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How Cell Cycle and Autophagy Impact Nanodrug Uptake

Study reveals key factors influencing nanodrug effectiveness in cancer cells.

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Nanodrugs are tiny particles used in medicine to deliver drugs in a more effective way. They have special properties because of their small size, which makes them useful for treating various diseases. Among different types of nanodrugs, lipid-based nanoparticles like Liposomes and Lipid Nanoparticles are particularly important. They help carry drugs to targeted areas in the body, improving treatment outcomes. For example, Doxil® is a widely used cancer drug that uses liposomes to deliver doxorubicin, while BNT162b2 is an mRNA vaccine that uses lipid nanoparticles.

The Role of Cell Cycle and Autophagy

Cells go through a process called the cell cycle, which involves growth and division. Different types of cells are in different stages of this cycle at any time. This is particularly true for cancer cells, which can be in various phases that affect how they respond to treatment. Researchers have found that cancer cells' ability to take up nanodrugs can depend on which phase of the cell cycle they are in. This variability, known as cell cycle heterogeneity, presents challenges in treating cancer effectively.

Another crucial process is autophagy, which helps cells maintain balance and respond to stress. Cancer cells often rely more on autophagy than healthy cells. This dependence on autophagy can also affect how well these cells take up nanodrugs. Previous research has shown that the interaction between cell cycle phases and autophagy may play a role in how effectively nanoparticles are taken up by cells.

Current Research Gaps

While there have been some studies on how the cell cycle affects the uptake of inorganic nanoparticles, there is limited information regarding organic nanoparticles like liposomes and lipid nanoparticles. Many studies have faced challenges, such as difficulties in accurately identifying different phases of the cell cycle or using techniques that disturb the cells during experiments. These issues have made it hard to draw clear conclusions from previous research.

A Novel Approach to Study Nanoparticle Uptake

To better understand how the cell cycle and autophagy influence the uptake of nanodrugs, researchers designed a study using special cancer cell lines. These cell lines were genetically modified to indicate the different phases of the cell cycle clearly. By combining this genetic modification with a method to collect cells in the M-phase of the cycle more easily, researchers could study how well different cell types took up lipid-based nanoparticles without interfering with their normal functions.

The researchers used two types of nanoparticles-liposomes and lipid nanoparticles-each labeled with a fluorescent dye for easy tracking. They treated the modified cancer cells with these nanodrugs and examined how much was taken up during different phases of the cell cycle.

Findings on Nanoparticle Uptake Across Cell Cycle Phases

Using advanced imaging techniques, the researchers captured images of the modified cancer cells treated with the nanodrugs. They measured how much of the fluorescent dye was present in the cells during the different phases of the cell cycle. The data suggested that M-phase cells took up the least amount of nanoparticles, while G2-phase cells took up the most.

The findings indicated a trend: as cells progressed from the G1-phase to the G2-phase, the uptake of nanoparticles increased. However, once the cells entered the M-phase, the uptake decreased significantly. This trend was consistent for both types of nanoparticles used in the study.

Implications of Autophagy on Nanoparticle Uptake

In addition to the cell cycle, the researchers also examined how autophagy affected the uptake of the nanoparticles. They found that cells lacking the autophagy-related gene ATG7 took up more nanoparticles compared to those with normal autophagy functions. This suggests that blocking autophagy could potentially increase the effectiveness of treatment with nanodrugs.

The results show that the interaction between the cell cycle and autophagy is complex but important for understanding how cancer cells respond to treatment. This knowledge opens up possibilities for combining nanodrugs with autophagy inhibitors, which could enhance the effectiveness of cancer therapies.

Conclusion

This research sheds light on how specific phases of the cell cycle and autophagy influence the uptake of lipid-based nanoparticles in cancer cells. By utilizing advanced techniques to examine these interactions, the study provides valuable insights for optimizing the use of nanodrugs in medicine. As more than 3,200 formulations of lipid-based nanoparticles are currently being tested in clinical trials, understanding these dynamics can contribute to developing more effective cancer treatments.

The findings emphasize the need for ongoing research to explore the exact mechanisms at play during nanoparticle uptake and how these can be leveraged for better therapeutic outcomes. Early indications suggest that refining treatment approaches based on cell cycle and autophagy interactions may yield promising avenues for future cancer therapies.

Original Source

Title: Construction and application of a technical platform for determining cell cycle- and autophagy-associated cellular accumulation of lipid-based nanoparticles

Abstract: Cellular accumulation of biomedical nanoparticles could be affected by cellular biological properties. However, little is known about the influence of cell cycle and autophagy on nanoparticle accumulation. Whats even more tough is that several long-lasting methodological barriers have hampered the experimental performance and restricted related research progress. Herein, a multi-functional platform was constructed for simultaneously overcoming existing obstacles by integrating several technical approaches, particularly mitotic shake-off, for thorough cell cycle phase separation. Strikingly, application of this platform revealed that G2-phase and M-phase cells, two cell populations previously muddled up together as G2/M-phase cells, respectively exhibited the maximum and minimum accumulation of lipid-based nanoparticles. Moreover, although further verification is needed, we have provided a novel line of evidence for enhanced nanoparticle accumulation by autophagy blockade. Besides providing a technical solution, this study discovered characteristic cell cycle- and autophagy-associated nanoparticle accumulations that may offer new insights for optimization and application of nanomedicines.

Authors: Meihua Sui, Y. Wang, G. Luo, H. Wang, Y. Zheng, X. Xu, W. Zhou, J. Lin, B. Chen, Y. Jin

Last Update: Nov 4, 2024

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2024.02.19.579560

Source PDF: https://www.biorxiv.org/content/10.1101/2024.02.19.579560.full.pdf

Licence: https://creativecommons.org/licenses/by-nc/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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