Studies On Action Mechanisms Of NsPEF-induced Tumor Apoptosis And Non-invasive Focusing Principles Of Sub-nsPEF

Recently, the effects of pulsed electric field (PEF) on cellular structures andfunction and treatment for bosoms have been emerged as the research focus in the fieldof bioelectromagnetics, and the unique bioelectric effects of tumor cell apoptosisinduced by nanosecond PEF (nsPEF) have attracted much attention from the cellbiologist. PEF-induced apoptosis has two unique advantages in clinical tumor treatment,namely, target-specific action and apoptosis of minimally invasive, which can greatlyreduce the damage effect on surrounding normal tissues; in the meantime theultra-wideband properties of subnanosecond PEF (sub-nsPEF) show great promise inthe field of non-invasive focusing for tumor treatment. Therefore, action mechanisms ofnsPEF-induced tumor apoptosis and non-invasive focusing principles of sub-nsPEF areinvestigated in this study, which can greatly boost the process of PEF in clinical tumortreatment.However, action mechanisms of nsPEF-induced tumor apoptosis and non-invasivefocusing principles of sub-nsPEF have to be indicated before the clinical application ofnsPEF and sub-nsPEF. Thus in depth study has to be performed on action mechanismsof nsPEF-induced tumor apoptosis and non-invasive focusing principles of sub-nsPEFwith the support of the national natural science foundation in key project (grant No.50637020), national natural science foundation in general project (grant No.50877083)and the ministry of education doctoral project (grant No.20100191110019). The majorachievements are as follows:①Full-circuit equivalent model of spherical cell was established with theconsideration of cellular structure dispersion and plasma membrane electroporation,then trans-membrane potentials of plasma membrane and nuclear membrane during theapplication of nsPEF and sub-nsPEF were calculated, and targeted effects of PEF wereindicated.②A FPGA controlled intense nsPEF therapeutic system was developed based ontraditional Marx generator and high-voltage high-power power electronic switch andobservation and control technology. This therapeutic system has the capability ofproducing repetitive pulses with a voltage of0~8kV, pulse width of200~1000ns, risetime of35ns and repetition rate of1~1000Hz. In addition, a sub-nsPEF therapeuticsystem with voltage up to100kV, pulse width of800ps and rise time of600ps was developed based on traditional nsPEF therapeutic system and peaking-tail cuttingswitch.③SKOV3was selected as experimental subject, and window effect between pulseduration and cell apoptosis was indicated; optimal parameters of nsPEF were performon tumor cells, and the experimental results indicate that both intrinsic and extrinsicpathways were involved in nsPEF-induced apoptosis; Melanoma is taken as theindication of the nsPEF treatment, complete ablation of local tumors and quickly scarvesting within the treated areas were indicated with in vivo imaging, tumor-inhibitionobservation and cameras follow-up; apoptosis initiation and angiogenesis inhibitionwere observed by DNA ladder test, expressions test of Bax, Bcl-2, MVD, VEGF andPCNA.④Simplified breast tissues model was established, and the propagation rules andfocusing properties of sub-nsPEF in this model were systemically investigated, thendigitized human brain model was introduced to study the focusing properties ofsub-nsPEF in complex biological tissues. The results indicate that fine focusing inlow-conductivity and high-permittivity biological tissues was achieved with thecombination of sub-nsPEF and impulse radiating antenna (IRA); good focusing inpractical breast tissue (=0.5S/m,=9) was obtained with the consideration of conicalantenna or lossy dielectric lens; concurrently, fine focusing in deep brain tissue (7-8cm)was achieved with the combination of IRA and parameter-optimized lossy dielectriclens.In summary, this paper investigated the action mechanisms of nsPEF andsub-nsPEF-induced bioelectric effects with the consideration of frequency dispersionand electroporation, then nsPEF and sub-nsPEF therapeutic systems for biomedicalstudy were developed. Besides, window effects, intrinsic and extrinsic pathways,efficacy assessment and treatment principles of nsPEF-induced tumor apoptosis weresystemically studied. Last but not least, non-invasive focusing of sub-nsPEF inbiological tissues was studied, which provided the material basis, theoretical andtechnical support fot the clinical application of nsPEF/sub-nsPEF treatment.