<p>Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response</p>

Abstract

Purpose: Some chemotherapeutics have been shown to induce both the release of damageassociated 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 tumorbearing 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.

A systematic review on poly(I:C) and poly-ICLC in glioblastoma: adjuvants coordinating the unlocking of immunotherapy

“…Although predominantly associated with poly(I:C)-mediated immune cell activation, poly(I:C)/poly-ICLC also induces type I IFN gene transcription and subsequent secretion of IFN-α and IFN-β by both human and murine GBM cells [ 28 – 40 ]. Surprisingly, poly(I:C) did not initiate IFN-β transcription in C6 rat glioma cells and some human GBM cell lines [ 41 , 42 ].…”

“…Of note, two reports showed a stronger IFN-β secretion upon targeting poly(I:C) to its cytosolic receptors rather than to TLR-3 [ 28 , 31 ], suggesting that the robustness of the poly(I:C)-induced type I IFN response might depend on which receptor pathway is primarily targeted. Nonetheless, promoting endocytosis in murine GBM cells also elevated IFN-β secretion [ 40 ]. Besides type I IFN, poly(I:C) also characteristically induces a release of pro-inflammatory cytokines [ 6 ].…”

“…Similar to the induction of pro-inflammatory cytokines, poly(I:C) elicits the secretion of chemokines from GBM cells which can attract tumorlytic lymphocytes. Poly(I:C)/poly-ICLC, targeted to either receptor pathway, stimulates GBM cell secretion of CXCL8, CXCL9, CXCL10, CCL2, CCL4 and CCL5 [ 29 – 34 , 37 – 40 , 45 ]. In transwell assays using supernatant of poly(I:C)-treated pGBM, chemoattraction of CD8 + and CD4 + T cells, but not NK cells, was increased in a manner that suggested involvement of those ligands for CCR5 and CXCR3 [ 30 ].…”

“…While poly(I:C) did not affect the susceptibility of U87 cells, it protected normal human brain cells from viral infection, replication and induced cell death [ 42 , 52 ]. Protection against VSV-rp30a is possibly conferred by MX1, a cellular antiviral protein that is profoundly induced by poly(I:C) in normal brain cells but barely modulated in GBM cells [ 40 , 42 ]. These observations argue for the adjuvant use of poly(I:C) in oncolytic virotherapy in order to protect healthy brain cells, though protection should be established upfront.…”

The Influence of Size and Chemical Composition of Silver and Gold Nanoparticles on in vivo Toxicity with Potential Applications to Central Nervous System Diseases

“…GNPs with sizes ranging from 10 to 30 nm, and modified with mRNAs 80 , 86 and polymers 17 have also shown beneficial effects on GBM. Ruan et al have reported three systems based on 40 nm GNPs that improved the median survival time of C6 glioma-bearing mice.…”