Targeted Theranostic Nanoparticles for Brain Tumor Treatment

Abstract

The poor prognosis and rapid recurrence of glioblastoma (GB) are associated to its fast-growing process and invasive nature, which make difficult the complete removal of the cancer infiltrated tissues. Additionally, GB heterogeneity within and between patients demands a patient-focused method of treatment. Thus, the implementation of nanotechnology is an attractive approach considering all anatomic issues of GB, since it will potentially improve brain drug distribution, due to the interaction between the blood⁻brain barrier and nanoparticles (NPs). In recent years, theranostic techniques have also been proposed and regarded as promising. NPs are advantageous for this application, due to their respective size, easy surface modification and versatility to integrate multiple functional components in one system. The design of nanoparticles focused on therapeutic and diagnostic applications has increased exponentially for the treatment of cancer. This dual approach helps to understand the location of the tumor tissue, the biodistribution of nanoparticles, the progress and efficacy of the treatment, and is highly useful for personalized medicine-based therapeutic interventions. To improve theranostic approaches, different active strategies can be used to modulate the surface of the nanotheranostic particle, including surface markers, proteins, drugs or genes, and take advantage of the characteristics of the microenvironment using stimuli responsive triggers. This review focuses on the different strategies to improve the GB treatment, describing some cell surface markers and their ligands, and reports some strategies, and their efficacy, used in the current research.

Keywords: active targeting; glioblastoma; gold nanoparticles; lipid nanoparticles; nanotechnology; theranostics.

Figure 1

Brain tumor structure and therapeutic brain delivery strategies for targeting the physiological blood–brain barrier (BBB), including transcellular lipophilic diffusion, paracellular hydrophobic diffusion, carrier mediated endocytosis, ATP-binding cassette (ABC)-transporters, adsorptive mediated transcytosis and receptor mediated endocytosis. In addition, it is represented the tumor microenvironment with tumor cells, glioma stem cells, CD4⁺ helper T cells, CD8⁺ cytotoxic T cells, fibroblasts, macrophages, growth factors, enzymes and proteins.

Figure 2

Intracellular pathways of cell entry for charged-cell penetrating peptides (CPPs): (A) Transient toroid pore formation; (B) membrane potential; (C) adaptative translocation; (D) micropinocytosis; and (E) clathrin-mediated endocytosis and caveolae/lipid raft-mediated endocytosis.

Figure 3

Morphology and permeability phases of the BBTB.

Figure 4

Tumor-associated macrophages (TAMs) in tumor microenvironment: macrophages phenotypic differentiation into either M1 or M2 subtype. M2 is the subtype of TAM involved in tumorigenesis and description of receptors, chemokines, cytokines and growth factor as targeting approaches [161].

Figure 5

Glioma stem cells (GSCs) mechanistic process, including proliferation, self-renewal, multidifferentiation and tumorigenic capability, and possible surface markers/pathways for targeting approaches [145,185,186,187,188,189,190].

Figure 6

Influence of the targeting approach on GSC function. The application of conventional therapies (A) lead to resistance of GSCs (B). GSCs cells, which are present in the specific perivascular niches, restart their growth process and develop tumor cells, due to their high number of surface markers, differentiation markers, and distinctive stimuli, such as cytokines, growth factors and the angiogenesis process (C). In this context, a targeting approach strategy involving the binding to the surface markers or cytokines, which are responsible for tumor growth or cytokines inhibition, may be an excellent strategy against GSCs (D), avoiding tumor recurrence (E).

Figure 7

Strategies to enhance the permeability of the blood–brain barrier for treatment of GB.

Figure 8

Schematic representation of core–shell nanostructures and possible modifications (Reprinted from [260] with permission from Elsevier, 2018).

Scheme 1

The main goal of the use of theranostic NPs.

Figure 9

Two prototypes of theranostic nanoparticles, combining lipid nanoparticles and gold nanoparticles, with characteristics such as small size (<100 nm), active targeting (tumor targeting and cell penetrating peptides) and a stimuli-responsive targeting (pH or temperature): (A) AuNPs attached on the NPs surface by electrostatic interaction; and (B) AuNPs with lipophilic characteristics encapsulated in NPs.

Scheme 2

Personalized medicine strategy considering the use of theranostic nanoparticles.