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Published on: March 8, 2018
Improved systemic pharmacokinetics, biodistribution, and antitumor activity of CpG oligodeoxynucleotides complexed to
1Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
Abstract:
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.
Insights
Dinitrophenylated CpG-oligodeoxynucleotides (CpG-ODNs) show improved tumor accumulation and enhanced antitumor immunity by utilizing endogenous IgG as a drug carrier. This novel approach overcomes rapid clearance and low tumor delivery issues of standard CpG-ODNs for cancer immunotherapy.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- CpG oligodeoxynucleotides (CpG-ODNs) are potent immune stimulants but exhibit poor therapeutic outcomes due to rapid clearance and low tumor accumulation after intravenous administration.
- Enhancing the pharmacokinetic profile and tumor targeting of CpG-ODNs is crucial for improving their efficacy in cancer immunotherapy.
Purpose of the Study:
- To investigate the potential of using endogenous immunoglobulin G (IgG) as a systemic drug carrier to improve CpG-ODN delivery and antitumor activity.
- To evaluate the pharmacokinetics, tumor accumulation, and therapeutic efficacy of dinitrophenyl (DNP)-conjugated CpG-ODNs in a murine colorectal tumor model.
Main Methods:
- Tritium-labeled CpG-ODNs conjugated with dinitrophenyl (DNP) haptens (DNP- and DNP(2)-[(3)H]-CpG-ODN) were administered intravenously to DNP-immunized mice bearing CT26 colorectal tumors.
- Pharmacokinetic and biodistribution studies were performed using liquid scintillation analysis of serum and tissue samples.
- Antitumor efficacy was assessed by monitoring tumor volume, and macroscopic and histological examination of tumors following repeated dosing.
Main Results:
- DNP-conjugated CpG-ODNs demonstrated a significant increase in systemic exposure (900-1650 fold) and half-life (100-300 fold) compared to unconjugated CpG-ODNs.
- Systemic clearance was markedly reduced (750-1500 fold), and tissue distribution decreased (13-37 fold), indicating improved systemic retention.
- Substantial and sustained tumor accumulation (approx. 30% injected dose/g) was observed for DNP-CpG-ODN, leading to up to 60% tumor growth inhibition and significant tumor necrosis.
Conclusions:
- Endogenous IgG can effectively mediate the systemic delivery of CpG-ODNs to solid tumors when conjugated with appropriate haptens like DNP.
- This IgG-mediated delivery strategy significantly enhances CpG-ODN pharmacokinetics, tumor accumulation, and antitumor efficacy, offering a promising approach for cancer immunotherapy.
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