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Published on: February 8, 2017
Targeted crystallization of mixed-charge nanoparticles in lysosomes induces selective death of cancer cells
Magdalena Borkowska1, Marta Siek1, Diana V Kolygina1,2
1Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan, Republic of Korea.
Abstract:
Lysosomes have become an important target for anticancer therapeutics because lysosomal cell death bypasses the classical caspase-dependent apoptosis pathway, enabling the targeting of 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. Here, we show that 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. This selectivity results from distinct pH-dependent aggregation events, starting from the formation of small, endocytosis-prone clusters at cell surfaces and ending with the formation of large and well-ordered nanoparticle assemblies and crystals inside cancer lysosomes. These assemblies cannot be cleared by exocytosis and cause lysosome swelling, which gradually disrupts the integrity of lysosomal membranes, ultimately impairing lysosomal functions and triggering cell death.
Insights
Researchers developed mixed-charge nanoparticles that selectively target cancer cell lysosomes. These nanoparticles induce lysosome swelling and cell death, offering a new approach for treating apoptosis-resistant cancers.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapeutics
Background:
- Lysosomes are key targets for anticancer drugs, offering an alternative cell death pathway that bypasses apoptosis resistance.
- Current lysosome-targeting agents lack cancer selectivity, limiting their use to combination therapies.
Purpose of the Study:
- To develop novel nanoparticles with enhanced selectivity for cancer cell lysosomes.
- To investigate the mechanism of nanoparticle-induced lysosomal disruption and cancer cell death.
Main Methods:
- Synthesized mixed-charge nanoparticles with varying ratios of positive and negative ligands.
- Investigated nanoparticle uptake and intracellular fate in cancer versus normal cells.
- Analyzed nanoparticle-induced changes in lysosomal morphology and function using microscopy and biochemical assays.
Main Results:
- Mixed-charge nanoparticles selectively accumulated in cancer cell lysosomes.
- pH-dependent nanoparticle aggregation within lysosomes led to lysosome swelling and membrane disruption.
- Impaired lysosomal function triggered cancer cell death, with minimal toxicity to normal cells.
Conclusions:
- Mixed-charge nanoparticles represent a promising strategy for selective cancer therapy by targeting lysosomal pathways.
- Nanoparticle-induced lysosomal dysfunction offers a novel mechanism to overcome apoptosis resistance in cancer treatment.
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