Macromolecular Gd(III) chelates are superior magnetic resonance imaging (MRI)
contrast agents for blood pool and
tumor imaging. However, their clinical development is limited by the safety concerns related to the slow excretion and long-term
gadolinium tissue accumulation. A generation 6 PAMAM Gd(III) chelate conjugate with a cleavable
disulfide spacer,
PAMAM-G6-cystamine-(Gd-DO3A), was prepared as a biodegradable macromolecular MRI
contrast agent with rapid excretion from the body. T(1) and T(2) relaxivities of the
contrast agent were 11.6 and 13.3 mM(-1)sec(-1) at 3T, respectively. Blood pool and
tumor contrast enhancement of the agent were evaluated in female nude mice bearing MDA-MB-231 human
breast carcinoma xenografts with a nondegradable conjugate PAMAM-G6-(Gd-DO3A) as a control.
PAMAM-G6-cystamine-(Gd-DO3A) resulted in significant contrast enhancement in the blood for about 5 mins, and Gd-DO3A was released from the conjugate and rapidly excreted via renal filtration after the
disulfide spacer was cleaved. The nondegradable control had much longer blood circulation and excreted more slowly from the body.
PAMAM-G6-cystamine-(Gd-DO3A) also resulted in more prominent
tumor contrast enhancement than the control. However,
PAMAM-G6-cystamine-(Gd-DO3A) demonstrated high toxicity due to the intrinsic toxicity of PAMAM
dendrimers. In conclusion, although
PAMAM-G6-cystamine-(Gd-DO3A) showed some advantages compared with the nondegradable control, PAMAM
dendrimers are not suitable carriers for biodegradable macromolecular MRI
contrast agents, due to their high toxicity.