Smart nanocarriers for glioblastoma multiforme (GBM) treatment

Currently, glioblastoma multiforme (GBM) is the most challenging tumour to cure. Although we are increasing our understanding of the mechanisms of GBM tumours, patient life expectancy has not been improved. Chemodynamic therapy (CDT) that modulates reactive oxygen species (ROS) in the tumour microenvironment (TME) to induce tumour cell apoptosis by ROS could provide a new strategy for GBM treatment.

Besides, in recent years, the emergence of gene therapy for GBM treatment has attracted much attention. Gene therapy has significant therapeutic potential to treat various cancers, as it can target the specific gene sequence of diseases with high selectivity. Therefore, the delivery of nano-drugs into the GBM microenvironment to enable CDT or gene therapy represents new ideas for the treatment of GBM.

Systemic administration is of great significance to the treatment of GBM as it will minimize the patient's physical burden. However, the systemic drug delivery efficiency is significantly reduced because of the blood-brain barrier/blood-tumour barrier (BBB/BTB). Nanocarriers can improve the delivery efficiency of anti-cancer drugs and break through the barriers of BBB/BTB.

Thanks to their small size and active transportation, they can be targeted for delivery to the tumour area or used as a gene delivery carrier, specifically targeted signalling pathways, and respond to endogenous stimulus. In this thesis, we developed two types of smart nanocarriers for GBM treatment.

In article 1#, we have developed a biomimetic nanocarrier (CDT agents) that uses simple cross-linking technology to prepare a polymer superstructure as a self-delivery entity, rather than complex encapsulation of proteins in the nanocarriers. The red blood cell (RBC) membrane is camouflaged on the surface of the nanoenzyme structure to facilitate delivery across the BBB/BTB.

The RBC@haemoglobin@glucose oxidase nanoparticles (RBC@Hb@GOx NPs) show excellent biocompatibility, smart responsiveness to TME and satisfactory accumulation at the GBM area. Finally, the as-fabricated can effectively produce toxic ROS and eliminate cancer cells in vitro and in vivo. In manuscript 1#, we developed a novel targeted antisense miRNA-21 oligonucleotide (ATMO-21) delivery system for GBM treatment.

The use of NPs to deliver small inhibiting microRNAs (miRNAs) has shown great promise for treating cancer. However, constructing a miRNA delivery system that targets brain cancers, such as GBM, remains technically challenging due to the existence of the BTB. We found that bradykinin ligand agonist-functionalized spermine-modified acetalated dextran NPs (SpAcDex NPs) could temporarily open the BBB/BTB by activating G-protein-coupled receptors that were expressed in tumour blood vessels and tumour cells, which increased transportation to and accumulation in tumour sites.

ATMO-21 achieved high loading in the SpAcDex NPs (over 90%) and underwent gradual controlled release with the degradation of the NPs in acidic lysosomal compartments. This allowed for, cell apoptosis and inhibition of vascular endothelial growth factor (VEGF) expression by downregulating hypoxia-inducible factor (HIF-1α) protein.

An in vivo orthotopic U87MG glioma model confirmed that the released ATMO-21 shows significant therapeutic efficacy in inhibiting tumour growth and angiogenesis, demonstrating that agonist-modified SpAcDex NPs represent a promising strategy for GBM treatment combining targeted gene therapy and antiangiogenic therapy.

Altogether, the studies presented in this thesis systemically elaborate the different ways of using nanocarriers to cross BBB/BTB and study of different treatment methods for GBM.