Superior performance of aptamer in tumor penetration over antibody : implication of aptamer-based theranostics in solid tumors

Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood vessels 3 h after intravenous injection. Taken together, these data indicate that aptmers are superior to antibodies in cancer theranostics due to their better tumor penetration, more homogeneous distribution and longer retention in tumor sites. Thus, aptamers are promising agents for targeted tumor therapeutics and molecular imaging

GENERALIZED SENSITIVITY ANALYSIS CAPABILITY WITH THE DIFFERENTIAL OPERATOR METHOD IN RMC CODE

Sensitivity analysis is an important way for us to know how the input parameters will affect the output of a system. Therefore, recently, there is an increased interest in developing sensitivity analysis methods in continuous-energy Monte Carlo Code due to the fact that Monte Carlo method can perform high-fidelity simulations of nuclear reactor. Previous studies mainly focused on developing sensitivity analysis method suitable for analyze eigenvalue. There are relatively few researches for performing sensitivity analysis of generalized response function by using continuous-energy Monte Carlo code. So, in this work, the differential operator method (DOM) has been investigated and implemented in continuous-energy Reactor Monte Carlo code (RMC) to perform sensitivity analysis of generalized response function in the form of ratios of reaction rate. The DOM implemented in RMC is based on the analog Monte Carlo transport mode and non-analog Monte Carlo transport mode. The correctness of the newly implemented method has been verified by comparing the results with those calculated by using the collision history-based method through the Jezeble and Flattop benchmark problems. In general, the results given by the DOM agree well with those obtained by the collision history-based method with an accuracy of 5%. Moreover, it is also shown that the non-analog Monte Carlo transport mode can obtain lower relative standard deviation of the sensitivity coefficients than the analog Monte Carlo transport mode

GENERALIZED SENSITIVITY ANALYSIS CAPABILITY WITH THE DIFFERENTIAL OPERATOR METHOD IN RMC CODE

Sensitivity analysis is an important way for us to know how the input parameters will affect the output of a system. Therefore, recently, there is an increased interest in developing sensitivity analysis methods in continuous-energy Monte Carlo Code due to the fact that Monte Carlo method can perform high-fidelity simulations of nuclear reactor. Previous studies mainly focused on developing sensitivity analysis method suitable for analyze eigenvalue. There are relatively few researches for performing sensitivity analysis of generalized response function by using continuous-energy Monte Carlo code. So, in this work, the differential operator method (DOM) has been investigated and implemented in continuous-energy Reactor Monte Carlo code (RMC) to perform sensitivity analysis of generalized response function in the form of ratios of reaction rate. The DOM implemented in RMC is based on the analog Monte Carlo transport mode and non-analog Monte Carlo transport mode. The correctness of the newly implemented method has been verified by comparing the results with those calculated by using the collision history-based method through the Jezeble and Flattop benchmark problems. In general, the results given by the DOM agree well with those obtained by the collision history-based method with an accuracy of 5%. Moreover, it is also shown that the non-analog Monte Carlo transport mode can obtain lower relative standard deviation of the sensitivity coefficients than the analog Monte Carlo transport mode

Research on the calculation method of sensitivity coefficients of reactor power to material density based on Monte Carlo perturbation theory

The ability to calculate the material density sensitivity coefficients of power with respect to the material density has broad application prospects for accelerating Monte Carlo-Thermal Hydraulics iterations. The second-order material density sensitivity coefficients for the general Monte Carlo score have been derived based on the differential operator sampling method in this paper, and the calculation of the sensitivity coefficients of cell power scores with respect to the material density has been realized in continuous-energy Monte Carlo code RMC. Based on the power-density sensitivity coefficients, the sensitivity coefficients of power scores to some other physical quantities, such as power-boron concentration coefficients and power-temperature coefficients considering only the thermal expansion, were subsequently calculated. The effectiveness of the proposed method is demonstrated in the power-density coefficients problems of the pressurized water reactor (PWR) moderator and the heat pipe reactor (HPR) reflectors. The calculations were carried out using RMC and the ENDF/B-VII.1 neutron nuclear data. It is shown that the calculated sensitivity coefficients can be used to predict the power scores accurately over a wide range of boron concentration of the PWR moderator and a wide range of temperature of HPR reflectors