Nanoparticle therapy in a zebrafish model of cancer
Chemotherapy, a standard treatment for cancer is associated with many side-effects, most notably toxicity and the need for frequent dosing. When the same drugs are encapsulated inside nanoparticles made of lipids or polymers they have the potential to release the drugs more slowly, thereby reducing the toxicity. Most of the research has been carried out in mouse models which have the disadvantage that they are opaque for imaging.
Since they have no adaptive immunity during the first weeks after birth, zebrafish embryos are ideally suited for xenotransplants (microinjection) of cancer cells, and thereby avoid immunological rejection; in mice one needs to use special, immune-compromised animals for this purpose. Despite this powerful feature, zebrafish cancer models have until now exhibited poor growth and lacked several characteristics typical of human cancers. Our group has recently injected mouse melanoma (skin cancer) cells into the zebrafish neural tube (the developing spinal cord) - resulting in strong tumor growth, in angiogenesis (new vessel formation) and in macrophage accumulation, all prominent features of human cancer. All these features are easy to see in the zebrafish embryo since it is optical transparent and genetically tractable, allows for real-time imaging of nanoparticles, and at the same time- in different colors, the cancer and immune cells, either macrophages or neutrophils. When we assessed NP containing the anticancer drug doxorubicin we found that these: 1 Lowered the toxicity when compared to the free drug; 2 Selectively accumulated in the cancer tissue; 3 Significantly inhibited cancer growth compared to free doxorubicin.
Focus of this Masters project.
- Analysis of the process of the dynamics and accumulation of nanoparticles in the site of the tumor. For this, different techniques of light and electron microscopy will be learnt and employed. The impact of NP size, material and surface chemistry will be evaluated with respect to the efficiency of accumulation at the cancer site, in collaboration with a group of UiO mathematicians.
- Drugs influencing angiogenesis and blood pressure will be studied to find the best conditions for therapy.
- Finally, drug-loaded NP will be tested for their therapeutic potential. We have a long-standing collaboration with two international groups (in Belgium and Germany) that provide us with new NP formulations for this project.
Students in our group will find a friendly and stimulating environment and will learn:
- Microscopy techniques:
Light microscopy: stereomicroscope/confocal/spinning disc, Softwares: Imagej and IMARIS
Electron microscopy: TEM and SEM.
- Histology/anatomy of zebrafish and antibody labeling of sections.
- Handling of zebrafish embryos and cancer cells including blood and neural tube microinjections
- Simple nanoparticle preparation including encapsulation of fluorescent dyes and drugs.