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.

Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact with FBs and CAFs compared to cancer cells. Hence, our goal was to elucidate the extent of NP uptake, retention, and toxicity in cancer cells, FBs, and CAFs to further understand the fate of NPs in a real tumor-like environment. The outcome of this would guide designing of NP-based delivery systems to fully exploit the TME for a better therapeutic outcome. We used gold nanoparticles as our model NP system due to their numerous applications in cancer therapy, including radiotherapy and chemotherapy. A cervical cancer cell line, HeLa, and a triple-negative breast cancer cell line, MDA-MB-231 were chosen as cancer cell lines. For this study, a clinically feasible 0.2 nM concentration of GNPs was employed. According to our results, the cancer cells and CAFs had over 25-and 10-fold higher NP uptake per unit cell volume compared to FBs, respectively. Further, the cancer cells and CAFs had over 30% higher NP retention compared to FBs. There was no observed significant toxicity due to GNPs in all the cell lines studied. Higher uptake and retention of NPs in cancer cells and CAFs vs FBs is very important in promoting NP-based applications in cancer therapy. Our results show potential in modulating uptake and retention of GNPs among key components of TME, in an effort to develop NP-based strategies to suppress the tumor growth. An ideal NP-based platform would eradicate tumor cells, protect FBs, and deactivate CAFs. Therefore, this study lays a road map to exploit the TME for the advancement of "smart" nanomedicines that would constitute the next generation of cancer therapeutics.

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.

Nanoparticles (NPs) have shown promise in both radiotherapy and chemotherapy. NPs are mainly transported along cellular microtubules (MTs). Docetaxel (DTX) is a commonly used chemotherapeutic drug that can manipulate the cellular MT network to maximize its clinical benefit. However, the effect of DTX on NP behaviour has not yet been fully elucidated. We used gold NPs of diameters 15 and 50 nm at a concentration of 0.2 nM to investigate the size dependence of NP behaviour. Meanwhile, DTX concentrations of 0, 10 and 50 nM were used to uphold clinical relevance. Our study reveals that a concentration of 50 nM DTX increased NP uptake by ~50% and their retention by ~90% compared to cells treated with 0 and 10 nM DTX. Smaller NPs had a 20-fold higher uptake in cells treated with 50 nM DTX vs. 0 and 10 nM DTX. With the treatment of 50 nm DTX, the cells became more spherical in shape, and NPs were redistributed closer to the nucleus. A significant increase in NP uptake and retention along with their intracellular distribution closer to the nucleus with 50 nM DTX could be exploited to target a higher dose to the most important target, the nucleus in both radiotherapy and chemotherapy.

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