Current advances in temozolomide encapsulation for the enhancement of glioblastoma treatment

Abstract

Glioblastoma is the most common and lethal brain tumor in adults. The incorporation of temozolomide (TMZ) into the standard treatment has increased the overall survival rate of glioblastoma patients. Since then, significant advances have been made in understanding the benefits and limitations of TMZ. Among the latter, the unspecific toxicity of TMZ, poor solubility, and hydrolyzation are intrinsic characteristics, whereas the presence of the blood-brain barrier and some tumor properties, such as molecular and cellular heterogeneity and therapy resistance, have limited the therapeutic effects of TMZ in treating glioblastoma. Several reports have revealed that different strategies for TMZ encapsulation in nanocarriers overcome those limitations and have shown that they increase TMZ stability, half-life, biodistribution, and efficacy, offering the promise for future nanomedicine therapies in handling glioblastoma. In this review, we analyze the different nanomaterials used for the encapsulation of TMZ to improve its stability, blood half-life and efficacy, paying special attention to polymer- and lipid-based nanosystems. To improve TMZ drug resistance, present in up to 50% of patients, we detail TMZ combined therapeutic with i) other chemotherapies, ii) inhibitors, iii) nucleic acids, iv) photosensitizers and other nanomaterials for photodynamic therapy, photothermal therapy, and magnetic hyperthermia, v) immunotherapy, and vi) other less explored molecules. Moreover, we describe targeting strategies, such as passive targeting, active targeting to BBB endothelial cells, glioma cells, and glioma cancer stem cells, and local delivery, where TMZ has demonstrated an improved outcome. To finish our study, we include possible future research directions that could help decrease the time needed to move from bench to bedside.

Keywords: encapsulation; glioblastoma; nanosystems; targeted delivery; temozolomide.

Figure 1

Limitations of current TMZ treatment that need to be overcome to improve its efficacy. TMZ features include its poor solubility, its hydrolyzation in contact with physiological medium and its unspecific toxicity. Tumor intrinsic features include inter- and intratumoral cell and molecular heterogeneity, drug resistance, and the blood-brain barrier.

Figure 2

Summary of different possibilities for TMZ encapsulation

Figure 3

Schematic illustration of combined therapeutical approaches with TMZ for GBM treatment, including i) other chemotherapies, ii) inhibitors, iii) nucleic acids, iv) alternative treatments, such as photodynamic therapy, photothermal therapy, and magnetic hyperthermia, v) immunotherapy, and vi) other less-explored molecules.

Figure 4

Illustration of local delivery for GBM including implantable wafers, convection-enhanced delivery and hydrogels, where implantable or in situ-formed hydrogels can be distinguished.

Figure 5

Schematic illustration of the most ligands and targets used in TMZ encapsulation systems.

Figure 6

Illustration of local delivery for GBM including implantable wafers, convection-enhanced delivery and hydrogels, where implantable or in situ-formed hydrogels can be distinguished.