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FRINATEK-Fri prosj.st. mat.,naturv.,tek

Ultrasound-mediated transport of nanoparticles in tissue: A predictive model

Alternative title: Ultralyd for å forbedre transport av nanopartikler i vev : Etablere en model for å forutsi transporten

Awarded: NOK 12.0 mill.

A prerequisite for successful cancer therapy is that all cancer cells are killed. Chemotherapy alone or in combination with other treatments is commonly used in cancer therapy. A problem in chemotherapy is that less than 1 % of the drug is taken up in tumours. Toxic effects towards healthy tissue restrict the doses that can be applied, which limit the therapeutic response. A promising strategy for increasing the tumour uptake of drugs, is to encapsulate drugs into nanoparticles, and take the advantage of the leaky blood vessels in tumours which permit nanoparticles to cross these capillary walls, but not capillaries in normal tissue. However, a challenge using nanoparticles in cancer therapy is to achieve sufficient dosage and homogenous distribution of the nanoparticles to all cancer cells, as the extracellular matrix surrounding the cells limits the penetration of drugs and nanoparticles to the cancer cell. Delivery of nanoparticles to brain tissue is even more challenging due to the blood-brain barrier. Tight junctions between cells lining the microvessels in the brain form a physical barrier. Thus, to be able to treat diseases in the brain, the blood-brain barrier has to be opened safely. Focused ultrasound especially in the presence of gas filled microbubbles has been shown to improve the delivery of nanoparticles and drugs into tumors and across the blood-brain barrier in mice. To optimize this promising therapy which now also is tested in cancer patients, we need to understand the underlying mechanisms better. The overall aim of the project is to obtain new knowledge on the transport mechanisms for nanoparticles and drugs in tissues. This is done by theoretically describing transport in tissue and combining modelling/computer simulations and experimental research, thereby creating a tool to help predict the delivery and distribution of nanoparticles and drugs in tumours and brain tissue after applying focused ultrasound. As a first experimental step, we have developed phantoms of collagen and hyaluronan the major constituents of extracellular matrix in tissue, and phantoms of agarose. An experimental set up imaging the movement of fluorescently labelled nanoparticles during ultrasound treatment has been established. This set up will be used to understand the contribution of focused ultrasound on the penetration of nanoparticles into the extracellular matrix and verify the theoretical predicted penetration of nanoparticles. The theoretical model we started with, is based on perturbation theory and the model predicts the acoustic streaming through tissue generated when applying ultrasound. The acoustic streaming can transport nanoparticles away from the blood vessel wall and into the extracellular matrix, and through simulations we will predict how far the nanoparticles can reach under various ultrasound exposures and given tissue properties. Our first approach is to study the effect of ultrasound without microbubbles. Microbubbles due to their size will not enter into the extracellular matrix. Next, the model and experiments will become more complex, moving into studies in mice and incorporating the microbubbles. Our strategy, combined modelling and experimental verification can be valuable in optimizing and improving cancer therapy and treating diseases in the brain.

A prerequisite for successful cancer chemotherapy is that the drugs reach all tumor cells. However, less than 1% of injected drugs accumulate in tumors. Encapsulating drugs into nanoparticles (NPs) improves the accumulation of drugs in tumors and reduces the toxic effect, but the tumor uptake of NPs is low and heterogeneous. Delivery of NPs to brain tissue is even more challenging due to the blood-brain barrier (BBB). Focused ultrasound (FUS) has been found to improve the delivery of NPs to tumor tissue either by acoustic radiation force or cavitation caused by microbubbles (MBs), and temporarily open the BBB. MBs will oscillate in the acoustic field which can generate mechanical effects on the vessel wall, enhancing the vascular permeability. The next step is the penetration throughout the interstitium. This transport process is poorly understood. We hypothesize that MBs in the blood vessels oscillating in the acoustic field cause the capillary wall to vibrate and generate interstitial flow and this flow transports NPs and drugs through the interstitium. To prove our hypothesis, we will establish a theoretical framework describing transport in porous media and combine modelling/computer simulations and experiments. The theoretical work and simulations will be carried out at the Center of Excellence Porelab at NTNU which has extensive competence on porous media transport. The results of the simulations will be continuously challenged and validated through experiments and advanced imaging of NPs in tissues. The interstitium will first be regarded as a network of flow pores, followed by a continuum model. This novel approach will bring new knowledge on FUS-mediated transport through tissue, optimizing FUS-mediated delivery of NPs and drugs and understanding the impact of interstitial flow generated by acoustic radiation force or the vibrating capillary wall. The new knowledge will lead to a model predicting the distribution of NPs and drugs in tumor and brain tissue.

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FRINATEK-Fri prosj.st. mat.,naturv.,tek