Abstract
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. 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. 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. These preclinical studies show the feasibility of using a MR-detectable prodrug enzyme to time prodrug administration in enzyme/prodrug cancer therapy.
Highlights
The success of enzyme/prodrug cancer therapy is limited by the uncertainty in the delivery of the enzyme in vivo
For the first time, we report on the in vivo detection of a drug-activating enzyme functionalized with multimodal magnetic resonance (MR) and optical imaging reporters to provide image-guided delivery of prodrug
The use of wild-type and vascular endothelial growth factor (VEGF)overexpressing MDA-MB-231 breast cancer xenografts allowed us to evaluate the role of increased vascular permeability in the delivery of the conjugate
Summary
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. The enzyme converts the prodrug to an active anticancer drug, achieving high concentrations in the tumor and sparing normal tissue. The resulting bCD-PLL conjugate (molecular weight, >300 kDa) extravasated into the tumor interstitium but not the normal tissues due to the high permeability of tumor vasculature and was detected by MRI and optical imaging [20]. The conversion of 5-FC to 5-FU was detected noninvasively in vivo with 19F MR spectroscopy [21, 22]
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