MR Imaging of a Paramagnetic HPMA Conjugate in an Animal Tumor Model

HPMA copolymers have been labeled with radioactive probes including 131I and 99mTc for noninvasive visualization of in vivo drug delivery of the conjugates with g-scintigraphy.31-33 Nuclear medicine is highly sensitive for detecting labeled conjugates, but its poor spatial resolution cannot provide detailed biodistribution of conjugates in tissues and organs. In comparison, contrast-enhanced MRI provides clear visualization of the biodistribution of paramagnetically labeled conjugates with high spatial resolution.

HPMA copolymers were labeled with an MRI contrast agent, Gd-DOTA, and investigated in an animal tumor model with contrast-enhanced MRI.34 The structure of a labeled conjugate, poly[HPMA-co-(MA-Gly-Gly-1,6-hexanediamine-(Gd-DOTA))], is shown in Figure 11.1. The molecular weight of the polymer conjugate was 25.6 kDa (PD = 1.50) and the Gd content was 0.33 mmol Gd/g polymer. The T1 relaxivity of the conjugate was 6.0 mM-1 s-1 per attached Gd(III) chelate at 3 T. Figure 11.2 shows the dynamic, contrast-enhanced, three-dimensional maximum intensity projection (MIP) (Figure 11.2a) and 2D coronal MR images (Figure 11.2b) of a mouse bearing a human prostate carcinoma DU-145 xenograft and a Kaposi's sarcoma xenograft. The conjugate was administrated intravenously at a Gd equivalent dose of 0.1 mmo1/kg body weight. The pharmacokinetics and biodistribution of the conjugate were clearly revealed in the contrast-enhanced MR images.

Strong MRI signal was observed in the heart, liver, kidneys and vasculature in the 3D images at the initial stage after the injection of the conjugates. The signal intensity decreased over a 60-min period; meanwhile, the signal intensity in the urinary bladder increased gradually, indicating that the conjugate was excreted via renal filtration. Significant contrast enhancement was still visible in the heart at 60 min. After 22 h, most of the conjugate was cleared from the body except the liver, as shown in Figure 11.2. The signal intensity in the liver was stronger at 22 h than in the precontrast image, suggesting significant interaction of HPMA copolymers with the liver.


CH2 C=O Nh CH2



FIGURE 11.1 The structure of poly[HPMA-co-(MA-Gly-Gly-1,6-hexanediamine-(Gd-DOTA))].

The coronal images cross-sectioning the tumor tissues showed heterogeneous uptake of HPMA copolymers in two different tumors (Figure 11.2b). The prostate carcinoma had a smaller size, but stronger MR signal than the Kaposi's sarcoma. For Kaposi's sarcoma, the contrast enhancement was mainly observed in the periphery of the tumor tissue and to a lower extent in the inner tumor tissue. A plausible explanation is that the interstitium of the large tumor was possibly necrotic, which would limit the access of the conjugate. The results suggested that tumor uptake of HPMA copolymers may vary from tumor to tumor and with different tumor sizes. It might affect the efficacy of the polymer conjugates and more detailed studies are needed to understand the possible correlations.

Preccntrast 1,3 min 4.4 min 9.7 min 20 min 60 min 22 h

FIGURE 11.2 Three-dimensional maximum intensity projection (MIP) (a) and 2D coronal MR images (b) of the male nude mouse bearing prostate carcinoma DU-145 (left) and human Kaposi's sarcoma (SLK) tumor (right) at different time points. The arrow points to the tumor. Imaging parameters were TR = 7.8 ms, TE = 2.7 ms, 25° flip angle, and 0.4-mm coronal slice thickness.

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