Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response

Int J Nanomedicine. 2020 Mar 6:15:1499-1515. doi: 10.2147/IJN.S240551. eCollection 2020.

Abstract

Purpose: Some chemotherapeutics have been shown to induce both the release of damage-associated molecular patterns (DAMPs) and the production of type I interferon (IFN-I), leading to immunogenic cell death (ICD). However, the standard chemotherapy drug for glioma, temozolomide (TMZ), cannot induce ICD as it cannot activate IFN-I signaling. Moreover, inefficient delivery of immunostimulants across the blood-brain barrier (BBB) is the main obstacle to overcome in order to induce local immune responses in the brain.

Methods: A new oligonucleotide nanoformulation (Au@PP)/poly(I:C)) was constructed by coating gold nanoparticles (AuNPs) with methoxypolyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP) followed by inducing the formation of electrostatic interactions with polyinosinic-polycytidylic acid (poly(I:C)). Intracranial GL261 tumor-bearing C57BL/6 mice were used to explore the therapeutic outcomes of Au@PP/poly(I:C) plus TMZ in vivo. The anti-tumor immune response in the brain induced by this treatment was analyzed by RNA sequencing and immunohistochemical analyses.

Results: Au@PP/poly(I:C) induced IFN-I production after endocytosis into glioma cells in vitro. Additionally, Au@PP/poly(I:C) was efficiently accumulated in the glioma tissue after intranasal administration, which allowed the nanoformulation to enter the brain while bypassing the BBB. Furthermore, Au@PP/poly(I:C) plus TMZ significantly improved the overall survival of the tumor-bearing mice compared with group TMZ only. RNA sequencing and immunohistochemical analyses revealed efficient immune response activation and T lymphocyte infiltration in the Au@PP/poly(I:C) plus TMZ group.

Conclusion: This study demonstrates that intranasal administration of Au@PP/poly(I:C) combined with TMZ induces ICD, thereby stimulating an in situ immune response to inhibit glioma growth.

Keywords: AuNPs; immunogenic cell death; in situ immune response activation; intranasal administration; poly(I:C).

MeSH terms

  • Administration, Intranasal
  • Animals
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / immunology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Delivery Systems
  • Female
  • Glioma / drug therapy*
  • Glioma / immunology*
  • Gold / therapeutic use
  • Humans
  • Interferon Type I / metabolism
  • Metal Nanoparticles / administration & dosage*
  • Metal Nanoparticles / therapeutic use*
  • Metal Nanoparticles / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • Poly I-C / chemical synthesis
  • Poly I-C / chemistry
  • Polyethylene Glycols / chemical synthesis
  • Polyethylene Glycols / chemistry
  • Polyethyleneimine / chemical synthesis
  • Polyethyleneimine / chemistry
  • Survival Analysis
  • T-Lymphocytes / drug effects
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use

Substances

  • Interferon Type I
  • Polyethylene Glycols
  • Gold
  • Polyethyleneimine
  • monomethoxypolyethylene glycol
  • Poly I-C
  • Temozolomide

Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81872893 to BD; 81903546 to XWL), the Fundamental Research Fund for the Central Universities (Grant Nos. 21617462) the Guangzhou Science Technology and Innovation Commission (Grant Nos. 201707010099) and the College Students’ Innovative Entrepreneurial Training Plan Program (Grant Nos. S201910559050).