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.

one of the major issues in cancer radiotherapy (Rt) is normal tissue toxicity. introduction of radiosensitizers like gold nanoparticles (Gnps) into cancer cells to enhance the local Rt dose has been tested successfully. However, it is not known how Gnps interact with other stromal cells such as normal fibroblasts (FBs) and cancer associated fibroblasts (CAFs) within the tumour microenvironment. It is known that FBs turn into CAFs to promote tumour growth. Hence, we used FBs and CAFs along with HeLa (our cancer cell line) to evaluate the differences in GNP uptake and resulting radiation induced damage to elucidate the GNP-mediated therapeutic effect in RT. The CAFs had the largest uptake of the GNPs per cell, with on average 265% relative to HeLa while FBs had only 7.55% the uptake of HeLa and 2.87% the uptake of CAFs. This translated to increases in 53BP1-related DNA damage foci in CAFs (13.5%) and HeLa (9.8%) compared to FBs (8.8%) with RT treatment. This difference in DNA damage due to selective targeting of cancer associated cells over normal cells may allow GNPs to be an effective tool in future cancer RT to battle normal tissue toxicity while improving local Rt dose to the tumour. Cancer is a family of diseases arising from dysregulation of the expression of multiple genes, leading to abnormal cell proliferation and cell death. As a result, there is significant morbidity in patients if left untreated 1. Before the age of 75, about 1 in 6 people will develop cancer while 1 in 9 will die from it 2. Aside from surgery, one of the main modalities employed in the treatment of cancer is radiotherapy (RT). RT aims to deliver high doses of ionizing radiation to cancerous tissue, inducing death from damage to important structures such as the DNA or mitochondria 3. Despite being used in 50% of all patients diagnosed with cancer, one of the major issues in current RT modalities is the normal tissue toxicity in radiosensitive tissue localized closely with the cancer 4,5. Furthermore, there are many radiobiological hurdles to overcome, such as the influence of cancer stem cells, tumour heterogeneity, tumour hypoxia, metabolic pathways, and other complications, that will increase the radioresistance of the tumour cells 6-8. While the introduction of targeting methods such as volumetric modulated arc therapy (VMAT) and image guided radiotherapy (IGRT) has improved the efficacy of RT, there is a limit of improvement when it comes to the use of RT as a singular treatment modality 9. In an effort towards reducing the normal tissue toxicity while increasing the damage to the tumour, radiosensitizers have been introduced 10. Radiosensitizers work via various pathways, such as targeting of the radioresistant hypoxic cells in tumours, or through production of reaction oxygen species (ROS) 10,11. The introduction of high atomic number materials into tumour tissue has been explored as a promising approach to enhance the local radiation dose 12-17 .

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.

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.

Rogue waves are individual ocean surface waves with crest height $$\eta$$ η or trough-to-crest height H that are large compared to the significant wave height $$H_s$$ H s of the underlying sea state: $$H/H_s>2.2$$ H / H s > 2.2 or $$\eta /H_s>1.25$$ η / H s > 1.25 . The physics of rogue wave generation and the potential of predicting the rogue wave risk are open questions. Only a few rogue waves in high sea states have been observed directly, but they can pose a danger to marine operations, onshore and offshore structures, and beachgoers. Here we report on a 17.6m high rogue wave in coastal waters with $$\eta /H_s=1.98$$ η / H s = 1.98 and $$H/H_s=2.9$$ H / H s = 2.9 which are likely the largest normalized heights ever recorded. Simulations of random superposition of Stokes waves in intermediate water depth show good agreement with the observation. Non-linear wave modulational instability, a well known cause for rogue waves in laboratory settings, did not contribute significantly to the rogue wave generation. A parameter obtained from a routine spectral wave forecast provides a practical risk prediction for rogue waves. These results confirm that probabilistic prediction of oceanic rogue waves based on random superposition of steep waves are possible and should replace predictions based on modulational instability.