Biophysical interaction of temozolomide and its active metabolite with biomembrane models: The relevance of drug-membrane interaction for Glioblastoma Multiforme therapy

Glioblastoma multiforme (GBM) is the most common type of malignant tumor that affects the central nervous system. It is considered to be the most aggressive type of tumor due to its high proliferation rate and high mortality rates of patients with GBM. Patients suffering from this type of brain tumor often exhibit resistance to various therapeutic solutions. Despite the fact that the first-line treatment for GBM combines radiotherapy, chemotherapy and surgery, patients die within a year of initial diagnosis.

A commonly used drug for the treatment of GBM is temozolomide. Temozolomide causes cell death by undergoing methylation and inducing DNA degradation in the cell. Although temozolomide undergoes rapid absorption and irreversible conversion to its active metabolite (i.e. 5 (3-methyltriazen-1-yl) imidazole-4-carboxamide metabolite (MTIC)) after oral administration, the pharmacological efficacy of the drug is affected by its low bioavailability. The low bioavailability of temozolomide has been attributed to its low permeability through tumor cell membranes, the blood-brain barrier, and the multidrug resistance mechanism of the p-glycoprotein pump that is found in the cell membrane of GBM. Although many researchers have indicated that the ability of MTIC to interact with blood-barriers and biological membranes will contribute significantly to its pharmacological activity, studies are yet to be carried out to investigate the interaction between temozolomide and/or its active metabolite with biological membranes. Hence, this study aimed to investigate the molecular interactions between temozolomide and its active metabolite with a mimetic biomembrane model.

Recently, Maria João Ramalho, Stéphanie Andrade, Manuel Álvaro Neto Coelho, Joana Angélica Loureiro, led by Dr. Maria do Carmo Pereira from the Laboratory for Process Engineering, Environment, Biotechnology and Energy (LEPABE) in Portugal, demonstrated the molecular interactions between temozolomide and its active metabolite MTIC with the lipidic components of a mimetic biomembrane model composed of DMPC and cholesterol. The authors used various biophysical parameters to evaluate the drugs’ partition coefficient, their preferential location within the membrane and their effects on membrane properties.

Professor Maria do Carmo Pereira and her research team observed that the interactions between MTIC and the biomembrane model are mainly due to the electrostatic and ion-dipole forces between the polar head of the phospholipids and the negatively charged MTIC species, while temozolomide molecules interact through hydrophobic interactions with the acyl chains of the phospholipid in the membrane. They also observed that the drug’s partition is dependent on the composition of lipid in the biomembrane model.

Although both temozolomide and its active metabolite MTIC produced a perturbation in the fluidity of the membrane, the temozolomide exhibited a higher affinity for the membrane and penetrated the bilayer in a greater extent compared to its active metabolite MTIC. The researchers found that temozolomide significantly decreased the cooperativity of the biomembrane model.

Dr. Maria do Carmo Pereira and her research team provided compelling evidence that the composition of membranes affects drugs partition, and the bio-distribution of drugs is dependent on its physicochemical properties as well as the characteristics of the membrane. These findings will advance further studies on the design of new therapeutic molecules and development of strategies to enhance the bioavailability and pharmacological efficacy of drugs. The research work is now published in European Journal of Pharmaceutics and Biopharmaceutics.