Modulation of gold nanoparticle mediated radiation dose enhancement through synchronization of breast tumor cell population

Abstract

Objective: The incorporation of high atomic number materials such as gold nanoparticles (GNPs) into tumor cells is being tested to enhance the local radiotherapy (RT) dose. It is also known that the radiosensitivity of tumor cells depends on the phase of their cell cycle. Triple combination of GNPs, phase of tumor cell population, and RT for improved outcomes in cancer treatment. Methods: We used a double-thymidine block method for synchronization of the tumor cell population. GNPs of diameters 17 and 46 nm were used to capture the size dependent effects. A radiation dose of 2 Gy with 6 MV linear accelerator was used to assess the efficacy of this proposed combined treatment. A triple negative breast cancer cell line, MDA-MB-231 was chosen as the model cell line. Monte Carlo (MC) calculations were done to predict the GNP-mediated cell death using the experimental GNP uptake data. Results: There was a 1.5- and 2- fold increase in uptake of 17 and 46 nm GNPs in the synchronized cell population, respectively. A radiation dose of 2 Gy with clinically relevant 6 MV photons resulted in a 62 and 38 % enhancement in cell death in the synchronized cell population with the incorporation of 17 and 46 nm GNPs, respectively. MC data supported the experimental data, but to a lesser extent. Conclusion: A triple combination of GNPs, cell cycle synchronization, and RT could pave the way to enhance the local radiation dose while minimizing side effects to the surrounding healthy tissue. Advances in knowledge: This is the first study to show that the combined use of GNPs, phase of tumor cell population, and RT could enhance tumor cell death.

Modulation of the Microtubule Network for Optimization of Nanoparticle Dynamics for the Advancement of Cancer Nanomedicine

“…The reduced accumulation of NPs in cells treated with 10 nM DTX, as compared to 0 nM DTX, could be due to the fragmented division seen in cells treated with 10 nM DTX ( Figure 2 f) [ 40 ]. The greater accumulation of NPs in cells treated with 50 nM DTX could be due to the cell cycle arrest in G2/M phase [ 20 , 40 , 41 ]. We also examined the NP accumulation when cells were treated with 1 nM DTX and observed an outcome much closer to the control and 10 nM conditions, as expected (see Supplementary Materials S2 ).…”

“…Manipulation of NPs' size and surface properties has been widely used to optimize the uptake of NPs in cancer cells in preclinical applications. Recent studies have exploited the cell cycle to further improve cellular NP uptake [20,21]. For example, arresting the cell cycle in the G2/M phase could result in a higher intracellular accumulation of NPs (see Figures S1-S3) [21].…”

Advances in Gold Nanoparticle-Based Combined Cancer Therapy

“…peptide and PEG molecules were on the order of 2 kDa and smaller NPs were able to maximize the ligand-receptor interaction of RGD peptide using their higher surface curvature [76,85]. Various factors can affect the pharmacokinetics of the GNPs.…”

“…Both in vitro and in vivo studies have demonstrated the synergistic effects of DTX when combined with radiotherapy [157,158]. Furthermore, it has been shown that the uptake of NPs, including GNPs, is increased when the cell population is synchronized in the G 2 /M phase [85,159]. This suggests the use of DTX concomitantly with other drugs or radiation, which was tested by Bannister et al as seen in Figure 8 [160].…”

“…Depending on the size of the PEG molecule and GNP, the uptake dynamics shown in Figure 4 D was changed. For example, it was shown that smaller GNPs had a higher uptake compared to GNPs of diameter 50 nm [ 76 , 85 ]. The peptide and PEG molecules were on the order of 2 kDa and smaller NPs were able to maximize the ligand–receptor interaction of RGD peptide using their higher surface curvature [ 76 , 85 ].…”