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

Abstract

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 Du1 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 ChinaCorrespondence: Xiaowen Liu; Bin Du Email [email protected]; [email protected]: 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

Keywords

• aunps
• poly (i:c)
• intranasal administration
• immunogenic cell death
• in situ immune response activation