Conventional cancer chemotherapy although very effective in killing cancer cells, frequently results in devastating side-effects from damage to normal tissue that can even contribute to patient mortality. One of the strategies to minimize damage to normal tissue is to deliver an activating enzyme that localizes only in the tumor and converts a non-toxic prodrug to a cytotoxic agent locally in the tumor. Such strategies have been previously tested but with limited success due in large part to the uncertainty in the delivery and distribution of the enzyme. Imaging the delivery of the enzyme to optimize timing the delivery of the prodrug administration for image-guided prodrug therapy would be of immense benefit for this strategy. The focus of this R21 application is therefore to design, characterize and test prototype novel agents for MR and optical image-guided prodrug enzyme therapy of the MDA-MB-231 human breast cancer xenograft. Both MR and optical reporter systems are included in these prototype agents since MR would be useful if such a strategy were to be developed for clinical applications, whereas the optical reporter has advantages in preclinical studies especially for visualizing the incorporation of the enzyme-conjugate with high-resolution microscopy. Two strategies will be investigated in the two specific aims: (i) image-guided delivery based on the hyperpermeability of tumor vasculature and (ii) image-guided prodrug therapy based on molecular targeting of tumor vasculature using the av?3 receptor. The response of the tumors to the therapy will be evaluated using vascular and metabolic 1H MRI/MRSI as well as histological analysis. For both vascular-targeted and vessel permeability based agents, cytosine deaminase (CD), the enzyme that converts the prodrug 5-fluorocytosine to 5-fluorouracil, will be conjugated to the biotinylated form of the contrast agent. CD converts the prodrug 5-FC to 5-FU that can be monitored with 19F MRS/I. Biotinylation of the agent will allow controlled clearance of the enzyme-conjugate from the systemic circulation by administration of avidin. The studies proposed in this application can also, in the future be, extended to image-guided targeting of tumor-associated macrophages, fibroblasts or metastatic tumors. In prodrug enzyme therapy an activating enzyme that converts a non-toxic prodrug to a cytotoxic drug is delivered to the tumor, resulting in localized cytotoxic drug action and minimizing the devastating side-of chemotherapy. Here we propose to design, characterize and test prototype novel agents for MR and optical image-guided prodrug enzyme therapy of the MDA-MB-231 human breast cancer xenograft. Such a strategy will allow the visualization of the prodrug enzyme to optimize the timing of the prodrug administration to when the enzyme concentration in tumor relative to normal tissue is the highest. ? ? ?
| Penet, Marie-France; Mikhaylova, Maria; Li, Cong et al. (2010) Applications of molecular MRI and optical imaging in cancer. Future Med Chem 2:975-88 |
| Li, Cong; Winnard Jr, Paul; Bhujwalla, Zaver M (2009) Facile synthesis of 1-(acetic acid)-4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-cyclododecane: a reactive precursor chelating agent. Tetrahedron Lett 50:2929-2931 |
| Li, Cong; Penet, Marie-France; Winnard Jr, Paul et al. (2008) Image-guided enzyme/prodrug cancer therapy. Clin Cancer Res 14:515-22 |
| Li, Cong; Wildes, Flonne; Winnard Jr, Paul et al. (2008) Conjugation of poly-L-lysine to bacterial cytosine deaminase improves the efficacy of enzyme/prodrug cancer therapy. J Med Chem 51:3572-82 |
