pDHPMA) were synthesized from N-(1,3-dihydroxypropyl)methacrylamide (DHPMA) as a monomer and enzyme-responsive short peptide (GFLG) as a chain transfer agent. Small molecular Gd-chelate (Gd-DOTA) was conjugated onto the copolymer backbone through a sulfide bond or a GSH-sensitive cleavable disulfide bond to produce two novel Gd-mCAs (pDHPMA-Cy5.5-DOTA-Gd or pDHPMA-Cy5.5-SS-DOTA-Gd) for tumor diagnosis. Their relaxivities were 10.49 and 10.24 mM-1 s-1 respectively, which were significantly higher than that of DTPA-Gd (3.97 mM-1 s-1). Compared with pDHPMA-Cy5.5-DOTA-Gd, pDHPMA-Cy5.5-SS-DOTA-Gd had a shorter Gd(iii) retention time but maintained a sufficient contrast efficacy. We have demonstrated that the conjugation of small molecular Gd-chelate to biodegradable macromolecular carriers through a ROX-sensitive biocleavable disulfide bond may be an efficient strategy for formulating safe biodegradable Gd-based pDHPMA copolymers as MRI contrast agents.
纳米级造影剂在体内组织中的蓄积可能会引发与纳米级系统中游离 Gd(iii)离子释放相关的不良反应，如肾源性系统性纤维化和脑内 Gd 沉积。本文提出了一种新型的 Gd 基大分子 MRI 造影剂（Gd-mCA）的制剂策略，该策略可能会显著降低 Gd(iii)的保留，但保持足够的成像对比度。采用 N-（1,3-二羟基丙基）甲基丙烯酰胺（DHPMA）作为单体，酶响应短肽（GFLG）作为链转移剂，合成了可生物降解的聚[N-（1,3-二羟基丙基）甲基丙烯酰胺]共聚物（pDHPMA）。小分子 Gd 螯合物（Gd-DOTA）通过硫醚键或 GSH 敏感可裂解二硫键连接到共聚物主链上，分别制备了两种新型 Gd-mCA（pDHPMA-Cy5.5-DOTA-Gd 或 pDHPMA-Cy5.5-SS-DOTA-Gd）用于肿瘤诊断。它们的弛豫率分别为 10.49 和 10.24 mM-1 s-1，明显高于 DTPA-Gd（3.97 mM-1 s-1）。与 pDHPMA-Cy5.5-DOTA-Gd 相比，pDHPMA-Cy5.5-SS-DOTA-Gd 的 Gd(iii)保留时间更短，但保持了足够的对比效果。我们已经证明，通过 ROX 敏感的生物可裂解二硫键将小分子 Gd 螯合物连接到可生物降解的大分子载体上，可能是一种有效的策略，可用于制备安全的可生物降解的 Gd 基 pDHPMA 共聚物作为 MRI 造影剂。
