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.

A case report: Gliosarcoma associated with a germline heterozygous mutation in MSH2

“…However, this study did not differentiate between sporadic or genetically related GBMs cases. Actually, the efficacy of TMZ can be influenced by factors such as O(6)-Methylguanine DNA methyltransferase (MGMT) and MMR ( 23 ). MGMT is a DNA repair enzyme that reverses DNA damage caused by alkylating agents, rendering tumors insensitive to TMZ chemotherapy ( 24 ).…”

Glioblastoma Therapy: Past, Present and Future

“…A number of anti-cancer drugs have been successfully delivered to the brain using nanocarriers, i.e., TMZ, paclitaxel, docetaxel, cisplatin, doxorubicin (DOX), vincristine and others [ 887 ]. Several nanoformulations are being developed to overcome the limitations of TMZ penetration to improve GB treatment [ 907 , 908 , 909 ]. Sharma et al developed a polyamidoamine (PAMAM) dendrimer-chitosan conjugate that increased TMZ brain concentration by almost two-fold [ 910 ], thus proving that polymer-based nanosystems can increase the stability of TMZ and control its release.…”

Light-driven micro/nanomotors in biomedical applications

“…In addition to the inherent barriers in the human body, the associated biological barriers will also be formed along with the production of diseases, such as the dense extracellular matrix (ECM) outside tumors, 142,143 atherosclerotic plaques, 8 and bacterial biofilms in bacterial infections, 144 which can affect the efficiency of drug delivery and in turn reduce the effectiveness of the drugs. In recent years, MNMs with excellent motion properties have been used to penetrate and even remove these barriers that accompany disease.…”

“…6,7 The so-called passive targeted delivery systems use the passive diffusion mechanism to enhance permeability and retention (EPR) effects to accumulate drugs in specific tissues. 8,9 However, EPR effects have been reported to be limited by heterogeneity and related physiological barriers, 10,11 with less than 0.7% of intravenously injected nanoparticles reaching solid tumor sites. 12 This indicates that the traditional passive targeted delivery of nanomaterials is challenging to achieve adequate transportation and tissue penetration of goods.…”