Nanocarrier-based drug combination therapy for glioblastoma

Abstract

The current achievements in treating glioblastoma (GBM) patients are not sufficient because many challenges exist, such as tumor heterogeneity, the blood brain barrier, glioma stem cells, drug efflux pumps and DNA damage repair mechanisms. Drug combination therapies have shown increasing benefits against those challenges. With the help of nanocarriers, enhancement of the efficacy and safety could be gained using synergistic combinations of different therapeutic agents. In this review, we will discuss the major issues for GBM treatment, the rationales of drug combinations with or without nanocarriers and the principle of enhanced permeability and retention effect involved in nanomedicine-based tumor targeting and promising nanodiagnostics or -therapeutics. We will also summarize the recent progress and discuss the clinical perspectives of nanocarrier-based combination therapies. The goal of this article was to provide better understanding and key considerations to develop new nanomedicine combinations and nanotheranostics options to fight against GBM.

Keywords: EPR effect; glioblastoma; local delivery; nanomedicine; nanoparticles; systemic delivery; theranostics.

Figure 1

Evolution of FDA-approved GBM treatment approaches.

Figure 2

Heterogeneous disruption in GBM. Significant BBB breakdown seen in the bulk tumor region (left panel) allows nanoparticle extravasation. Regions with infiltrating GBM and GSC cells show less or no breakdown of the BBB (middle and right) preventing NPs or other therapeutics to reach these cells.

Figure 3

The EPR effect is influenced by stromal parameters such as dense extracellular matrix (A), hypercellularity (B), hypoxia (C) and high interstitial fluid pressure (D). At blood vessel level (insert), heterogeneity in vascular permeability, tight junction expression (E) and pericyte coverage (F) result in varying clinical manifestations of EPR.

Figure 4

(A) and (B): Radioactive [⁶⁴Cu]CLS/ZnS QDs as PET/self-illuminating luminescence imaging agents show promising in vivo visualization possibilities. Adapted with permission from , copyright 2014 American chemical society.

Figure 5

(A) and (B) Using an exogenous magnetic field to target liposomes loaded with multiple imaging agents and therapeutic drugs to an intracranial tumor. The integrated QDs can be used for fluorescence guided resection. Adapted with permission from , copyright 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.