Improved systemic pharmacokinetics, biodistribution, and antitumor activity of CpG oligodeoxynucleotides complexed to endogenous antibodies in vivo.
CpG oligodeoxynucleotides (CpG-ODNs) fail to elicit antitumor immunity after intravenous administration presumably due to their rapid renal clearance and low tumor accumulation. To address this issue, we tested the hypothesis that endogenous IgG can be used as systemic drug carriers to improve the pharmacokinetics, tumor accumulation, and antitumor activity of intravenously administered CpG-ODNs. To this end, tritium-labeled CpG-ODNs conjugated with one or two dinitrophenyl (DNP) haptens (DNP- and DNP(2)-[(3)H]-CpG-ODN) were intravenously dosed into DNP-immunized Balb/c mice bearing subcutaneous CT26 colorectal tumors. Serum and tissue samples for pharmacokinetic and biodistribution profiling were collected at predetermined timepoints and analyzed by liquid scintillation. In antitumor efficacy studies, DNP-immunized, CT26 tumor-bearing mice were intravenously dosed with PBS, CpG-ODN, or DNP-CpG-ODN every five days. Tumor volumes and macroscopic and histological examination of resected solid tumors were used to quantitatively and qualitatively assess tumor growth inhibition. Relative to [(3)H]-CpG-ODN, dinitrophenylated [(3)H]-CpG-ODNs displayed substantial increases in systemic exposure (900-1650 fold) and half-life (100-300 fold), marked decreases in systemic clearance (750-1500 fold) and volume of tissue distribution (13-37 fold), as well as substantial and sustained tumor accumulation (approximately 30% vs. <2% injected dose/g). Antitumor efficacy studies demonstrated that DNP-CpG-ODN inhibited tumor growth by up to 60% relative to PBS control whereas CpG-ODN treatment had no apparent effect. Macroscopic and histological examination of harvested tumors at various timepoints revealed the presence of regions of necrotic tissue only in tumors from mice treated with DNP-CpG-ODN. Collectively, these results show the potential of endogenous IgG to mediate the systemic delivery of CpG-ODN to solid tumors and to enhance their antitumor activity following intravenous administration.
Palma
Enzo
E
Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
Cho
Moo J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004136:Dinitrobenzenes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D004337:Drug Carriers; D006207:Half-Life; D006241:Haptens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D007114:Immunization; D007074:Immunoglobulin G / Q000378:metabolism*; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D004136:Dinitrobenzenes; D004337:Drug Carriers; D006241:Haptens; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides