LIPOSOMAL CONTRAST AGENTS FOR MR IMAGING

本申请涉及脂质体造影剂的发展 用于磁共振成像(MRI)以改进肝脏的检测 和脾转移，并作为肿瘤血流灌注的标志。 当前的诊断成像技术，如闪烁照相和计算机 体层摄影术(CT)不能最佳地发现肝或脾病变， 尤其是淋巴瘤。水溶性的碘化造影剂已经被 用来提高CT对恶性肿瘤的检测，但有 与血管外血管快速平衡所带来的问题 空间和快速排泄。为了克服这个问题，脂质体加碘 针对网状内皮系统的造影剂也有 被用于CT，并导致了对恶性肿瘤的更好的检测， 然而，它们的使用受到了高毒性剂量的脂质的限制 需要提供足够的碘来提供对比度增强 CT.MRI造影剂，最引人注目的是Gd-DTPA，提供对比度 增强浓度至少比CT对比度低十倍 媒体，伴随而来的毒性，由于高剂量的脂肪应该是 减少了。此外，因为脂质体可能只存在于 通过有窗上皮的循环，可以预料到 脂质体造影剂将成为更好的肿瘤指示剂 与游离Gd-DTPA相比，Gd-DTPA可能具有更多的血管密度和灌注量 指导治疗的后果。 直径为50至400 nm的大单层囊泡将通过 不同包埋造影剂的冻融挤压工艺 包括Gd-DTPA、Gd-DOTA和磁铁矿等多种脂类 作文。囊泡将根据大小来表征， 捕集效率、在生理盐水、血清和储存中的体外稳定性， 大鼠体外舒张性和循环清除性。成像 正常大鼠和荷瘤大鼠将在造影剂前后和 大鼠肝内肿瘤的MRI图像与组织学对照 分析。生物分布和毒性测试将在适当的 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.