Image-Guided Enzyme/Prodrug Cancer Therapy

Abstract

Purpose: The success of enzyme/prodrug cancer therapy is limited by the uncertainty in the delivery of the enzyme in vivo. This study shows the use of noninvasive magnetic resonance (MR) and optical imaging to image the delivery of a prodrug enzyme. With this capability, prodrug administration can be timed so that the enzyme concentration is high in the tumor and low in systemic circulation and normal tissue, thereby minimizing systemic toxicity without compromising therapeutic efficiency. Experimental Design: The delivery of a multimodal imaging reporter functionalized prodrug enzyme, cytosine deaminase, was detected by MR and optical imaging in MDA-MB-231 breast cancer xenografts. Stability of the enzyme in the tumor was verified by 19 F MR spectroscopy, which detected conversion of 5-fluorocytosine to 5-flurouracil. The optimal time window for prodrug injection determined by imaging was validated by immunohistochemical, biodistribution, and high-performance liquid chromatographic studies. The therapeutic effect and systemic toxicity of this treatment strategy were investigated by histologic studies and tumor/body weight growth curves. Results: The delivery of the functionalized enzyme in tumors was successfully imaged in vivo. The optimal time window for prodrug administration was determined to be 24 h, at which time the enzyme continued to show high enzymatic stability in tumors but was biodegraded in the liver. Significant tumor growth delay with tolerable systemic toxicity was observed when the prodrug was injected 24 h after the enzyme. Conclusion: These preclinical studies show the feasibility of using a MR-detectable prodrug enzyme to time prodrug administration in enzyme/prodrug cancer therapy.

Intrabiliary RF Heat-enhanced Local Chemotherapy of a Cholangiocarcinoma Cell Line: Monitoring with Dual-Modality Imaging—Preclinical Study

“…The advantages of this optical imaging technique include its low cost, high sensitivity, and noninvasive and real-time depiction of the biologic events in tumors (28). However, the main weaknesses of optical imaging, which limit its clinical applications, are the poor tissue penetration of fluorescent lights and the low spatial resolution of the targets (28,29). Developing molecular imaging techniques for interventional therapies may address this issue for translation of optical imaging from preclinical applications in small animals to clinical practice in humans (30).…”

Oligonucleotide-Based Theranostic Nanoparticles in Cancer Therapy

“…The prodrug-activating bacterial cytosine deaminase (bCD) was cross-linked to a PEI-PLL copolymer to produce bCD-PLL-PEI. bCD converts the nontoxic prodrug 5-fluorocytosine into the toxic 5-fluorouracil, which is detectable by 19F MR spectroscopy [180,181]. PLL was chosen as the linker between PEI and bCD to avoid the loss of activity by PEI and thus maintain bCD activity.…”

Molecular Imaging of the Tumor Microenvironment

“…Exciting new areas that should rapidly develop in the future include targeting specifi c microenvironments or stromal compartments using image-guided incorporation of nanoand microdevices into tumors for slow release of therapeutic agents and gene delivery and image-guided pro-drug enzyme therapy (13). As shown in Figure 1, visualization of the prodrug enzyme cytosine deaminase (bCD) and poly-L-lysine (PLL) functionalized with biotin, rhodamine, and Gd 3+ -1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with MRI can be used to time prodrug administration.…”

“…As shown in Figure 1, visualization of the prodrug enzyme cytosine deaminase (bCD) and poly-L-lysine (PLL) functionalized with biotin, rhodamine, and Gd 3+ -1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with MRI can be used to time prodrug administration. Image-guided timing of 5-fl uorocytosine prodrug administration to coincide with the maximum concentration of the enzyme in the tumor and the minimum concentration in normal tissue, minimized damage from the active drug 5-fl uorouracil in normal tissue while maximizing damage to cancer cells (13).…”