We will in this project develop natural nanoparticles for cancer therapy. Cells in our body can communicate with other cells via tiny information packages. These packages are small vesicles called exosomes. Exosomes can affect the receiving cell. As exosomes represent a natural delivery system in our body, we will test whether we can use exosomes for more precise delivery of drug to tumors. It is relatively simple to manipulate the contents of exosomes, and also to attach addressing labels to direct exosomes to site of interest. We will in this project use NK-cell as donor cell to make therapeutic exosomes. NK cells represents our natural defense against cancer cells, and are naturally equipped with an armada of tools to kill cancer cells. Some of these tools will also be present in NK-cell derived exosomes. We will further develop these natural NK-cell derived exosomes by equipping them with address labels to specific tumors. We have since the project started tested and compared exosomes produced in NK-cell lines and primary NK cells under different activating conditions. We have found that certain activating conditions yield exosomes with superior ability to kill a wide diversity of solid tumor cell lines. This work is now under review. We are currently studying the utility of specific subsets of exosomes derived from NK cells, and the intracellular origin of the vesicles. We are also producing address labels (nanobodies) to be attaced to the exosomes. Our goal is to start our first proof-of-concept animal studies wihtin the next project year.
A challenge in nanomedicine is the development of safe and non-immunogenetic delivery vehicles. Exosomes are promising future natural nanodelivery vehicles of drugs. Enclosed in exosomes, chemicals and bio-molecules are protected from elimination, and therefore more effectively reach their site of action. Exosomes may thus overcome the most critical issue of nanomedicine, such as efficient invasiveness and safety. With this proposal, we will explore the therapeutic utility of nano-sized natural biological vesicles, exosomes, as delivery vehicles in cancer therapy. Exosomes are natural intercellular shuttles in our body, capable of modifying the function of target cells. They are increasingly exploited as therapeutic tools in nanomedicine due to their non-immunogenicity, and the relative ease of engineer targeting units and modifying their cargo. In terms of cancer therapy, exomes are extremely well suited due to high performance in acidic environments, such as within solid tumors, and their ability to infiltrate tumor tissues. We will exploit NK-cell derived exosomes as delivery vectors. Exosomes mirror their cell of origin, and NK cells express a particularly broad array of surface proteins able to interact with diverse tumor ligands. As exosomes are highly stable, our aim is thus to generate off-the-shelf, therapeutic NK-cell derived exosome products for tumor therapy. We will generate NK-exosomes with universal tumor-targeting capabilities through a set of integrated work packages to design protocols to engineer and produce NK-exosomes, verifying tumor targeting via 2D and 3D tumor models, and finally evaluate the utility of engineered NK-exosomes to target tumor in vivo using tumor models in humanized mice.