Drown in your own garbage
A group of researchers from the Institute of Fundamental Sciences and Ulsan National Institute of Science and Technology, South Korea, has discovered a new approach for the selective destruction of several types of cancer cells.
Lysosomes are bubbles filled with a large number of enzymes and acids that destroy and recycle damaged and unwanted cellular components. In other words, they are both a waste container and a recycling center. As a rule, lysosomes get rid of the by-products of the decomposition process by releasing their contents outside the cell. The destruction of the walls of lysosomes and the release of their toxic contents inside the cell leads to damage to cellular components that cannot be restored, and in extreme cases causes cell death.
Since the lysosomes of cancer cells are easier to damage than the lysosomes of normal cells, the researchers evaluated the possibility of using this strategy as a promising alternative for cancer therapy resistant to traditional treatments. The difficulty was that only a few potential therapeutic agents can affect lysosomes, and most of them lack selectivity for cancer.
A new study published in the journal Nature Nanotechnology shows that nanoparticles coated with a mixture of positively and negatively charged molecules can selectively kill cancer cells by affecting their lysosomes. The death of cancer cells is a consequence of a cascade of transport and aggregation phenomena, starting with the formation of small clusters of nanoparticles on the cell surface and ending with the assembly of micron-sized nanoparticle crystals inside cancer lysosomes. Crystals of nanoparticles cause lysosomal edema, gradual loss of integrity of lysosomal membranes and, finally, cell death.
The aggregation of nanoparticles with a mixed charge is supported by an acidic environment typical of cancer cells. Non-malignant cells also assimilate nanoparticles with a mixed charge, but their aggregation is limited, and nanoparticles quickly leave these cells.
The team compared thirteen different cell lines of sarcoma, melanoma, breast and lung cancer with four types of non-cancerous cells. The nanoparticles were effective against all thirteen cancer lines without harming normal cells.
Nanoparticles with a mixed charge destabilize the lysosomes of cancer cells and selectively destroy them. Histograms in the bottom row show that nanoparticles with a mixed charge selectively kill thirteen cancer cell lines (right), without harming four normal types and lines of epithelial or fibroblast cells (left).
Aggregation of nanoparticles during their passage through the endolysosomal system of cancer cells is a complex process. The researchers found that a mixture of nanoparticles containing ligands with a positive and negative charge (80% and 20%, respectively) demonstrates high selectivity in cancer, which is probably related to the pH sensitivity of negatively charged ligands. At the low (acidic) pH characteristic of cancer cells and cancer lysosomes, these ligands are protonated and interact with similar ligands on neighboring nanoparticles, contributing to their aggregation. The balance between mutual attraction (bonds between negative ligands and interactions of nanoparticle nuclei) and electrostatic repulsion between positively charged ligands on neighboring particles determines the degree of aggregation of nanoparticles. In general, the interaction of nanoparticles, serum proteins and the internal environment of cells consistently leads to the weakening of cancer lysosomes.
Clusters of nanoparticles can change the lipid composition of the lysosome membrane, affect its integrity and make it less mechanically stable. Unexpectedly, the group also found that some proteins, such as the cell growth signaling molecules mTORC1, are displaced from the surface of cancer lysosomes containing nanoparticles. This is important because the growth and division of cancer cells occurs in the presence of mTORC1, and nanoparticles turn it off in cancer cells.
Nanoparticles are about the same size as an average protein molecule, and therefore they are too small to be seen with most dynamic microscopy methods of living cells, but crystals consisting of several nanoparticles can be observed. The researchers used a combination of complementary approaches, including dark field microscopy, confocal microscopy and transmission electron microscopy, as well as biochemical and computational methods to fully assess the effects of mixed charge nanoparticles on lysosomal organelles.
The effect of aggregation of nanoparticles inside lysosomes. The image shows the trajectories of (white) lysosomes (red) in cancer (left) and normal (right) cells. Aggregates of nanoparticles (green) in cancer cells weaken the ability of lysosomes to explore the inside of the cell. Scale ruler = 10 microns.
The mixed charge strategy can be applied to other types of nanoparticles, such as polymer-based particles, dendrimers, or iron oxide nanoparticles.
The authors intend to test the effectiveness of nanoparticles with a mixed charge against tumors in animal models.
Article M.Borkowska et al. Targeted crystallization of mixed-charge nanoparticles in lysosomes induces selective death of cancer cells is published in the journal Nature Nanotechnology.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Institute of Basic Science: Selective killing of cancer cells by cluttering their waste disposal system.