Diagnostic and Therapeutic Approaches for Glioblastoma and Neuroblastoma Cancers Using Chlorotoxin Nanoparticles

Abstract

Glioblastoma multiforme (GB) and high-risk neuroblastoma (NB) are known to have poor therapeutic outcomes. As for most cancers, chemotherapy and radiotherapy are the current mainstay treatments for GB and NB. However, the known limitations of systemic toxicity, drug resistance, poor targeted delivery, and inability to access the blood-brain barrier (BBB), make these treatments less satisfactory. Other treatment options have been investigated in many studies in the literature, especially nutraceutical and naturopathic products, most of which have also been reported to be poorly effective against these cancer types. This necessitates the development of treatment strategies with the potential to cross the BBB and specifically target cancer cells. Compounds that target the endopeptidase, matrix metalloproteinase 2 (MMP-2), have been reported to offer therapeutic insights for GB and NB since MMP-2 is known to be over-expressed in these cancers and plays significant roles in such physiological processes as angiogenesis, metastasis, and cellular invasion. Chlorotoxin (CTX) is a promising 36-amino acid peptide isolated from the venom of the deathstalker scorpion, Leiurus quinquestriatus, demonstrating high selectivity and binding affinity to a broad-spectrum of cancers, especially GB and NB through specific molecular targets, including MMP-2. The favorable characteristics of nanoparticles (NPs) such as their small sizes, large surface area for active targeting, BBB permeability, etc. make CTX-functionalized NPs (CTX-NPs) promising diagnostic and therapeutic applications for addressing the many challenges associated with these cancers. CTX-NPs may function by improving diffusion through the BBB, enabling increased localization of chemotherapeutic and genotherapeutic drugs to diseased cells specifically, enhancing imaging modalities such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), optical imaging techniques, image-guided surgery, as well as improving the sensitization of radio-resistant cells to radiotherapy treatment. This review discusses the characteristics of GB and NB cancers, related treatment challenges as well as the potential of CTX and its functionalized NP formulations as targeting systems for diagnostic, therapeutic, and theranostic purposes. It also provides insights into the potential mechanisms through which CTX crosses the BBB to bind cancer cells and provides suggestions for the development and application of novel CTX-based formulations for the diagnosis and treatment of GB and NB in the future.

Keywords: blood-brain-barrier (BBB); chlorotoxin (CTX); glioblastoma (GB); matrix metalloproteinase 2 (MMP-2); nanoparticles (NPs); neuroblastoma (NB).

Figure 1

The characteristics and therapeutic challenges associated with glioblastoma (Figure adapted with permission from Bastiancich, Da Silva, and Estève 2021, Frontiers in Oncology, image created using BioRender.com).

Figure 2

Proposed molecular targets for CTX. CTX is isolated from the venom of the deathstalker scorpion (Leiurus quinquestriatus) (a) and is composed of a 36-amino acid peptide stabilized by four disulfide bonds (b). CTX has been shown to block Cl- channels and bind to overexpressed cell surface receptors found in various tumors such as: ClC-3, MMP-2, Annexin A2, NRP-1, and ERα (c), all these receptors interact with CTX and ultimately contribute to an overall inhibition/suppression of cellular growth and migration (d) (Image created with BioRender.com).

Figure 3

Summary of CTX-NPs for diagnostic and therapeutic potential. Different classes of NPs are synthesized (a) and designed to be target specific for cancer cells through surface functionalization with CTX peptide and other targeting molecules (b). CTX-NPs have applications in diagnostic and therapeutic fields, where the two overlap NPS are considered as having theranostic applications (c). The image was created using BioRender.com.

Figure 4

Principle of localized nanoparticle-mediated hyperthermia in cancer cells. Metallic NPs (e.g., AuNPs, PtNPs, or bimetallic NPs) or magnetic NPs (e.g., IONPs/SIONPs) (a) are designed to target specific cancer cells that overexpress specific cell surface receptors and allow intracellular uptake of NPs through receptor-mediated endocytosis (b). Cells are exposed to an external heating source (e.g., NIR light, AMF, and RF-fields) (c) which induces local heating (41–47 °C) (d) and results in thermal destruction of cells through mitochondrial swelling, protein denaturation, alteration in signal transduction, cell rupturing and induction of necrosis/apoptosis (e).