title: Cells designed to deliver anticancer drugs by apoptosis.
abstract: We describe a new drug delivery strategy that uses genetically engineered endothelial cells (ECs) to deliver drugs to tumor cells by apoptosis. Immortalized ECs were genetically engineered to express a flk-1:fas fusion protein. When exposed to the flk-1 ligand, vascular endothelial growth factor (VEGF), which is overexpressed by many tumors, these cells underwent extensive apoptosis. These apoptotic ECs, when loaded with drug, promote drug delivery by phagocytosis of drug-loaded apoptotic bodies by the tumor cells and by increased drug transport through the more permeable apoptotic membrane. In the current study, severe combined immunodeficient mice bearing s.c. tumors that expressed high levels of VEGF were treated either intratumorally or i.v. every 4 days for a total of five doses with saline control, free Taxol, and immortalized ECs (imECs) expressing the flk-1:fas fusion protein (imEC/HFF) loaded with Taxol (imEC/HFF-T). Intratumoral treatments also included imEC/HFF and imECs loaded with Taxol (imEC-T). Tumor size was monitored for a minimum of 44 days. Whether administered intratumorally or i.v., imEC/HFF-T cells produced greater inhibition of tumor growth than all other treatments, including Taxol. It was noteworthy that 5 of 16 of the imEC/HFF-T-treated animals were tumor free at the termination of the studies, compared with 2 of 16 animals treated with Taxol. A cell distribution experiment showed that flk-1:fas fusion protein expression ECs as well as parental ECs accumulated in tumor and spleen with the highest level, followed by liver, lung, kidney, and brain. Significant apoptosis of flk-1:fas expression cells was observed in tumor, apparently driven by VEGF secreted from tumor cells. Apoptosis-induced drug delivery offers a new avenue for targeted drug delivery research that uses biological control mechanisms.
authors.affiliation: Department of Pharmacology Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ma
authors.forename: Karin A
authors.initials: KA
authors.lastname: Reed
authors.forename: James M
authors.initials: JM
authors.lastname: Gallo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D008222:Lymphokines / Q000494:pharmacology; D017239:Paclitaxel / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017978:Receptors, Growth Factor / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D014018:Tissue Distribution; D023822:Tissue Engineering; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019014:fas Receptor / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019014:fas Receptor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D017239:Paclitaxel