主讲者：Cong Li 博士
JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine
演讲题目：
影像导向酶-前药疗法
IMAGE-GUIDED ENZYME/PRODRUG THERAPY
时间：2008年1月4日 下午四点
地点：医学院（西院） 5号楼 305会议室
（重庆南路227号）
主办单位：
上海交通大学医学院
上海交通大学Med-X研究院
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主要内容：Imaging the delivery of a drug activating enzyme to a tumor creates a unique
opportunity for optimizing the delivery of cytotoxic therapy while minimizing normal tissue toxicity.In this study, a multimodal imaging reporter conjugated therapeutic enzyme was prepared for image-guided enzyme/prodrug cancer therapy (Figure 1). Cytosine deaminase (CD) converts the nontoxic prodrug 5-fluorocytosine (5FC) to the anti-cancer drug 5-fluorouracil (5FU). Poly-L-lysine (PLL) was functionalized with Gd3+-DOTA and rhodamine, to dynamically monitor the distribution of bCD by either MRI or optical imaging. The resulting bCD-PLL conjugate extravasates into the tumor interstitium, but not normal tissues, due to the high permeability of tumor vasculature.
Confocal fluorescence microscopy of human breast cancer MDA-MB-231 cells showed that bCDPLL was internalized efficiently and colocalized with lysosomes. In vivo MRI demonstrated that bCD-PLL extravasated into MDA-MB-231 tumor xenografts within 10 m of i.v. injection, and significant MR contrast at the tumor site sustained as long as 24 hours (Figure 2a). In vivo optical imaging showed tumor/muscle ratio of bCD-PLL attained to 8.9 at 24 h postinjection. Efficient conversion of 5FC to 5FU at the tumor site was validated by both in vivo 19F MRS and ex vivo HPLC studies even prodrug was injected 24 h after the enzyme. Immunofluorescence confocal microscopic images indicated bCD-PLL is degradable in the liver. H&E staining showed large necrotic areas in tumor sections, but not in liver, kidney and intestine sections after the treatment of bCD-PLL/5FC. Moreover, significant tumor growth delay and recoverable mouse body weight were observed when prodrug was injected 24 h after the enzyme, which suggests that 24 h is a good timewindow for prodrug injection. In summary, this study demonstrated that the imaging-guided enzyme/prodrug strategy is promising in minimizing the systemic toxicity without the compromise of therapeutic efficiency during chemotherapy. This work is supported by NIH P50 CA103175.
