Temozolomide: An Overview of Biological Properties, Drug Delivery Nanosystems, and Analytical Methods

Abstract

Temozolomide (TMZ) is an imidazotetrazine prodrug used to treat glioblastoma multiforme. Its physicochemical prop-erties and small size confer the ability to cross the blood-brain barrier. The antitumor activity depends on pH-dependent hydrolysis of the methyldiazonium cation, which is capable of methylating purine bases (O6-guanine; N7-guanine, and N3-adenine) and causing DNA damage and cell death. TMZ is more stable in acidic media (pH ≤ 5.0) than in basic media (pH ≥ 7.0) due to the protonated form that minimizes the catalytic process. Because of this, TMZ has high oral bioavailability, but it has a half-life of 1.8 h and low brain distribution (17.8%), requiring a repeated dos-ing regimen that limits its efficacy and increases adverse events. Drug delivery Nanosystems (DDNs) improve the phys-icochemical properties of TMZ and may provide controlled and targeted delivery. Therefore, DDNs can increase the efficacy and safety of TMZ. In this context, to ensure the efficiency of DDNs, analytical methods are used to evaluate TMZ pharmacokinetic parameters, encapsulation efficiency, and the release profile of DDNs. Among the methods, high-performance liquid chromatography is the most used due to its detection sensitivity in complex matrices such as tissues and plasma. Micellar electrokinetic chromatography features fast analysis and no sample pretreatment. Spec-trophotometric methods are still used to determine encapsulation efficiency due to their low cost, despite their low sen-sitivity. This review summarizes the physicochemical and pharmacological properties of free TMZ and TMZ-loaded DDNs. In addition, this review addresses the main analytical methods employed to characterize TMZ in different ma-trices.

The landscape of circRNAs in gliomas temozolomide resistance: Insights into molecular pathways

“…TMZ is stable in acidic pH and is hydrolyzed in physiological pH (higher than 7) and finally turns into MTIC. Then, MTIC is also hydrolyzed and converted into methyl diazonium ions which can cause purine and pyrimidine bases to be methylated and ultimately cause DNA damage and induce apoptosis [ 44 , 45 ]. Because TMZ can disrupt DNA replication by alkylating the O6 site of guanine (O6MeG), more than 50 % of patients with GBM do not respond to this drug due to the mechanism of methylguanine methyltransferase (MGMT) [ 46 , 47 ].…”

Folic acid‐decorated astrocytes‐derived exosomes enhanced the effect of temozolomide against glioma

“…Temozolomide (TMZ) is a first‐line drug for the clinical treatment of brain tumors, with excellent properties such as lipophilicity, acid stability, less toxic side effects, and ability to penetrate the blood–brain barrier (BBB) 5,6 . TMZ is hydrolyzed at physiological pH ≥7.4, releasing a methyldiazonium cation to methylate purine bases (O6‐guanine, N7‐guanine, and N3‐adenine), stimulating anti‐tumor activity 7 . However, TMZ does not possess specific targeting to glioma cells and is unstable, making it prone to degradation under human environmental conditions; thus, clinically, frequent administration is required to maintain an effective TMZ concentration 7,8 .…”

“…5,6 TMZ is hydrolyzed at physiological pH ≥7.4, releasing a methyldiazonium cation to methylate purine bases (O6-guanine, N7-guanine, and N3-adenine), stimulating anti-tumor activity. 7 However, TMZ does not possess specific targeting to glioma cells and is unstable, making it prone to degradation under human environmental conditions; thus, clinically, frequent administration is required to maintain an effective TMZ concentration. 7,8 Importantly, frequent administration not only leads to low drug utilization, but also causes serious damage to normal cells.…”

“…7 However, TMZ does not possess specific targeting to glioma cells and is unstable, making it prone to degradation under human environmental conditions; thus, clinically, frequent administration is required to maintain an effective TMZ concentration. 7,8 Importantly, frequent administration not only leads to low drug utilization, but also causes serious damage to normal cells. 9,10 Hence, the development of TMZ carriers with specific targeting has become a new research hotspot.…”