The degradation and clearance of Poly(N-hydroxypropyl-l-glutamine)-DTPA-Gd as a blood pool MRI contrast agent

Abstract

Although polymeric magnetic resonance imaging (MRI) agents have significantly improved relaxivity and prolonged circulation time in vivo compared with current imaging agents, the potential for long-term toxicity prevents their translation into the clinic. The aim of this study was to develop a new biodegradable, nonionic polymeric blood pool MRI contrast agent with efficient clearance from the body. We synthesized PHPG-DTPA, which possesses two potentially degradable sites in vivo: protein amide bonds of the polymer backbone susceptible to enzymatic degradation and hydrolytically labile ester bonds in the side chains. After chelation with Gd3+, PHPG-DTPA-Gd displayed an R1 relaxivity of 15.72 mM−1 · sec −1 (3.7 times higher than that of MagnevistT). In vitro, DTPA was completely released from PHPG polymer within 48 h when incubated in mouse plasma. In vivo, PHPG-DTPA-Gd was cleared via renal route as shown by micro-single photon computed tomography of mice after intravenous injection of 111In-labeled PHPG-DTPA-Gd. MRI of nude rats bearing C6 glioblastoma showed significant enhancement of the tumor periphery after intravenous injection of PHPG-DTPA-Gd. Furthermore, mouse brain angiography was clearly delineated up to 2 h after injection of PHPG-DTPA-Gd. PHPG-DTPA-Gd’s biodegradability, efficient clearance, and significantly increased relaxivity make it a promising polymeric blood pool MRI contrast agent.

Silk structure and degradation

“…The results of this study suggest that PBS is the optimal choice of degradation solution for studying in vitro degradation properties of biological materials. In general, PBS is the most commonly used solution for degradation [17,21,22]. PBS has a stable pH value and osmotic pressure, without oxidation agents or any enzymes, so the degradation of the materials in PBS represents hydrolysis under physiological pH and osmotic pressure [23].…”

“…Thus, the degradation of the materials in PBS relies upon hydrolysis under physiological pH and osmotic pressure [23]. Plasma is a better choice of degradation solution for the evaluation of in vitro degradation of materials [22]. The enzyme in tissue solution also play a crucial role in the degradation of the materials in animal tissues [10,24].…”

“…The degradation of materials includes both in vitro and in vivo degradation. In vitro degradation experiments are performed in a degradation solution, with PBS (phosphate buffered solution) being the most commonly used [17,21,22]. A PBS solution is characterized by a stable pH value and osmotic pressure, having no oxidative properties [23] and no enzymes present.…”

A new biodegradable and biocompatible gadolinium (III) -polymer for liver magnetic resonance imaging contrast agent

“…The reason for the phenomenon might be that the hydrolysis and enzymolysis cleave the backbone and the side-chains of the gadolinium-copolymer, resulting in effectively excreting the degradable products with relative smaller molecular weight. The appearance of gadolinium (III) in the urine-bladder and feces indicated that the degradable products might be cleared from the mice through the renal and hepatobiliary metabolism [28][29][30].…”

“…The liver is a well perfused organ, and any T 1 effect of the contrast agent in the blood would cause the increased signal in the liver. Furthermore, ACL-A 2 -DOTA-Gd might be degraded in the body, and the released segments might diffuse into the liver interstitium [28], leading an increased signal in liver. In contrast to the rapid decreased signal of Gd-DOTA in the liver, the experimental group with injection of ACL-A 2 -DOTA-Gd presented the substantially increased signal, and the signal-time persisted for a longer period.…”