Traceable Nanoparticles with Dual Targeting and ROS Response for RNAi‐Based Immunochemotherapy of Intracranial Glioblastoma Treatment

Abstract

The chemotherapy of glioblastoma is severely hindered by the immunosuppressive tumor microenvironment, especially the tumor growth factor β (TGF‐β), an immunosuppressive cytokine. In this study, it is proposed to employ RNAi‐based immunomodulation to modify the tumor immune microenvironment and improve the effect of chemotherapy. Herein, a nanotheranostic system (Angiopep LipoPCB(Temozolomide+BAP/siTGF‐β), ALBTA) with dual targeting and ROS response is established for intracranial glioblastoma treatment. The traceable nanoparticles exhibit strong siRNA condensation, high drug loading efficiency, good serum stability, and magnetic property. They can efficiently cross the blood–brain barrier and target to glioblastoma cells via receptor‐mediated transcytosis. The zwitterionic lipid (distearoyl phosphoethanol‐amine‐polycarboxybetaine lipid) in ALBTA promotes endosomal/lysosomal escape, and thus enhances the cytotoxicity of temozolomide and improves gene silencing efficiency of siTGF‐β. ALBTA significantly improves the immunosuppressive microenvironment and prolongs the survival time of glioma‐bearing mice. Moreover, ALBTA can be accurately traced by MRI in brain tumors. The study indicates that this immunochemotherapeutic platform can serve as a flexible and powerful synergistic system for treatment with brain tumors as well as other brain diseases in central nervous system.

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

“…RMT is the most commonly adopted strategy, which involves the binding of target ligands conjugated onto the nanoparticle to corresponding receptors expressed on the surface of brain endothelial cells to improve the delivery of loaded therapeutic agents into the brain. [ 2,11–13 ] Recently, several target ligands including transferrin, lactoferrin, and angiopep‐2 have been exploited to cross BBB by receptor‐mediated transcytosis. [ 12,14–16 ] However, the less than 1.0% of the brain accumulation rate of these nanoparticles cannot meet the requirements of clinical use, which is due to the low efficiency of ligand upload on nanoparticles, weak binding ability with receptors, and the competition of high concentration of endogenous ligands in the blood.…”

Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas

“…This strategy has attracted much attention, yet the efficacy of drugs and the pharmacokinetics remain to be confirmed. With the development of nanotechnology and nanomedicine in the recent decades, various drug delivery vehicles, such as liposomes [21][22][23], hydrogels [24], micelles [25,26], polymers [27][28][29] and inorganic nanoparticles [30][31][32][33][34][35] have been developed to incorporate therapeutics and to deliver them into tumor sites and CNS.…”

Hybrid Vesicular Drug Delivery Systems for Cancer Therapeutics

“…Schematic illustration of the synthesis process of dually targeted gene and drug delivery vehicle. Adapted with permission . Copyright 2018, Wiley.…”

“…In the aforementioned system, the positively charged nanoparticles were electrostatically conjugated to siRNA against TGFβ. Afterward, the surfaces of the nanoparticles were coated with maleimide‐functionalized lipid envelopes made of a zwitterionic lipid called distearoyl phosphoethanol‐aminepolycarboxybetaine (DSPE‐PCB), and the final nanoparticle was functionalized with a targeting ligand against angiopep‐2 that could target glioblastoma cells …”