Multifunctional Nanopolymers for Blood–Brain Barrier Delivery and Inhibition of Glioblastoma Growth through EGFR/EGFRvIII, c-Myc, and PD-1

Abstract

Glioblastoma (GBM) is the most prevalent primary brain cancer in the pediatric and adult population. It is known as an untreatable tumor in urgent need of new therapeutic approaches. The objective of this work was to develop multifunctional nanomedicines to treat GBM in clinical practice using combination therapy for several targets. We developed multifunctional nanopolymers (MNPs) based on a naturally derived biopolymer, poly(β-L-malic) acid, which are suitable for central nervous system (CNS) treatment. These MNPs contain several anticancer functional moieties with the capacity of crossing the blood–brain barrier (BBB), targeting GBM cells and suppressing two important molecular markers, tyrosine kinase transmembrane receptors EGFR/EGFRvIII and c-Myc nuclear transcription factor. The reproducible syntheses of MNPs where monoclonal antibodies are replaced with AP-2 peptide for effective BBB delivery were presented. The active anticancer inhibitors of mRNA/protein syntheses were Morpholino antisense oligonucleotides (AONs). Two ways of covalent AON-polymer attachments with and without disulfide bonds were explored. These MNPs bearing AONs to EGFR/EGFRvIII and c-Myc, as well as in a combination with the polymer-attached checkpoint inhibitor anti-PD-1 antibody, orchestrated a multi-pronged attack on intracranial mouse GBM to successfully block tumor growth and significantly increase survival of brain tumor-bearing animals.

Zinc Oxide Nanorods for Light-Activated Gas Sensing and Photocatalytic Applications

“…The design of advanced nanomaterials , for various high-technology assets such as sensors, , light-emitting diodes, energy harvesting and converting devices, , electronics, transportation, , biomedical devices, – electronic equipment for aerospace technology, , satellite technology, and other applications has been becoming a topic of growing interest. Particularly, this is driven by the growing need for environmental protection and monitoring of ecological situations under extremely severe conditions in highly polluted and poisoned areas.…”

A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach

“…This facilitates receptor-mediated transcytosis of LNP through the BBB and into the brain extracellular space 187 . Notably, multifunctional nanopolymers (MNPs) have been also used for the therapy of CNS owing to the capacity to cross the BBB 188 . Remarkably, Sun et al have studied the application of a CNS-selective delivery system, employing saposin C-dioleoylphosphatidylserine (DOPS) nanovesicles for neuronopathic GD therapy and revealed that the administration of a saposin C-DOPS-GCase successfully delivers functional GCase across a range of tissues, with a pronounced affinity for the brain 189 .…”

Designing Gold Nanoparticles for Precise Glioma Treatment: Challenges and Alternatives

“…Therefore, the need for more effective and less toxic treatments remains a pressing concern in the scientific and clinical communities. Current and continuous research endeavors hold the promise of uncovering novel strategies to address the complexities of GBM treatment [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Researchers are actively engaged in exploring novel strategies that could provide more effective and advanced solutions for managing the complex and aggressive GBM tumor, including boron neutron capture therapy (BNCT).…”