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Pharmaceutical Research

, 35:80 | Cite as

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

  • Caixing Wu
  • Xiaofei Xiang
  • Yang Yue
  • Lin Li
  • Yesen Li
  • Chong Zhang
  • Yuhong Xu
Research Paper
  • 198 Downloads

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.

Key Words

CpG-ODN PEG immune modulation systemic administation 

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Zhejiang-California International NanoSystems InstituteZhejiang UniversityHangzhouChina
  2. 2.School of PharmacyShanghai Jiao Tong UniversityShanghaiChina
  3. 3.College of Pharmacy and ChemistryDali UniversityDaliChina

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