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Synthetic nanoparticles as mini-pills for the treatment of tumours

Little is yet known about the risks and dangers of the tiny particles that play a key role in the field of nanotechnology because many applications are still under development. The technology is therefore not without controversy. However, there are promising possibilities for equipping artificial particles with new functions, such as optimizing the targeted delivery of drugs in the human body or developing a non-invasive type of cancer therapy. The chemist Julia Voigt is a doctoral student in the Institute for Macromolecular Chemistry led by Prof. Dr. V. Prasad Shastri at the University of Freiburg. She has developed a method that enables her to chemically address biological structures such as human endothelial cells.

Prof. Dr. V. Prasad Shastri, Julia Voigt and Jon Christensen (from left to right) are jointly studying the world of tiny particles. © Julia Voigt, University of Freiburg

"Nanos" is ancient Greek for “dwarf”. And the particles on which the nanotechnologists from the University of Freiburg are pinning their hopes really are tiny. These so-called nanoparticles are aggregates consisting of a few to several thousand atoms or molecules that are no bigger than a few 100 nanometres in size. Nanoparticles can be given novel physical and chemical properties such as a particularly high electrical conductivity or chemical reactivity.

Nanoparticles are found in sunscreens, deodorants and toothpastes as well as in foods such as ketchup and salad dressing. Nanotechnology is of particular importance in the field of medicine. Since liposomes specifically accumulate in tumour tissue due to the permeability of the tumour’s blood vessels, it seems like a clever idea to equip liposome-like nanoparticles with properties that can destroy cancerous tissue. Jon Christensen, Julia Voigt and her supervisor Prof. Dr. V. Prasad Shastri from the Institute for Macromolecular Chemistry in Freiburg are studying how the surface chemistry of particles impacts on the interaction of the particles with cells. Julia Voigt’s doctoral thesis is particularly focused on the chemical aspects.

The secret: fat and a negative charge

To date, there have not been very many experiments that examine ways to chemically addresss biological units. Julia Voigt explains her idea, which is to evoke a cell response without thinking along biological lines: “Cells are usually studied by biologists, and what immediately comes to mind with biologists is antibodies and complicated biological structures.” Are there any other ways? Would a non-biological perspective help solve some of the problems encountered when using nanoparticles to deliver therapeutics? The answer is yes, as Voigt’s doctoral thesis on whether nanoparticles are able to recognize specific cell types simply by their chemical structure has shown.

Voigt has shown that special chemical polymers, so-called polystyrene sulfonates (PSS), have the sought-after effect. These PSS are synthetic, organic molecules that are also taken up by endothelial cells, i.e. cells that line the blood vessel wall. A nanoparticle that can enter the human body through the suggested door does not have a very complex structure: basically, it is a massive lipid sphere inside which fat-soluble substances can be dissolved and to whose surface PSS are attached. The modification of the surface with negatively charged particles leads to the particularly effective uptake of the particles by the cells. As the cell membrane also has a negative charge, special interactions can occur in the lipophilic regions of the lipid rafts. Positively charged particles would most likely lead to far too strong unspecific binding and to a completely different effect.

Endocytosis by way of caveolae

Immunofluorescence image shows endothelial cells with nuclei where PSS nanoparticles (red) turn orange when overlapping with the protein caveolin (green) in the caveolae of the cells. © Julia Voigt, University of Freiburg

Voigt found that the membrane and the particles only weakly repelled each other, if at all, despite the fact that they had the same charge. She is convinced that hydrophobic attraction leads to some kind of weak binding. “Like attracts like. The interaction between the nanoparticles and the caveolar regions of the cell membrane enables the two to merge,” says Voigt.

A large number of funnel-shaped caveolae is found in the membranes of endothelial cells. Caveolae are special types of lipid rafts, lipid-rich membrane domains. They contain large quantities of caveolin proteins and are involved in endocytosis, to give just one example of their potential functions. This type of cellular uptake is ideal for pathogens, which survive the intrusion into the human body because the substances that are enclosed by the caveosomes (i.e. endosomes formed in the caveolar regions) are not necessarily degraded. 

Voigt’s experiments have shown that lipid particles with negatively charged PSS always home in on caveolae. The researchers therefore concluded that such nanoparticles are perfect for targeting endothelial cells. 

In addition, Voigt is also investigating how free polystyrene sulfonate molecules behave in a solution with endothelial cells and found that the molecules blocked the caveosomal uptake of other nanoparticles and prevented them from being endocytosed. “This is a general principle, and is not just restricted to the particles we are investigating. We have identified a chemical substance that binds to a biological structure,” says Voigt pointing out that PSS is not very specific, that the basic structure is all that matters and that other lipophilic molecules with similar structures can also be used.

Nanoparticle synthesis per ouzo effect

Chemist Julia Voigt (left) and a colleague synthesize PSS nanoparticles. © Julia Voigt, University of Freiburg

The PSS nanoparticles are easy to produce; their production is based on the well-known ouzo effect, also known as the louche effect. Ouzo is a transparent liquid with a high alcohol content. The alcohol dissolves strongly hydrophobic essential anisole. The addition of water turns the liquid into a milky emulsion. This is because the essential oils dissolve well in alcohol, but not so well or not at all in water. The addition of water leads to an oil-in-water emulsion where oil particles are surrounded by water. Light is scattered at the oil-water interface, which is a purely physical effect, the solution appears milky and the particles precipitate. Voigt uses acetone instead of alcohol, and lipid spheres instead of anisole, but the mechanism is exactly the same. “I can alter the surface of my particles just by adding different electrolytes to the water. I used PSS, which led to the modification of the nanoparticles by giving them the properties we were after,” says Voigt.

The researchers’ nanoparticles have the potential to be used as drug delivery systems for the treatment of tumours. Many chemotherapy and other drugs are fat-soluble and therefore cannot be administered by way of injection into the blood circulation. Nano-pills made of lipids can be used to enclose the anti-tumour drug and they carry negatively charged PSS, which specifically recognize epithelial cells. One option might be to inject the nano-pills directly into the tumour tissue where they would then destroy the epithelial cells that make up the blood vessels of tumours and thus starve the tumour by cutting it off from the supply of nourishment. Another option is to combine the nanoparticle strategy with other targeting methods in order to make some parts of the nanoparticles specific for cancer cells and some specific for endothelial cells. “Tumours often recur after chemotherapy as the treatment does not destroy all cancer cells. Some cancer cells can remain and the cancer might come back,” says Voigt suggesting that the outcome of chemotherapy might be improved by simultaneously targeting and eliminating cancer cells and epithelial cells that supply the tumour with nourishment.

Further information:
Prof. Dr. V. Prasad Shastri
Institute for Macromolecular Chemistry and BIOSS
University of Freiburg
Stefan-Meier-Str. 31
79104 Freiburg
Tel.: +49 (0)761 / 203 - 6268
E-mail: prasad.shastri(at)makro.uni-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/synthetic-nanoparticles-as-mini-pills-for-the-treatment-of-tumours