Engineering Biomimetic Carriers as Gene Editing Platforms for Treating Brain Tumors

Date
2022
Authors
Rodgers, Tina Marie
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Abstract

Glioblastoma Multiforme (GBM) is the most common, aggressive, and lethal form of brain cancer. GBM tumor is made of small populations of glioblastoma stem cells (GSCs), which are responsible for chemotherapeutic resistance, tumorigenic activity, and relapse during treatment. Existing GBM therapy consist of surgical resection with succeeding localized radiation therapy and chemotherapy. The blood brain barrier (BBB) is the largest biological challenge to overcome in the treatment of GBM. This semi-permeable membrane is highly selective, limiting the blood borne particles allowed to cross. Unlike chemotherapy, gene editing therapy can manipulate the genome to kill cancer cells, protect healthy tissue and improve immune response to a tumor. Unfortunately, exogeneous plasmids cannot penetrate mammalian cells. Here, we designed and synthesized a polymeric non-viral carrier to deliver gene editing tools across a 3D BBB in vitro model and into glioblastoma cells. Poly (β-amino ester) nanoparticles (PEG-PDHA NPs) are fabricated and surface functionalized with the rabies virus glycoprotein for mimicking rabies virus (RV) transient pathway across the BBB. The genetic tools piggyBAC transposon (PBCAG-eGFP) and achaete-scute family bHLH transcription factor 1 CRISPR guide RNA (ASCL1-gRNA) are encapsulated into PEG-PDHA NPs and RV-like NPs, respectively. PBCAG-eGFP is used as a model plasmid for optimization of the nanoformulation, while ASCL1-gRNA is used as therapeutic to restore neuronal lineage potential, promote terminal differentiation, and attenuate tumorigenicity in GBM. The RV-like NPs system developed here is capable to deliver ASCL1-gRNA across a 3D in vitro model of the BBB and into glioblastoma cells at an efficiency of 12%, causing non-cytotoxic effects and outperforming commercially available Lipofectamine 3000 reagent.

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Keywords
Glioblastoma multiforme
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Department
Biomedical Engineering