Targeted Nanotechnology in Glioblastoma Multiforme

Abstract

Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs.

Keywords: blood–brain barrier; cancer stem cell; glioma; nanomedicine; nanotechnology; targeted therapy.

FIGURE 1

The blood-brain barrier (BBB) and the glioblastoma multiform (GBM) niche. The BBB is selective and restrictive to a variety of molecules. Endothelial cells and the basement membrane, together with strong lateral tight junctions, maintain the selective permeability. A possible strategy to reach the glioma core is to use nanocarriers coupled with target guiding molecules that, for example, bind to the membrane receptors of both tumor niche infiltrated BBB or healthy BBB, and which carry nanomedicines. Glioblastoma is composed of heterogeneous cell populations and the cancer stem cells are responsible for treatment resistance.

FIGURE 2

Nanocarrier characteristics. Nanocarriers have four main features: a shell that can vary in type, length, density and crosslinking molecules; a core, which can be hydrophobic, anionic or cationic depending on which crosslinked molecule needs to be carried; surface targeting molecules which can be antibodies, proteins, vitamins, peptides and aptamers; and lastly the cargo, which can be chemotherapeutics, nucleic acids, proteins, fluorophores or other imaging dyes. Usually nanocarriers are divided into five subtypes: liposomes (lipid bilayer structures), polymeric micelles (lipid monolayers), dendrimers (highly branched structures), and nanoparticles (organic or inorganic). Recently, new strategies have focused on carrying bio-cargoes, such as plasmids coding for proteins involved in programmed cell death or agents to silence the genes important for the cancer stem cell survival through genetic knockout using the CRISPR/CAS9 system or genetic knockdown using siRNAs.

FIGURE 3

Proposed strategy. This proposed therapeutic strategy targeting the GBM cancer stem cells (CSCs) as a novel treatment, would use liposomes as nanocarriers, because they can shield and carry molecules of different sizes and charges. Liposomes, with a shell coated using aptamers or antibodies specific to CSC markers, such as CD133, CD15, CD44, integrin-α6, or A2B5, would carry antitumor antibiotics (doxorubicin) or genome editing tools such as SOX2, TRAIL, miR-124, miR-137, and IFN-β, to modulate tumor survival/death gene expression. Alternatively, the use of gold nanoparticles targeting brain markers, like glial fibrillary acidic protein, is recommended to bypass the BBB and deliver genome editing tools.