Drug delivery in glioblastoma therapy: a review on nanoparticles targeting MGMT-mediated resistance

ABSTRACT

Introduction

Glioblastoma multiforme (GBM) is the deadliest type of brain cancer with poor response to the available therapies, mainly due to intrinsic resistance mechanisms. Chemotherapy is based on alkylating agents, but DNA-repair mechanisms can revert this cytotoxic effect. O⁶-methylguanine-DNA methyltransferase (MGMT) protein is the primary mechanism for GBM resistance. Therefore, different strategies to suppress its activity have been explored. However, their clinical use has been hindered due to the high toxicity of MGMT inhibitors verified in clinical trials.

Areas covered

This review article aims to provide the current progress in the development of novel drug delivery systems (DDS) to overcome this resistance. Here, we also review the current knowledge on MGMT-mediated resistance and the clinical outcomes and potential risks of using MGMT inhibitors.

Expert opinion

To overcome therapeutic limitations, nano-based approaches have been proposed as a suitable solution to improve drug accumulation in the brain tumor tissue and decrease systemic toxicity. DDS to overcome MGMT-mediated resistance in GBM have been mostly developed to deliver MGMT inhibitors and for gene therapy to modulate MGMT gene expression.

KEYWORDS:

• Brain delivery
• nanomedicine
• nanoparticles
• brain tumor
• drug resistance
• MGMT gene promoter
• MGMT protein

Article highlights

• MGMT-mediated resistance limits therapeutic success in GBM patients

• Concomitant therapy of alkylating agents and MGMT inhibitors enhance sensitivity to treatment

• MGMT inhibitors exacerbate the toxicity of alkylating agents in the healthy tissues

• Brain tumor-targeting NPs can reduce systemic toxicity and enhance the therapeutic success

• Further development is required to introduce DDS targeting MGMT-resistance to the clinical practice

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed receipt of research funding from NIH and is a co-owner for Accelerating Combination Therapies*. Ashvattha Therapeutics Inc. has also licensed one of her patents (*includes equity or options). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by LA/P/0045/2020 (ALiCE), UIDB/00511/2020 and UIDP/00511/2020 (LEPABE), funded by national funds through FCT/MCTES (PIDDAC); Project 2SMART - engineered Smart materials for Smart citizens, with reference NORTE-01-0145-FEDER-000054, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); FCT supported J.A.L under the Scientific Employment Stimulus - Institutional Call - [CEECINST/00049/2018] and M.J. Ramalho under the Scientific Employment Stimulus - Individual Call – (CEECIND/01741/2021); and Prize Maratona da Saúde for Cancer Research.