Trained Macrophage Bioreactor for Penetrating Delivery of Fused Antitumor Protein.

Abstract

Macromolecular protein drugs are promising anti-neoplastic agents based on their precise tumor affinity and innocuousness to normal tissues. Although direct delivery of protein drugs remains impractical due to its short half-life in circulation, inefficiency in tumor accumulation, and poor penetrability in intratumoral distribution. Recently, biogenetic cell-based drug vectors have been widely reported for antitumor drug delivery. Macrophage is naturally independent with endogenous proteolysis, elimination of reticuloendothelial system, and immune surveillance. Meanwhile, its innate recruitment behaviors responsive to chronic inflammation signals make it a potential cellular vector for tumor targeting drug delivery. In this study, we develop a trained macrophage bioreactor for tumor homing and an in situ expression of fused antitumor protein. The recombinant tumor necrosis factor related apoptosis-inducing ligand is coded on a plasmid vector with penetrating domain on the C terminus, which improves the intratumoral distribution by facilitating protein dispersion in tumor tissue after in situ secretion. The combination of tumor-infiltrating macrophage bioreactor and multifunctional fused protein drug embodies a new effective tumor homing system for antitumor protein delivery.