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Department of Molecular Pathology [Y-C. L-L., S. N., M. T. K.], Clinical Investigation [V. G.], and Surgery [S. A. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland [D. S.], and Department of Infectious Diseases, Center for Disease Control and Prevention, Fort Collins, Colorado 80522 [T. R. B.]

An effective strategy of delivering recombinant DNA or protein by nonviral vectors faces two major challenges: (a) the selective delivery to the specific target tissue; and (b) a long-term expression of the protein once inside the cells. The present study describes a receptor-mediated delivery strategy using recombinant fusion protein consisting of malaria circumsporozoite (CS) protein as a ligand and bacterial cytosine deaminase (CD), which catalyzes the production of 5-fluorouracil from its prodrug 5-fluorocytosine. We demonstrate that the CD-CS fusion protein can be internalized in a receptor-mediated manner, providing a target delivery. The internalized CD-CS is capable of synthesizing 5-fluorouracil from the exogenously added 5-fluorocytosine and elicits cell killing with bystander activities. Most importantly, the internalized recombinant protein is stable and remains functional for at least several days, probably because of the entrapment of the fusion protein in particular cytoplasmic compartments that are free from cytoplasmic degradation machinery. Thus, it is possible to use a simple recombinant fusion strategy to enhance intracellular protein stability for manufacturing biological active product in a cell type-specific manner. The application of this strategy in the treatment of liver cancers and liver metastasis of colorectal cancers is discussed.