Poly(L-glutamic acid) Gd(III)-DOTA conjugate with a degradable spacer for magnetic resonance imaging
Poly(L-glutamic acid) Gd(III)-DOTA conjugate with a degradable spacer for magnetic resonance imaging
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DOI：
10.1021/bc0340464
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发表时间：
2003-07-01
影响因子：
4.7
通讯作者：
Buswell, HR
中科院分区：
文献类型：
--
作者：
Lu, ZR;Wang, XH;Buswell, HR
大分子Gd（III）配合物作为MRI造影剂的临床应用受到排泄缓慢和潜在毒性的阻碍，这是由于药剂代谢引起的Gd（III）离子释放造成的。一个聚合物Gd（III）螯合物共轭与可裂解的间隔已被设计来解决这个问题。聚（L-谷氨酸）-胱胺-[Gd（III）-DOTA]通过胱胺（一种可裂解的二硫键间隔基）与PGA（MW = 50 000）缀合，然后与GdCl 3络合来制备。Gd（III）DOTA螯合衍生物在与半胱氨酸（内源性血浆硫醇）孵育时容易从聚合物缀合物中释放。该缀合物在听到OVCAR-3人卵巢癌异种移植物的裸鼠中产生显著的MRI血池对比增强。观察到小分子造影剂Gd（DTPA-BMA）的对比度增强不太显著。药代动力学MRI研究显示，来自缀合物的Gd（III）螯合物以与Gd（DTPA-BMA）相似的动力学模式在膀胱中累积，表明螯合物由内源性硫醇释放并通过肾过滤排出。初步结果表明，这种新的设计具有很大的潜力，以解决大分子MRI造影剂的安全性问题。
The clinical application of macromolecular Gd(III) complexes as MRI contrast agents is impeded by their slow excretion and potential toxicity due to the release of Gd(III) ions caused by the metabolism of the agents. A polymer Gd(III) chelate conjugate with a cleavable spacer has been designed to solve this problem. Poly(L-glutamic acid) - cystamine -[Gd(III)-DOTA] was prepared by the conjugation of DOTA to PGA (MW = 50 000) via cystamine, a cleavable disulfide spacer, followed by the complexation with GdCl3. A Gd(III) DOTA chelate derivative was readily released from the polymer conjugate in the incubation with cysteine, an endogenous plasma thiol. The conjugate produced significant MRI blood pool contrast enhancement in nude mice hearing OVCAR-3 human ovarian carcinoma xenographs. Less significant contrast enhancement was observed for a small molecular contrast agent, Gd(DTPA-BMA). The pharmacokinetic MRI study showed that the Gd(III) chelate from the conjugate accumulated in the urinary bladder in a similar kinetic pattern to Gd(DTPA-BMA), suggesting that the chelate was released by the endogenous thiols and excreted through renal filtration. The preliminary results suggest that this novel design has a great potential to solve the safety problem of macromolecular MRI contrast agents.