Chemodynamic Therapy of Glioblastoma Multiforme and Perspectives

Abstract

Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood-brain barrier (BBB) to reach the GBM is another endless marathon. In this review, the physiology of the BBB has been elaborated to understand the mechanism of crossing these potential barriers to treat GBM. Moreover, the designing of Fenton-based nanomaterials has been discussed for the production of reactive oxygen species in the tumor area to eradicate the cancer cells. For effective tumor targeting, biological nanomaterials that can cross the BBB via neurovascular transport channels have also been explored. To overcome the neurotoxicity caused by inorganic nanomaterials, the use of smart nanoagents having both enhanced biocompatibility and effective tumor targeting ability to enhance the efficiency of CDT are systematically summarized. Finally, the advancements in intelligent Fenton-based nanosystems for a multimodal therapeutic approach in addition to CDT are demonstrated. Hopefully, this systematic review will provide a better understanding of Fenton-based CDT and insight into GBM treatment.

Keywords: Fenton reaction; Fenton-based nanomaterials; chemodynamic therapy; glioblastoma multiforme; reactive oxygen species.

Scheme 1

Schematic illustration of Fenton-based CDT of GBM by applying biocompatible smart nanomaterials to cross the BBB through vascular transport channels for effective targeted therapy.

Figure 1

Schematic representation of BBB and structure of transport pathways across the BBB. (A) Diagrammatic representation of potential BBB of the neurovascular system. (B) The complicated junctional complex of the BBB: (I) tight junctions; (II) adherents junctions; (III) GAP junctions [23]. Reused under Creative Commons Attribution License. (C) The structure of major BBB transport pathways present in the neurovascular system. The transport pathways include carrier-mediated transport, receptor-mediated transport, ion transport, and active flux [24]. Reused under Creative Commons Attribution License.

Figure 2

(A) Schematic demonstration of the in vivo multimodal sequential CDT based on mitochondria targeting nanomaterials. The level of endogenous H₂O₂ was elevated through the activation of NOX-associated cascade reaction via bioactive cisplatin. The Fe-based nanocomposite subsequently catalyzed H₂O₂ into toxic ^•OH to induce autophagy and inhibited tumor progression. (B) Chemical structure of bioactive cisplatin (DEPE-PEG_2k-Pt (IV)) [43]. Reproduced with permission from [43] Copyrights 2021, WILEY. (C) Schematic representation of cancer therapy catalyzed by Fe-based nanomaterials [44]. Reproduced with permission from [44] Copyrights 2020, WILEY. (D) ESR spectrum of ¹O₂ entrapped by TEMP [45]. Reproduced with permission from [45] Copyrights 2020, AMERICAN CHEMICAL SOCIETY.

Figure 3

(A) Diagrammatic representation of Fe-based nanozyme preparation and enzyme-based cascade initiation by angiopep-2 and Fe-based nanozyme modification for ROS generation to induce the lysosome-based autophagy for the therapy of GBM. (B) Diagrammatic representation of enzymatic mimicking via Fe-based nanozyme. The removal process of H₂O₂ by using Fe-based nanozyme with increased properties like GPx under the glutathione reductase coupled process. (C) Fluorescence images of nude mice bearing orthotopic tumor following treatment different samples. (D) Demonstration of the changes in the body weight of the tumor-bearing mice after the treatment with Fe-based nanozymes. (n  =  6, one-way ANOVA and Tukey multiple comparisons tests, ** p < 0.05, *** p < 0.001) (E) Demonstration of the survival rates of the tumor-bearing mice after the treatment with Fe-based nanozymes [66]. Reproduced with permission from [66] Copyrights 2022, ELSEVIER.

Figure 4

(A) Diagrammatic representation of employing Cu-based nanomaterials for cuproptosis and CDT. (B) The generation of ROS by the Cu-based nanomaterial at different concentrations. (C) After treatment by Cu-based nanomaterials, the tumor volume curve of the tumor-bearing mice. (Scale bar: 25 μm) (D) After treatment by Cu-based nanomaterials, the body weight of the tumor-bearing mice. (E) Demonstration of therapeutic efficiency of the Cu-based nanomaterials [71]. Reproduced with permission from [71] Copyrights 2024, AMERICAN CHEMICAL SOCIETY.

Figure 5

(A) Graphical representation of localized NIR-II laser-assisted CDT post-craniectomy. The laser excitation increased the temperature and further accelerated the Fenton reaction to speed up the production of ^•OH. The extra ROS production induced mitochondrial polarization and causes cell apoptosis. (B) In vivo IR thermal images of the orthotopic GBM area pre- and post-excitation by 1064 nm laser. (C) Changes in the body weight of mice bearing orthotopic GBM, signal intensity of semiquantitative bioluminescence in the brain, inhibition analysis of mean tumor, and analysis of survival rates of mice bearing orthotopic GBM in each group. (D) Demonstration of bioluminescence images of mice bearing orthotopic U87MG tumor from each group [52]. Reproduced with permission from [52] Copyrights 2022, ELSEVIER.

Figure 6

(A) Diagrammatic representation of Mn-based for image-guided multimodal chemotherapy/CDT for the treatment of GBM. (B) Transmission electron microscopy images demonstrating the structure of Mn-based nanomaterials at different pH levels. (C) In vitro MRI T₁ map of Mn-based nanomaterials at different concentrations. (D) T₂-weighted MRI figures of GBM within two weeks after treatment with different Mn-based nanomaterials [47]. Reproduced with permission from [47] Copyrights 2020, WILEY.

Figure 7

(A) Diagrammatic representation of the therapeutic process of applying smart nanomaterials for multimodal GBM therapeutic modality. (B) The in vitro photothermal therapy setup sample model and the IR thermal images of smart nanomaterials at different intervals. (C) ^•OH production in various conditions. (D) Demonstration of the tumor volume after treatment for 9 days. (E) In vivo MRI of the mice bearing tumor [83]. Reused under Creative Commons Attribution License.