nanoAUTOPHAGY - health implications of nanoparticle-induced changes in autophagy

nanoAUTOPHAGY’s main aim is to identify how various nanoparticles affect the cell’s “renovation system” called autophagy. This knowledge will enable us to predict nanomaterial toxicity and improve the use of nanoparticles in medicine. Autophagy is a cellular renovation mechanism taking place in the lysosomes, which degrades cytoplasmic cargo such as damaged organelles, protein aggregates, microorganisms, and unneeded proteins. The main function is to protect the cells against these potentially harmful components and to generate energy or recycle nutrients. When nanoparticles are taken up by cells, they most often accumulate in lysosomes and have been shown to affect this important lysosomal renovation process. Accumulation of toxic autophagic cargo is a known risk-factor in diseases such as cancer, chronic inflammatory diseases, and neurodegeneration. This implies that nanomaterial-induced impairment of autophagy could potentially have widespread consequences for human health. Our aim is to characterize how various types of nanomaterials affect the autophagic degradation activity, and we have therefore established a panel of methods to measure the activity of various types of autophagy. In collaboration with SINTEF we have studied a group of polymer nanoparticles developed as drug delivery vehicles. We have revealed that small structural differences in the nanoparticle composition affect autophagy at different stages, and we have elucidated some of the underlying mechanisms. Specifically, we have found that oxidative stress induced by the nanoparticle treatment has a dual effect on autophagy. Low levels of stress promote autophagy, whereas high levels block autophagy and eventually lead to cell death. We have identified some of the underlying signaling mechanisms also for this effect. Further, we work with various types of newer polymer-based and lipid-based nanomaterials, which have been developed to deliver either drugs, such as chemotherapy, or mRNA, and we specifically study how these types of nanomaterials affect autophagy in cancer cells and in normal cells.

In-depth knowledge of the interaction between nanoparticles and biological systems is imperative for optimal exploitation of nanomaterials in biomedicine, and for development of safe and sustainable nanotechnology. Previous studies have indicated that nanoparticles strongly affect autophagy - a lysosomal renovation mechanism responsible for maintaining cellular homeostasis by degrading damaged organelles and protein aggregates. Nanoparticle exposure leads to accumulation of autophagic structures and markers, which is commonly taken as evidence for increased autophagy. However, many toxic aspects of nanomaterials may rather be explained by a net inhibition of autophagic degradation capacity, resulting in oxidative stress, inflammation, and accumulation of toxic autophagic cargo. These effects are known risk-factors for diseases such as cancer, chronic inflammatory diseases, and neurodegeneration, which implies that nanomaterial-induced impairment of autophagy could potentially have widespread consequences for human health. In this project we will employ our strong expertise within the fields of autophagy, intracellular transport, and nanoparticle biology to identify the involvement of autophagy in known nanoparticle effects. We will first establish a comprehensive screening platform for detecting functional autophagy both in cellular systems and in vivo (fruit flies). By screening a panel of nanoparticles we will identify the intricate relationship between nanoparticle properties and changes in endolysosomal homeostasis and autophagy. Moreover, we will reveal the wide range of impacts such changes impose both in vitro and in vivo, by determining the impact on stress responses, neurotoxic aggregate-clearance, cell polarity and development. In sum, we anticipate that our studies will substantially improve our knowledge of the biological effects of nanoparticles on cells and organisms, which is key to harness nanomaterials in biomedicine and to predict nanotoxicity.

Publications from Cristin

Measuring Autophagic Cargo Flux with Keima-Based Probes

Perturbation of cellular redox homeostasis dictates divergent effects of polybutyl cyanoacrylate (Pbca) nanoparticles on autophagy

Cabazitaxel-loaded poly(alkyl cyanoacrylate) nanoparticles: Toxicity and changes in the proteome of breast, colon and prostate cancer cells

Mechanism of cellular uptake and cytotoxicity of paclitaxel loaded lipid nanocapsules in breast cancer cells.

Physicochemical characterization, toxicity and in vivo biodistribution studies of a discoidal, lipid-based drug delivery vehicle: Lipodisq nanoparticles containing doxorubicin

Structural Variants of poly(alkylcyanoacrylate) Nanoparticles Differentially Affect LC3 and Autophagic Cargo Degradation

Biological response and cytotoxicity induced by lipid nanocapsules

12

No publications found

Mammalian ATG8 proteins and the role of autophagy in cancer formation and progression

The effects of anti-cancer drug-nanomaterials on autophagy in malignant and non-malignant cells

Exploring autophagic inducers and inhibitors with cargo-based autophagy assays

Transautophagy: Research and Translation of Autophagy Knowledge 2020

Small variations in nanoparticle structure dictate differential cellular stress responses and mode of cell death

1

No publications found

No publications found