II42MR Imaging of PGAMcE6GdDOTA Conjugate in an Animal Tumor Model

Most anti-cancer drugs are lipophilic and the conjugation of lipophilic drugs to a polymeric carrier may also modify the in vivo behavior of the polymers. Mesochlorin e6 (Mce6) is a lipophilic photosentizer for photodynamic therapy.41,42 A paramagnetic poly(l-glutamic acid) Mce6 conjugate was prepared to investigate the pharmacokinetics, biodistribution and drug delivery efficiency of the PGA-Mce6 conjugate with contrast-enhanced MRI.43 The structure of the conjugate is shown in Figure 11.7. A PGA-1,6-hexanediamine-(Gd-DOTA) conjugate was also prepared from the same poly(l-glutamic acid) as a control. Mce6 content was 2.5 mol% in PGA-Mce6-1,6-hexanediamine-(Gd-DOTA) and Gd content was 20 and 29 mol% for PGA-Mce6-1,6-hexanediamine-(Gd-DOTA) and PGA-1,6-hexanediamine-(Gd-DOTA), respectively. The T1 relaxivity was 8.46 and 8.33 mM-1 s-1 for PGA-Mce6-1,6-hexa-nediamine-(Gd-DOTA) and PGA-1,6-hexanediamine-(Gd-DOTA), respectively. The small amount

FIGURE 11.7 The structure of PGA-Mce6-1,6-hexanediamine-(Gd-DOTA).

of Mce6 in PGA-Mce6-1,6-hexanediamine-(Gd-DOTA) significantly reduced the hydrodynamic volume and molecular weight distribution of the conjugate. The weight (Mw) and number (Mn) average molecular weights decreased from 101 and 49 kDa of PGA-1,6-hexadiamine-(Gd-DOTA) to 49 and 34 KDa for PGA-Mce6-1,6-hexadiamine-(Gd-DOTA). The lipophilic Mce6 may alter the conformation of the polymers, resulting in a smaller hydrodynamic volume for PGA-Mce6-1,6-hexa-diamine-(Gd-DOTA).

A contrast-enhanced MRI study demonstrated that PGA-Mce6-1,6-hexanediamine-(Gd-DOTA) had significantly different pharmacokinetics and biodistribution from PGA-1,6-hexanediamine-(Gd-DOTA) in female nu/nu athymic mice bearing human breast carcinoma MB-231 xenografts. Figure 11.8 shows coronal dynamic MR images of mice injected with PGA-Mce6-1,6-hexanedia-mine-(Gd-DOTA) and PGA-1,6-hexanediamine-(Gd-DOTA) at a dose of 0.07 mmol-Gd/kg. The conjugates demonstrated different dynamic contrast enhancement patterns in the heart and liver. PGA-Mce6-1,6-hexadiamine-(Gd-DOTA) had a strong contrast enhancement in the liver and relatively weak enhancement in the heart, whereas PGA-1,6-hexadiamine-(Gd-DOTA) exhibited

FIGURE 11.8 Coronal contrast-enhanced MR slice images for PGA-Mce6-(Gd-DOTA) conjugate and PGA-(Gd-DOTA) conjugate through the heart (b) before and at 5, 15, 30, 60, and 120 min post-injection.

strong enhancement in the heart and relatively weak enhancement in the liver. The conjugation of Mce6 significantly altered the pharmacokinetics and biodistribution of the poly(l-glutamic acid). The results indicated that PGA-Mce6-1,6-hexadiamine-(Gd-DOTA) had higher liver accumulation than PGA-1,6-hexadiamine-(Gd-DOTA). Consequently, it cleared from the blood circulation more rapidly than PGA-1,6-hexadiamine-(Gd-DOTA), which could also be attributed to the larger hydrodynamic volume of PGA-1,6-hexadiamine-(Gd-DOTA).

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