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CpG-PEG Conjugates and their Immune Modulating Effects after Systemic Administration

Pharmaceutical Research volume 35, Article number: 80 (2018) Cite this article

Abstract

Purpose

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs were found to be able to target cells that express Toll-like receptor 9 to modulate innate and adaptive immune reactions. But their in vivo application in immunotherapy against cancer has not been successful. We attempted in this study to examine polyethylene-glycol (PEG) conjugated CpG ODNs and investigated their mechanism of immune modulation in anti-cancer therapy.

Methods

CpG-PEG conjugates with different PEG lengths were synthesized. In vitro activity as well as in vivo pharmacokinetics and pharmacodynamics properties were evaluated.

Results

CpG-PEG20Ks were found to be able to persist longer in circulation and activate various downstream effector cells. After intravenous injection, they resulted in higher levels of IL-12p70 in the circulation and lower M-MDSC infiltrates in the tumor microenvironment. Such activities were different from those of CpG ODNs without PEGylation, suggesting different PK-PD profiles systemically and locally.

Conclusions

Our data support the development of CpG-PEGs as a new therapeutic agent that can be systemically administered to modulate immune responses and the microenvironment in tumor tissues.

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Abbreviations

ODN:

Oligodeoxynucleotides

CpG:

5’-Cytosine-phosphate-Guanine-3’

PEG:

Polyethylene glycol

CpG-PEG:

PEG conjugated CpG ODNs

IL:

Interleukin

M-MDSC:

M type myeloid derived suppressor cells

PK:

Pharmacokinetics

PD:

Pharmacodynamics

OS:

Overall survival

PFS:

Progression free survival

GalNac:

N-Acetylgalactosamine

DOTAP:

1,2-Dioleoyl-3-trimethylammonium-propane

PEI:

Polyethylenimine

TLR9:

Toll-like receptor 9

CpG-SH:

CpG ODNs containing the sulfhydryl group

HPLC:

High performance liquid chromatography

IgG:

Immunoglobulin G

OVA:

Ovalbumin

IFN-γ:

Interferon gamma

ELISA:

Enzyme-linked immunosorbent assay

BMDCs:

Bone-marrow-derived dendritic cells

DEC-205:

A type I C-type lectin receptor that is expressed on various antigen presenting cell subsets

PBS:

Phosphate-buffered saline

q-PCR:

Quantitative- polymerase chain reaction

EPR:

Enhanced permeability and retention

TCEP:

Tris(2-carboxyethyl)phosphine

TEAA:

Triethylamine and acetic acid

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Author notes

  1. Caixing Wu, Xiaofei Xiang and Yang Yue contributed equally to this work.

Affiliations

  1. Zhejiang-California International NanoSystems Institute, Zhejiang University, Hangzhou, China

    Caixing Wu & Yesen Li

  2. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China

    Xiaofei Xiang, Yang Yue, Lin Li & Chong Zhang

  3. College of Pharmacy and Chemistry, Dali University, Dali, China

    Yuhong Xu

Authors
  1. Caixing Wu
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  2. Xiaofei Xiang
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  4. Lin Li
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  5. Yesen Li
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Correspondence to Yuhong Xu.

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Wu, C., Xiang, X., Yue, Y. et al. CpG-PEG Conjugates and their Immune Modulating Effects after Systemic Administration. Pharm Res 35, 80 (2018). https://doi.org/10.1007/s11095-018-2355-z

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  • DOI: https://doi.org/10.1007/s11095-018-2355-z

Key Words

  • CpG-ODN
  • PEG
  • immune modulation
  • systemic administation