Pg As A Carrier Of Diagnostic Agents 1061 Magnetic Resonance Imaging

Noninvasive imaging of intravascular compartments is of critical importance in the clinic. Many diseases such as infections, ulcers, cardiovascular diseases, and solid tumors involve gross hemor-rhaging, abnormal vascular growth, and/or vascular occlusion.63,64 Magnetic resonance imaging (MRI) with blood-pool contrast agents can be used to perform minimally invasive angiography, assess angiogenesis, quantify and measure the spacing of blood vessels, and measure blood volume and flow.63,64 MRI blood-pool contrast agents are often paramagnetic gadolinium (Gd) chelates of high-molecular-weight polymers that are largely retained within the intravascular space during MRI.65 Recent studies showed that tumor vascular permeability measurements obtained using polymeric contrast agents enhanced dynamic MRI that correlated with tumor microvessel density counts, suggesting that MRI can be used to characterize tumor angiogenic activity.66,67

Furthermore, MRI with polymeric contrast agents may permit more accurate grading of tumor invasiveness than those with smaller molecular weight contrast agents, such as Gd-diethylenetria-minepentaacetic acid (DTPA).68,69

Investigators have synthesized various polymeric contrast agents for MRI, including human

serum albumin, polylysine, , dextran, , dendrimers, polyamide, , and grafted copolymers,80 and they evaluated them as blood-pool imaging agents. Although most of these agents fulfill the criteria for long blood circulation time and high MRI relaxivity, their safety remains unestablished. The clinical applications of many current macromolecular contrast agents are limited by slow excretion from the body and the potential toxicity of free Gd3 + ions released by

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the metabolism of the contrast agents. , , For albumin-based products, the possibility of immunogenic responses makes the use of serum proteins less attractive. Dendrimer-based blood-pool agents have the advantage of extremely narrow molecular weight distributions; however, these agents are not biodegradable.

Ideally, polymeric contrast agents are degraded and cleared from the body after completion of MRI. Based on its good biocompatibility and biodegradability, the metal chelator DTPA was conjugated with PG, and the physicochemical and imaging properties of the resulting polymeric contrast agents were evaluated.83 One of these agents, PG-Bz-DTPA-Gd, was synthesized from PG and monofunctional p-aminobenzyl-DTPA (penta-ieri-butyl ester). It was found that PG-Bz-DTPA-Gd was readily degraded upon exposure to an aqueous buffered solution containing cath-epsin B. The T\ relaxivity of PG-Bz-DTPA-Gd at 1.5 T was four times greater than that of small-molecular-weight Gd-DTPA. Figure 10.2 compares the parametric AUC magnetic resonance images for signal intensity integrated over 90 s and 10 min after intravenous injection of gado-pentetate dimeglumine (Magnevist; Gd-DTPA) and PG-Bz-DTPA-Gd. Magnevist (743 Da) is a contrast agent that is clinically used. Whereas Magnevist rapidly diffused into the extravascular fluid space over 90 s, PG-Bz-DTPA-Gd was largely retained in the blood vessels for up to 10 min. Indeed, contrast enhancement of the vascular compartments was still visible 2 h after injection of PG-Bz-DTPA-Gd.83

In an effort to increase the rate of polymer degradation, Lu et al.84 prepared PG-cystamine-[Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)] (molecular weight of PG, 50,000 Da) where the metal chelator DOTA was conjugated with PG using a disulfide bond. They showed that glutathione and other endogenous sulfhydryl-containing biomolecules could exchange their free SH group with an S-S bond in PG-cystamine-[Gd(III)-DOTA], resulting in

90s 10 min

Magnevist

PG-Bz-DTPA-Gd

FIGURE 10.2 (See color insert following page 522.) Comparison of parametric AUC magnetic resonance images obtained at 90 s and 10 min after intravenous injection of Magnevist and PG-Bz-DTPA-Gd. Arrow: Blood vessel.

Magnevist

PG-Bz-DTPA-Gd

FIGURE 10.2 (See color insert following page 522.) Comparison of parametric AUC magnetic resonance images obtained at 90 s and 10 min after intravenous injection of Magnevist and PG-Bz-DTPA-Gd. Arrow: Blood vessel.

COOH

FIGURE 10.3 Structure of PAMAM16-PG-(ICG)-folate containing folic acid molecules at the termini of the polymer and dye molecules (ICG-NH2) at the side chains of the polymer. (From Tansey, W., Ke, S., Cao, X. Y. et al., J. Control. Rel., 94, 39-51, 2004. With permission.)

COOH

COOH

Folic acid

FIGURE 10.3 Structure of PAMAM16-PG-(ICG)-folate containing folic acid molecules at the termini of the polymer and dye molecules (ICG-NH2) at the side chains of the polymer. (From Tansey, W., Ke, S., Cao, X. Y. et al., J. Control. Rel., 94, 39-51, 2004. With permission.)

rapid release of Gd(III)-DOTA from the polymer and subsequent clearance of Gd-containing species from the body. Use of PG-cystamine-[Gd(III)-DOTA] produced significant blood-pool contrast enhancement on MRI scans of the heart and blood vessels in nude mice bearing OVCAR-3 human ovarian carcinoma xenograft when compared with use of small-molecular-weight contrast agents.

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