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

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

Category
Academic article
Abstract
Nanoparticle drug carriers trigger a variety of cellular stress responses, including ER stress and antioxidant responses, but may also affect the intracellular degradative pathway autophagy. This can impose profound effects on drug delivery, cellular treatment responses, and nanoparticle cytotoxicity. We recently demonstrated that even small variations in the alkyl side chains of poly(alkylcyanoacrylate) (PACA) drug carrier nanoparticles, namely butyl (PBCA), ethylbutyl (PEBCA), or octyl (POCA), differentially induce ER stress and redox imbalance in human cell lines. Here, we systematically investigate how these PACA variants affect autophagy. Interestingly, treatment with PEBCA or POCA particles led to intracellular accumulation of the autophagosome marker LC3-II, but via different mechanisms. PEBCA induced an integrated stress response-and ATF4-mediated increase in LC3B mRNA, whereas POCA blocked autophagic degradation of LC3-II and long-lived proteins in bulk. PBCA also increased LC3B mRNA via the integrated stress response and ATF4, but unlike PEBCA, it inhibited LC3 lipidation and autophagic cargo degradation. Our data demonstrate that even subtle variations in NP structure can have profoundly different impacts on autophagy, and that careful monitoring of autophagic flux and cargo degradation is critical for drawing accurate conclusions. Our findings have important implications for the choice of PACA monomer in different therapeutic settings.
Client
  • Research Council of Norway (RCN) / 274574
  • Research Council of Norway (RCN) / 228200
Language
English
Author(s)
  • Tonje Sønstevold
  • Nikolai Engedal
  • Yrr Asbjørg Mørch
  • Tore Geir Iversen
  • Tore Skotland
  • Kirsten Sandvig
  • Maria Lyngaas Torgersen
Affiliation
  • University of Oslo
  • Oslo University Hospital
  • SINTEF Industry / Biotechnology and Nanomedicine
Year
Published in
Journal of Biomedical Nanotechnology
ISSN
1550-7033
Publisher
American Scientific Publishers
Volume
16
Issue
4
Page(s)
432 - 445