iRGD Modified Chemo‐immunotherapeutic Nanoparticles for Enhanced Immunotherapy against Glioblastoma

Abstract

Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8+ T lymphocytes and inhibit CD4+ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma.

Through Scalp and Skull NIR‐II Photothermal Therapy of Deep Orthotopic Brain Tumors with Precise Photoacoustic Imaging Guidance

“…To construct efficient brain tumor treatment paradigms, so far, most efforts have been devoted to developing advanced therapeutic systems such as chemo and gene therapy . These methods strongly rely on sophisticated design of drug delivery systems (DDS) to transport drug/gene into tumors and realize release in a controlled manner.…”

“…These methods strongly rely on sophisticated design of drug delivery systems (DDS) to transport drug/gene into tumors and realize release in a controlled manner. However, the DDS accumulation in normal tissues often leads to unwanted side‐effects . In addition, GBM cells can rapidly develop drug resistance, which causes limitations of the available therapeutics .…”

Supramolecular Immunotherapy of Cancer Based on the Self‐Assembling Peptide Design

“…The diameter of the nanoparticles remained almost unchanged after 48 h of incubation in water, Dulbecco's modified Eagle's medium (DMEM), and PBS containing 10% fetal bovine serum, demonstrating Reproduced with permission. [69] Copyright 2018, Wiley-VCH. Figure 8.…”

Injectable Biomaterials for Treatment of Glioblastoma

“…[ 84 ] Another nanoscale formulation promoting antitumor immunity is mesoporous silica nanoparticles that target the BBB/tumor and deliver immune checkpoint inhibitor 1‐methyltryptophan to orthotopic GBM tumors. [ 85 ] While IV administration of these technologies has its benefits, limitations include biodistribution in nontarget tissues possibly attributed to inter‐ and intratumoral variability of vascular permeability and expression of the target ligand. [ 86 ] Nanoparticle circulation also alters the drug dose delivery as nanoparticles are subject to clearance (both renal and immune).…”