[DDS Research Aimed at Optimizing Gene and Cell Therapies].

Abstract

My research has focused on optimizing drug delivery system (DDS) related gene and cell therapies. In my gene therapy research, I first developed a polyethylene glycol (PEG)-conjugated adenovirus vector (PEG-Ad) to allow modulation of adenovirus pharmacokinetics and achieve tumor targeting. Evaluating correlations between PEG-Ad blood retention, tumor tissue delivery, liver accumulation, and gene expression is an important step toward creating tumor-targeting PEG-Ad, demonstrating that a 90% PEGylation rate optimally reduced liver accumulation and improved tumor targeting via enhanced permeability and retention. To enhance tumor targeting specificity, we designed Cys-Gly-Lys-Arg-Lys (CGKRK)-PEG-Ad, in which the tumor-targeting peptide CGKRK was attached to the end of the PEG chain. Although CGKRK-PEG-Ad exhibited similarly reduced liver accumulation to that of PEG-Ad, its tumor delivery was higher than that of PEG-Ad, demonstrating its potent therapeutic efficacy against metastatic tumors. Next, I worked to optimize tumor immunotherapy by controlling immune cells in vivo dynamics. In this study, cytokines were used to activate antitumor immune cells, and chemokines were used to induce intratumoral infiltration by antitumor immune cells. While intratumoral administration of Arg-Gly-Asp (RGD)-Ad-C-C motif chemokine ligand 27 (CCL27) alone did not produce an antitumor effect against OV-HM tumors; however, co-administration with RGD-Ad-interleukin-12 (IL-12) demonstrated a stronger antitumor effect than administration of RGD-Ad-IL-12 alone. Infiltration of cluster of differentiation 3 (CD3)- and perforin-positive cells into tumor tissues was increased by combined administration of RGD-Ad-CCL27 and RGD-Ad-IL-12 compared with administration of RGD-Ad-IL-12 alone. These results demonstrate the importance of controlling the in vivo dynamics of antitumor immune cells.