Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response
Received 29 November 2019
Accepted for publication 25 February 2020
Published 6 March 2020 Volume 2020:15 Pages 1499—1515
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Linlin Sun
Peidi Yin, 1 Huifeng Li, 1 Chao Ke, 2 Guangxu Cao, 1 Xiaoqian Xin, 3 Junjiao Hu, 4 Xiangran Cai, 4 Lingfeng Li, 1 Xiaowen Liu, 3 Bin Du 1
1Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, People’s Republic of China; 2Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China; 3Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, People’s Republic of China; 4Medical Imaging Center, The First Affiliated Hospital, Jinan University, Guangzhou 510630, People’s Republic of China
Correspondence: Xiaowen Liu; Bin Du
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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, poly(I:C), intranasal administration, immunogenic cell death, in situ immune response activation
Corrigendum for this paper has been published