Image-guided enzyme/prodrug cancer therapy.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
These preclinical studies show the feasibility of using a MR-detectable prodrug enzyme to time prodrug administration in enzyme/prodrug cancer therapy.
Li
Cong
C
Johns Hopkins University In Vivo Cellular Molecular Imaging Center Program, The Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Penet
Marie-France
MF
Winnard
Paul
P
Artemov
Dmitri
D
Bhujwalla
Zaver M
ZM
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D002380:Catalogs, Drug as Topic; D043525:Cytosine Deaminase / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D005472:Fluorouracil / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil