Modulation of nanoparticle uptake, intracellular distribution, and retention with docetaxel to enhance radiotherapy

Abstract

Objective: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. Methods: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. Results: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. Conclusion: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. Advances in knowledge: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.

Gold nanoparticle mediated radiation response among key cell components of the tumour microenvironment for the advancement of cancer nanotechnology

“…Furthermore, the GNPs appear to localize closer to the nuclei in the CAFs and HeLa while being more distributed throughout the cells in the FBs. It is known that the vesicles and organelles in the cells are transported along the microtubules (MTs) within the cells 43 . Similarly, vesicles containing GNPs within the cell have previously been shown to travel along the MTs following uptake 44 .…”

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 ).…”

Advances in Gold Nanoparticle-Based Combined Cancer Therapy

“…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]. DTX used as a synchronizing agent when paired with GNPs lead to higher uptake, a higher localization of the GNPs to the nucleus, and a larger, synergistic response to radiotherapy.…”

“…DTX used as a synchronizing agent when paired with GNPs lead to higher uptake, a higher localization of the GNPs to the nucleus, and a larger, synergistic response to radiotherapy. Reproduced with permission from [160]. Copyright 2020 British Journal of Radiology.…”