Autophagic blockage by metformin-loaded PLGA nanoparticles causes cell cycle arrest of HepG2 cells

Aim: To fabricate and characterize metformin-loaded PLGA nanoparticles and investigate their inhibitory effect on HepG2 cells. Materials & methods: The nanoparticles were prepared using a double emulsification method, then characterized and subjected to a series of in vitro assays on HepG2 cells. Results: The nanoparticles were similar to 277.9 nm in size, and the entrapment efficiency and drug loading of metformin were 31.3 and 14.4%, respectively. In vitro studies suggested that the nanoparticles showed a higher inhibitory effect on HepG2 cells compared with metformin alone, mainly attributed to its blockage of autophagy, and ultimately result in cell cycle inhibition. Conclusion: The metformin-loaded PLGA nanoparticles could inhibit mTOR activity, increase p53 levels and decrease HIF1A levels, which ultimately caused HepG2 cell cycle arrest. Plain language summary: Metformin, a well-known drug for the treatment of diabetes, has potential anticancer effects. Our experiment is fabricating metformin into nanoformulations (tiny particles) to enhance its anticancer effect. Cancer cells respond to nutrient-deficient environments by autophagy, this involves breaking down internal structures to scavenge for nutrients, which is one of the reasons why cancer cells are so resilient. If we can interfere with this autophagy of cancer cells, we can reduce the viability of cancer cells. Speaking of autophagy, we have tomention lysosomes, which are acidic organelles within the cell that are the end point of autophagy. Lysosomes need to maintain an acidic environment to ensure the activity of various enzymes within them. These enzymes break down a variety of biological components into 'building blocks' which can be used to make other structures. Our study found that the nanoformulation disrupts the lysosomal acidic environment and thus causes autophagy blockage. As a result, cancer cells are unable to cope with nutrient deficiencies through autophagy and suffer the negative effects of autophagy blockage, such as the inability to degrade damaged organelles and proteins within the cancer cell. This causes the growth and proliferation of cancer cells to slow down and results in the death of the cancer cells.