Multifunctional Nanomaterial Platforms for Cancer Immunotherapy
Anthony Brouillard , Anujan Ramesh, Sahana Kumar, Dipika Nandi, Ashish Kulkarni
Although immunotherapy is becoming a more viable option for cancer treatment, there are still obstacles to overcome such as heterogeneous tumor responses and insufficient treatment efficacy. Current immunotherapies allow for targeted immune system manipulation, but responses amongst patients varies due to the heterogeneous nature of tumors. The work presented will be about the development and investigation into multifunctional nanomaterials that can be used in order to increase treatment efficacy. One aspect of the tumor microenvironment that can be modified is tumor-associated (M2) macrophages, which have pro-tumor characteristics that can decrease immune activity leading to cancer progression.
Our recent study on macrophage phenotype manipulation in the tumor microenvironment using dual synergistic nanoparticles (DSNs) has shown to increase inflammatory (M1) macrophage responses. Since macrophages can consist of up to 50% of the tumor mass, the increase in anti-tumor macrophage activity led to tumor regression in an aggressive breast cancer model. This was done using liposome-based nanoparticles with chemically-modified inhibitors that “re-educate” macrophages from pro-tumor to anti- tumor phenotypes. In addition to this system, we are currently developing multifunctional "immunobridges" with orthogonal binding regions that allow for increased immune cell – cancer cell communication to induce cancer cell death. Specifically enhancing T-cell interactions with cancer cells has the potential to cause highly specific and potent killing through activating T-cell receptors that induce the release of cytotoxic molecules. Current technologies are unable to elicit more potent responses via T- cells without being cleared early from the body, and are made mainly through biological synthesis in cells. This talk will discuss the use and synthesis of bi-lobal latex nanoparticles and chemically- conjugated dendrons that allow for orthogonal and customizable targeting for optimal and simultaneous binding to T-cells and cancer cells. These platforms discussed will address issues with current immunotherapies and how a shift to multifunctional platforms will increase efficacy and potency of responses to immunotherapy.
Modeling and Simulation of Surface Morphological Evolution of Plasma-Facing Materials in Nuclear Fusion Devices
Chao-Shou Chen and Dimitrios Maroudas
Tungsten (W) is the chosen plasma-facing component (PFC) material in the International Thermonuclear Experimental Reactor (ITER) due to its superior thermomechanical properties and low sputtering yield. A large body of experimental evidence has established that PFC tungsten suffers severe surface degradation as a result of exposure to high fluxes of helium (He) generated in the fusion reaction and extreme heat loads. Specifically, high fluxes of low-energy helium ions implanted in tungsten within the temperature range from 900 K to 2000 K is responsible for the formation of the so-called “fuzz” nanostructure, which consists of fragile nanometer-sized tendrils. The formation of such surface nanostructure has adverse effects on the mechanical behavior and structural response of PFC tungsten as well as on the reactor performance.
The goal of this research is to develop hierarchical models and simulation tools capable of predicting the surface morphological evolution of PFC tungsten over the relevant spatiotemporal scales for the formation of surface nanostructure and examine a number of factors that impact such evolution. So far, our analysis has been based on self-consistent dynamical simulations according to an atomistically-informed continuous-domain surface evolution model that has been developed following a hierarchical multiscale modeling strategy. The model accounts for PFC surface diffusion driven by the compressive stress originating from the over-pressurized He bubbles in a thin material layer, which forms in the near-surface region of PFC tungsten as a result of helium implantation, in conjunction with the formation of self-interstitial W atoms that diffuse toward the surface. The model also accounts for the softening of the elastic moduli of PFC tungsten, both thermal softening at high temperature and softening due to He accumulation in tungsten upon implantation. We establish that this elastic softening accelerates nanotendril growth on the PFC surface, which is a precursor for fuzz formation. We also explore the role that the rate of He accumulation to a saturation level in the near-surface region of irradiated tungsten plays in the onset of fuzz formation. For PFC tungsten surfaces such as W(110), where surface diffusion is characterized by a low activation energy barrier, we find that accelerating the rate of He accumulation accelerates the growth rate of nanotendrils emanating from the surface. Finally, we introduce an incubation time for nanotendril growth on the PFC surface to predict and explain the minimum exposure time required to observe fuzz formation on PFC tungsten surfaces. Future upgrades to incorporate into the model subsurface bubble dynamics, bubble bursting, dislocation loop punching, material property anisotropies, and further changes in material thermophysical properties in the damaged near-surface layer also will be discussed.
Acknowledgments: We thank Dr. Dwaipayan Dasgupta, Dr. Asanka Weerasinghe, and Prof. Brian D. Wirth, for helpful discussions on this work. This research was supported by the U.S. Department of Energy, Offices of Fusion Energy Sciences and Advanced Scientific Computing Research through the Scientific Discovery through Advanced Computing (SciDAC) project on Plasma-Surface Interactions (Award No. DE-SC0018421).
Reference: C.-S. Chen, D. Dasgupta, A. Weerasinghe, B. D. Wirth, and D. Maroudas, Nuclear Fusion (2020), DOI: 10.1088/1741-4326/abbf64