Abstract
Nanotechnology offers advanced biomedical tools for diagnosis and drug delivery, stressing the value of investigating the mechanisms by which nanocarriers interact with the biological environment. Herein, the cellular response to CD44-targeted nanoparticles (NPs) was investigated. CD44, the main hyaluronic acid (HA) receptor, is widely exploited as a target for therapeutic purposes. HA NPs were produced by microfluidic platform starting from HA with different molecular weights (Mw, 280, 540, 820 kDa) by polyelectrolyte complexation with chitosan (CS). Thanks to microfluidic technology, HA/CS NPs with the same physical features were produced, and only the effects of HA Mw on CD44-overexpressing cells (human mesenchymal stem cells, hMSCs) were studied. This work provides evidence of the HA/CS NPs biocompatibility regardless the HA Mw and reveals the effect of low Mw HA in improving the cell proliferation. Special attention was paid to the endocytic mechanisms used by HA/CS NPs to enter hMSCs. The results show the notable role of CD44 and the pronounced effect of HA Mw in the NPs’ internalization. HA/CS NPs uptake occurs via different endocytic pathways simultaneously, and most notably, NPs with 280 kDa HA were internalized by clathrin-mediated endocytosis. Instead, NPs with 820 kDa HA revealed a greater contribution of caveolae and cytoskeleton components.
Highlights
Over the last years, the development of nanotechnology to diagnose, screen, treat and prevent diseases has been significantly improved if it is considered that 43 nanomedicines have been approved by the European Medicines Agency (EMA), 71 by the US Food andDrug administration (FDA) and another 128 are currently in clinical trials [1,2].nanotechnology is expected to play an important role in providing new tools for various biomedical applications and create new solutions for the diagnosis and therapy of currently uncurable diseases [3,4]
We aim to highlight if a relationship exists between hyaluronic acid (HA) molecular weight (Mw) and the CD44-mediated NPs internalization and extent of binding
NPs’ uptake mechanism, HA/CS NPs made of different HAs (280, 540, 820 kDa Mw) but with similar sizes, size distributions and surface charges were produced
Summary
Nanotechnology is expected to play an important role in providing new tools for various biomedical applications and create new solutions for the diagnosis and therapy of currently uncurable diseases [3,4]. For the application of nanoparticles (NPs) as treatment of disease, the role. Pharmaceuticals 2022, 15, 103 of NPs targeting is crucial. The accumulation of NPs in a diseased tissue can be achieved by “passive” or “active” targeting. The unique size of NPs is responsible for passive targeting. Owning to their nanometric dimensions NPs are able to pass through loose junctions and accumulate in a diseased tissue, but they suffer from several limitations such as lack of control in uptake and, being off-target drug delivery. Active targeting exploits a targeting moiety (e.g., ligand, antibody, peptide) and its interaction with a receptor which is upregulated in a diseased tissue results in a less off-target delivery [6,7]
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