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

Rameshwar Patil,Arshia Ramesh,Eggehard Holler,Alexander V Ljubimov,Keith L Black,Mohammad Harun Rashid,Liron L Israel,Saya Davani,Tao Sun,Julia Y Ljubimova

doi:10.3390/nano11112892

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.

Highlights

Glioblastoma (GBM), the deadliest brain cancer, has a very poor prognosis that has not improved in the past 35 years [1,2,3]
We found that epidermal growth factor receptor (EGFR) inhibition in intracranial glioblastoma multiforme (GBM) grown in two xenogeneic mouse models using a poly(β-L-malic) acid (PMLA)-based nanopolymer blocked the expression of c-Myc and other cancer stem cells (CSCs) markers, with a concomitant decrease in PD-L1, the ligand of PD-1 checkpoint [30]
Understanding the biological mechanisms that are implicated in mutations found in gliomas, and the role of the tumor microenvironment and immunosuppression, is vital in designing novel classes of interventions that are safe, efficacious, and can provide a lasting response

Summary

Introduction

Glioblastoma (GBM), the deadliest brain cancer, has a very poor prognosis that has not improved in the past 35 years [1,2,3]. Gliomas have been well-characterized by genomic and molecular marker analysis under The Cancer Genome Atlas (TCGA) project [4,5,6]. These studies have revealed significant GBM heterogeneity, which may necessitate the finding of new treatment targets and novel treatment strategies. The tumor microenvironment including immune cells is another important regulator of malignant growth, mediating tumor invasion and escape from immune surveillance [7]. It serves as a niche for cancer stem cells (CSCs) that

Objectives

Methods

Results

Conclusion