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Targeted crystallization of mixed-charge nanoparticles in lysosomes induces selective death of cancer cells

Mixed charge nanoparticles targeting the lysosomes in cancerous cell with marginal cytotoxicity

 

Lysosomal organelles comprise a dynamic system of acidic vesicular compartments (pH ≈ 4.8) receiving cargoes from the plasma membrane destined for degradation and/or recycling. In cancer cells, these degradation pathways are deregulated, causing various alterations in the structure and function of lysosomal membranes. lysosomal cell death (LCD)4 triggered by LMP commonly bypasses the classical caspase-dependent apoptosis pathway, opening up a new strategy for targeting apoptosis- and drug-resistant cancers. However, only a few small molecules—mostly repurposed drugs—have been tested so far, and these typically exhibit low cancer selectivity, making them suitable only for combination therapies.


Mixed charge nanoparticles in cancer lysosomes for selective killing of cancer cells

 

Prof. Gryzybowski with the Prof. Cho in collaboration demonstrated mixed-charge nanoparticles covered with certain ratios of positively and negatively charged ligands can selectively target lysosomes in cancerous cells while exhibiting only marginal cytotoxicity towards normal cells. These effects emerge from a remarkable succession of transport and aggregation phenomena: NP clustering at the cell surface and internalization of ~50–100 nm NP clusters via endocytosis, their gradual accumulation in multivesicular endosomes followed by transport to the lysosomes, further pH-dependent assembly into ordered [+/−] NP supracrystals inside lysosomes, induction of osmotic flows and lysosomal swelling, gradual loss of the integrity of lysosomal membranes and, finally, cell death. In contrast, in normal cells, [+/−] NP aggregation is limited and they are excluded from cells via exocytosis, causing these cells little harm.

 

The study has been supported through the IBS Center for Soft and Living Matter.

 

This work is detailed in a paper published in the Nature nanotechnology, and highlighted on the front cover (M. Borkowska et al., Targeted crystallization of mixed-charge nanoparticles in lysosomes induces selective death of cancer cells, Nature Nanotechnology) DOI: 10.1038s41565-020-0643-3.