MR Imaging of PGAGdDOTA Conjugate in an Animal Tumor Model

Poly(l-glutamic acid)-1,6-hexanediamine-(Gd-DOTA) conjugate was prepared using a synthetic procedure similar to that of PGA-cystamine-Gd-DOTA conjugate synthesis40 to noninvasively

CH2 Ch2 Nh

Gd3-NN

FIGURE 11.3 The structure of HPMA-MAFITC copolymers labeled with Gd(III)-DOTA.

(a) AiAiat

(a) AiAiat

AIA rat fjj Healthy rat % 43 h baseline

AIA rat fjj Healthy rat % 43 h baseline

(k) Healthy rat (|) Healthy rat 1h 2 h n) Healthy ra -« 48 h ,,,

FIGURE 11.4 The MR images of rats taken at different time points. The acquired images were post-processed using the maximum intensity projection (MIP) algorithm. P-Gd(III)-DOTA is abbreviated as P-Gd. (A-H) AIA rat images at baseline (a) and 5 min (b), 1 h (c), 2 h (d), 3 h (e), 8 h (f), 32 h (g), 43 h (h) post-injection of P-Gd(III)-DOTA. (i-n) Healthy rat images at baseline (i) and 5 min (j), 1 h (k), 2 h (l), 8 h (m), 48 h (n) post-injection of P-Gd(III)-DOTA. Arrow points to the diseased joint (Adapted from Wang, D. etal., Pharm. Res., 21, 1741, 2004. With permission.)

study delivery efficiency of the conjugate. The structure of the conjugate is shown in Figure 11.5. PGA-1,6-hexanediamine-(Gd-DOTA) conjugates, H a high molecular weight (50kDa, PD = 1.12) conjugate and a low molecular weight conjugate (20 kDa, PD = 1.08) were investigated by contrast-enhanced MRI to study the size effect of conjugates on the efficiency of in vivo drug delivery. The conjugates with different molecular weights had similar Gd content (41.7% for 50 kDa conjugate and 40.2 mol% for 20 kDa conjugate) and T\ relaxivity (9.44 and 9.20 mMK 1 s K1 for 50 and 20 kDa conjugates, respectively). The conjugates were intravenously administered into female nu/nu athymic mice bearing human breast carcinoma MB-231 xenografts at a dose of 0.07 mmol-Gd/kg. Dynamic contrast-enhanced MRI clearly revealed the size effect of the conjugates on their pharmacokinetics and in vivo tumor delivery efficiency in the animal model.

Figure 11.6 shows the T1-weighted coronal MR images of mice before and at various time points after injection with the conjugates. Strong contrast enhancement was observed in the heart at the initial stage post-injection and then gradually faded away for both conjugates. The signal intensity decreased more rapidly for the low molecular weight conjugate than the high molecular weight conjugate, validating the concept that the blood circulation of the conjugates is prolonged

CH CH

NH(CH2)6NH c

COO-

Gd3+

-OOC

FIGURE 11.5 The structure of poly(L-glutamic acid)-1,6-hexanediamine-(Gd-DOTA) conjugate.

m so kna so kna

Precontrast 1 min 12 min 20 min 26 min 1h 2 h 3 h 4 h 24 h

FIGURE 11.6 Coronal MR slice images of mice bearing MB-231 breast cancer tumors using PGA-1,6-hexa-nediamine-(Gd-DOTA) conjugates with different molecular weights. The images were taken at different time points using a 3D FLASH pulse sequence (1.74-ms TE, 4.3-ms TR, 25° RF tip angle, 120-mm FOV, and

I.6-mm coronal slice thickness).

Precontrast 1 min 12 min 20 min 26 min 1h 2 h 3 h 4 h 24 h

FIGURE 11.6 Coronal MR slice images of mice bearing MB-231 breast cancer tumors using PGA-1,6-hexa-nediamine-(Gd-DOTA) conjugates with different molecular weights. The images were taken at different time points using a 3D FLASH pulse sequence (1.74-ms TE, 4.3-ms TR, 25° RF tip angle, 120-mm FOV, and

I.6-mm coronal slice thickness).

with increase in molecular weights. The low-molecular-weight conjugate (20 kDa) was cleared from the blood circulation within 30 min after-injection. The dynamic changes in signal intensity in the liver correlated well to that in the heart. The enhancement in the liver returned to the background level 24 h after the injection, indicating low liver uptake of the PGA conjugates.

The contrast enhancement pattern in the tumor tissue was similar to that of HPMA conjugates in Kaposi's sarcoma. Strong signal was observed at tumor periphery and little in the inner tumor tissue. The dynamic MR images showed that the intensity and duration of tumor enhancement strongly depended on the size of the conjugates, indicating size-dependent tumor accumulation. Rapid clearance of the low molecular weight conjugate (20 kDa) from the blood circulation resulted in low and short accumulation in the tumor tissue. The high molecular weight conjugate (50 kDa) had a long blood circulation time, resulting in an increased contrast enhancement for at least 4 h. The enhancement also gradually extended into inner tumor tissue, indicating diffusion of the conjugate further into the tumor. The results clearly showed that drug delivery with polymeric conjugate into tumor tissue was a slow process and H conjugates with high molecular weight and long blood circulation time was more effective for tumor delivery than the conjugate with low molecular weight. Contrast-enhanced MRI clearly revealed the size effect of the conjugates on their pharmacokinetics and in vivo drug delivery efficiency.

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