Aim : Heating by nanoparticles, which are located in the tissue to be treated, is a well-recognized method in hyperthermic oncology. Our objective is to investigate selective, nanoscopic heating without concentrating extra artificial nanoparticles. We have in silico calculation to study the heating of the transmembrane protein clusters (rafts) on cell-membrane. The transmembrane protein domains have significantly higher dielectric constant than their lipid neighborhood in the membrane. This difference causes a local gradient in the Specific Absorption Rate (SAR), which could be a factor of heating of the membranes locally, as well as exciting the receptors for various signal transduction in the cells. We suppose that this process determines the observed cellular effects of modulated electro-hyperthermia (mEHT, trade-name: oncothermia). Materials and Methods: In silico models with highly specialized software (Computer Simulation Technology (CST), Darmstadt, Germany) were performed visualizing the selectivity for the membrane domains. Local raft models were created to simulate the electromagnetic (EM) effect of a 13.56 MHz excitation between two perfect electrical conductor plates, simulating the equipotential conditions of the sides of the membrane in the vicinity of the raft. The simulations were performed with near-field (EQS) solver of CST. The electric field, current density, and electric loss density were monitored by the simulations. The applied material properties and parameters refer to the recent literature. Results: In silico models show ten times higher energy-absorption of the transmembrane domains than that of its lipid-membrane surrounding, and intra- and extracellular neighborhood. Depending on the size, orientation, and location of the membrane rafts, the value of SAR varies, but we use only two simplified models to see the absorption properties. Taking into account the characteristics of the EM field effects we showed that the selective energy-absorption increased further by the cell-cell interactions. The model-calculation could confirm the opportunity of the local membrane heating. Conclusion: Our results indicate the heating in nanoscopic range with energy-absorption by the transmembrane proteins. The heated protein-clusters (membrane rafts) are used the same way as the artificial nanoparticles, while these absorbers are natural parts of the biological system.
One of the main objectives of modulated electro-hyperthermia (mEHT) [
The main components of the cell membrane are sphingolipid, cholesterol, steroid, carbohydrate and transmembrane proteins. The rafts are structured parts of the membrane, a cluster of transmembrane proteins, and contain high proportion of saturated lipids and cholesterols as well [
The size of the membrane rafts depends on the ratio of protein and lipid content, which differs in their location and could change by time. The geometry of the planar rafts in the recent literature is 25 - 700 nm, 100 - 200 nm and 10 - 100 nm average diameter, [
The dielectric constant and the conductivity determine the electric properties of the membrane and the rafts. The raft and its micro-environment have a considerable diversity, which complicates its average characterization. The dielectric constant (relative permittivity, εr) of the intra- and extracellular space is approx. εr ≈ 73 [
The raft domain contains a high portion of protein; therefore, this region has undoubtedly higher permittivity than its membrane neighborhood. The average dielectric constant of the raft domain takes into consideration the proteins in the cluster. The protein permittivity has multiple variants in the literature. There is measurement showing an extreme high εprotein ≈ 6300 value in the integral protein next to the low εlipid ≈ 2 value in the lipid region, and the transmembrane region of the protein also has low permittivity because the ability of polarization is blocked in this area [
The transmembrane protein clusters have even more heterogeneity and complex interactions, and so their simulation and measurements are more complicated. The hydrophobic region of the proteins shows low dielectric constant 2 < εprotein < 5; however, the outer regions with bounded water increase up to more than εprotein > 100 in some regions, and proves the extreme values in some cases [
The electric conductivity also shows the difference between the raft and non-raft part of the membrane. The average conductivity of the cell membrane is 3 × 10−7 S/m, [
The absorbed energy heats the mass of the raft. The mass determines their developed temperature. The membrane mass is made up of 52% protein, 40% lipid, and 8% carbohydrate, [
Our objective is to calculate the specific energy distribution in the above described well heterogeneous membrane structures, with particular emphasis of the energy-absorption of their rafts. The summary of the values of parameters, which are used in this article to examine the electric loss distribution in the membrane raft domains is presented in
The CST EM Studio from Computer Simulation Technology software (Darmstadt, Germany) [