LIPOSOMAL CONTRAST AGENTS FOR MR IMAGING

本申请涉及脂质体造影剂的开发 用于磁共振成像（MRI），以改善肝脏检测 和脾转移瘤，并用作肿瘤灌注的标志物。 目前的诊断成像技术，如脑血管造影和计算机 断层摄影术（CT）不能最佳地检测肝或脾病变， 尤其是淋巴瘤。水溶性碘化造影剂已经被 用于提高CT对恶性肿瘤的检测，但 由于与血管外的快速平衡而伴随的问题 空间和快速排泄。为了克服这个问题，脂质体碘化 靶向网状内皮系统的造影剂也 用于CT并改善了恶性肿瘤的检测， 然而，限制其使用的是高毒性剂量的脂质， 需要输送足够的碘以提供对比度增强， CT. MRI造影剂，最明显的是Gd-DTPA， 浓度至少比CT造影剂低10倍时增强 媒体，伴随的毒性，由于高剂量的脂质应该是 降低此外，由于脂质体可能仅存在于 通过有孔上皮循环，可以预期， 脂质体造影剂将作为肿瘤的更好指示剂 与游离Gd-DTPA相比， 指导治疗的后果。 将通过以下方法制备直径为50至400 nm的大单层囊泡： 使用各种包封造影剂的冻融挤出程序 包括Gd-DTPA、Gd-DOTA和磁铁矿使用各种脂质 组合物的囊泡的特征在于大小， 捕获效率，在生理盐水、血清和储存中的体外稳定性， 体外松弛性和大鼠循环清除率。成像 将在对比前后对正常和荷瘤大鼠进行检查， 大鼠肝内肿瘤，MRI图像与组织学相关 分析.生物分布和毒性试验将遵循适当的 脂质体系统。

This application addresses the development of liposomal contrast agents for Magnetic Resonance Imaging (MRI) to improve the detection of liver and spleen metastases and to serve as a marker of tumor perfusion. Current diagnostic imaging techniques such as scintigraphy and computed tomography (CT) do not optimally detect hepatic or splenic lesions, particularly lymphoma. Water-soluble iodinated contrast agents have been used to improve the detection of malignancy by CT, but there are attendant problems due to rapid equilibration with the extravascular space and rapid excretion. To overcome this problem, liposomal iodinated contrast media, which target to the reticuloendothelial system have also been used for CT and have resulted in improved detection of malignancy, However, a limitation to their use had been the high toxic doses of lipid needed to deliver sufficient iodine to provide contrast enhancement by CT. MRI contrast agents, most noticeably Gd-DTPA, provide contrast enhancement at concentrations at least ten-fold lower than CT contrast media, the attendant toxicity due to high doses of lipid should be reduced. Additionally, because liposomes may only exist from the circulation via fenestrated epithelia, it may be expected that the liposomal contrast agent will serve as a better indicator of tumor vascularity and hence perfusion than free Gd-DTPA, which may have consequences for directing therapy. Large unilamellar vesicles of 50 to 400 nm diameter will be prepared by a freeze-thaw extrusion procedure with various enapsulated contrast media including Gd-DTPA, Gd-DOTA and magnetite using a variety of lipid compositions. The vesicles will be characterized with respect to size, trapping efficiency, in vitro stability in saline, serum and on storage, in vitro relaxivity and clearance from circulation of rats. Imaging of normal and tumor-bearing rats will be done pre- and post-contrast and for rats with intrahepatic tumors, MRI images correlated with histological analysis. Biodistribution and toxicity testing will follow on appropriate liposomal systems.