Nature Sub-journal: New breakthrough in the fight against cancer! Kill cancer cells by swelling the lysosomes!

April 5, 2020 /
Biovalley BIOON /-- nano
particles are covered with a mixture of positive and negative electricity ligands, clustered in the super-conditor of cancer cell lysosomes, destroying the integrity of the lysosome membrane and killing cells, but not any anti-cancer drugs nano-
medicine shows great potential in promoting the diagnosis and treatment of diseases To do this, the therapeutic diagnostic reagents are loaded onto nano
particles and/or into nanoparticles to increase their solubility while prolonging blood circulation in order to deliver the drug more efficiently to the lesionsite In addition, the pharmacokinetics and targeting efficiency of the drug can be improved by optimizing the size, shape and surface properties of the carrier Many nanoparticle-based drug systems have been approved for cancer treatment, and many more are undergoing clinical trials
or preclinical evaluation However, the challenges of clinical transformation remain, for example, off-target toxicity Despite extensive research, only a small fraction of the nanoparticles (usually less than 1%) of the nanoparticles that the system drugged can enter the of the tumor The rest carries toxic drugs into healthy tissues and organs, causing off-target toxicity and harmful side effects image source: http://cn.bing.com
So there's an urgent need to explore new strategies that either show better targeting or don't contain drugs at all In an article published in the journal Nature Nanotechnology, Borkowka et al proposed a "no-drug" strategy to kill cancer cells by controlling the aggregation of inert gold nanoparticles in lysosomes lysosomes are organelles that process waste and receive and digest goods from inside and outside the cell The accumulation of undigested substances causes the lysosome to expand, which increases the permeability of the lysosome membrane and ultimately leads to cell death Thus, lysosomes provide a target for cancer treatment by manipulating the aggregation of cargo, such as inert nanoparticles According to derjaguin, Landau, Verwey, and Overbeek (DLVO) theories, the agglomeration of nanoparticles relies heavily on long-distance electrostatic repulsions, which are sensitive to the charge on the surface of particles and the ion strength and pH of the medium These parameters can be used to control the agglomeration of nanoparticles Since the acidity of tumor tissue (pH s 6.5-6.9) is stronger than that of healthy tissue (pH-7.4), and the lysosome is stronger (pH-4.8), it provides activation for the polymerization behavior of the surface charge of the reasonably engineered nanoparticles when they interact with cells to achieve this concept, Borkowka et al have prepared nanoparticles with mixed surface charges (Figure 1b) by modifying their surfaces with positively charged N, N, N-trimethyl (11-trimethyl) ammonium chloride (TMA) and negatively charged 11-carpy argon (MUA) on the surface of 5 nanometers of gold nanoparticles respectively .1 The nanoparticles, mixed at a ratio of 4:1 (TMA:MUA), can aggregate the pH response to the pH in aqueous solution containing 10% of the fetal bovine serum, and can be gathered at pH at pH - 4.5 - -5.5 It is worth noting that these nanoparticles exhibit similar behavior in the culture of cancer cells They quickly cluster on the surface of the cell, with an extracellular pH of about 6.5 The clusters are swallowed internally and then condensed into larger particles in the more acidic lysosomes large accumulations of gold nanoparticles slow the movement of the lysosomes, making it difficult for them to be removed through cell vomiting In addition, nanoparticle aggregates increase osmotic pressure inside the lysosome, forcing the lysosome to expand Swelling increases the permeability of the lysosome membrane, which eventually leads to cell death; it is worth noting that this strategy works well for 13 different types of cancer cells, including sarcoma, breast cancer , prostate and lung cancer, and melanoma In contrast, healthy cells are not affected due to the neutral extracellular environment of healthy tissue Instead, nanoparticles are removed by cell vomiting and do not cause damage to normal cells Borkowka et al have shown that only nanoparticles with a ratio of 4:1 between TMA and MUA can kill cancer cells through pH-induced aggregation Nanoparticles covering only cationion ligands are cytotoxic to both cancerous and healthy cells This can be explained that pure cation nanoparticles can easily penetrate both types of cells through direct membrane penetration, making the mass film permeable Nanoparticles with more and more negative ion ligands lose cytotoxicity because they do not attach well to a negatively charged mass film, making them difficult to internalize image source: http://cn.bing.com
this cancer treatment involves only bio-inert and basic biocompatible gold nanoparticles The healing force comes from the aggregation of nanoparticles triggered by changes in the physical and chemical microenvironment of the cell and the lysosome As a result, the inevitable adverse effects of traditional therapies may be eliminated by design In addition, lysosome cell death provides a different mechanism for killing cancer cells than most anticancer drugs use, which may offer a new possibility to combat drug resistance Although the performance of mixed-charge nanoparticles in vitro selectively killing cancer cells is encouraging, there is still a long way to go to achieve clinical transformation First, it will be a major challenge to prove its effectiveness in the body, as the accumulation of nanoparticles is very sensitive to pH and is more complex in the biological environment of the body In addition, the removal of superproducts after treatment of disease is also a matter of concern One possible alternative is to use biodegradable polymers instead of gold nanoparticles However, precisely modifying the surface of polymer nanoparticles to achieve a specific proportion of the mixed surface charge will add a new challenge In addition, the mechanism of pH sensitivity aggregation of hybrid charged nanoparticles still needs to be fully understood The explicit effects of positively charged ligands, negatively charged ligands and protein crowns are all to be clarified and demonstrated In vitro data suggest that selective lying cancer cells by using pH-dependent nanoparticles to gather, provides a promising strategy for advancing cancer treatment and opens the door to potential disease treatment without addressing the adverse consequences associated with toxic drugs (BioValleyBioon.com) Reference: , Qiu, J., Xia, Y.
Killing cancer cell by rupturing theirlysly
Nat Nanotechnol (2020) http://doi.org/10.1038/41565-020-0639-z
Borkowka, M., Siek, M., Kolygina, D et al.
Targeted crytallization of mixed-charge nanoparticle in lyoome alysed i'r dlysion of cancer cell Nat Nanotechnol (2020) http://doi.org/10.1038/41565-020-0643-3.