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

• Published in: British journal of radiology 2020-02, Vol.93 (1106), p.20190742
• Main Authors: Bannister, Aaron Henry, Bromma, Kyle, Sung, Wonmo, Monica, Mesa, Cicon, Leah, Howard, Perry, Chow, Robert L, Schuemann, Jan, Chithrani, Devika Basnagge
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological Transport; Cell Survival - drug effects; Cell Survival - radiation effects; Docetaxel - pharmacokinetics; Docetaxel - pharmacology; Drug Synergism; Female; Gold - pharmacokinetics; Gold - pharmacology; HeLa Cells; Humans; Metal Nanoparticles; Radiation-Sensitizing Agents - pharmacokinetics; Radiation-Sensitizing Agents - pharmacology; Triple Negative Breast Neoplasms - radiotherapy; Tumor Cells, Cultured; Uterine Cervical Neoplasms - radiotherapy
• ISSN: 0007-1285; 1748-880X
• DOI: 10.1259/bjr.20190742

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. 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. 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 RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. 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. This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.