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Open AccessArticle

On-Chip Synthesis of Hyaluronic Acid-Based Nanoparticles for Selective Inhibition of CD44+ Human Mesenchymal Stem Cell Proliferation

1
Department Drug Sciences, University of Pavia, V.le Taramelli 12, 27100 Pavia, Italy
2
Department of Public Health, Experimental and Forensic Medicine, Histology and Embryology Unit, University of Pavia, Via Forlanini 10, 27100 Pavia, Italy
3
Polymerix srl, V.le Taramelli 24, 27100 Pavia, Italy
4
Immunology and Transplantation Laboratory, Pediatric Hematology Oncology Unit, Department of Maternal and Children’s Health, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy
5
Department of Physics, University of Pavia, Via Bassi 6, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(3), 260; https://doi.org/10.3390/pharmaceutics12030260
Received: 17 February 2020 / Revised: 5 March 2020 / Accepted: 11 March 2020 / Published: 13 March 2020
(This article belongs to the Special Issue Microfluidics as a Tool for Drug Delivery)
In this study, an innovative microfluidics-based method was developed for one-step synthesis of hyaluronic acid (HA)-based nanoparticles (NPs), by exploiting polyelectrolytic interactions between HA and chitosan (CS), in order to improve reliability, reproducibility and possible scale-up of the NPs preparation. The on-chip synthesis, using a staggered herringbone micromixer, allowed to produce HA/CS NPs with tailored-made size and suitable for both parenteral (117.50 ± 4.51 nm) and loco-regional (349.15 ± 38.09 nm) administration, mainly composed by HA (more than 85% wt) with high negative surface charge (< −20 mV). HA/CS NPs were successfully loaded with a challenging water-insoluble molecule, Everolimus (EVE), an FDA- and EMA-approved anticancer drug able to lead to cell cycle arrest, reduced angiogenesis and promotion of apoptosis. HA/CS NPs resulted to be massively internalized in CD44+ human mesenchymal stem cells via CD44 receptor-mediated endocytosis. HA/CS NPs selectiveness towards CD44 was highlighted by blocking CD44 receptor by anti-CD44 primary antibody and by comparison to CS-based NPs cellular uptake. Eventually, high effectiveness in inhibiting cell proliferation was demonstrated on-chip synthetized EVE loaded HA/CS NPs by tracking in vitro DNA synthesis. View Full-Text
Keywords: hyaluronic acid-based nanocarriers; Everolimus; chitosan; microfluidics; CD44 targeting; human mesenchymal stem cells hyaluronic acid-based nanocarriers; Everolimus; chitosan; microfluidics; CD44 targeting; human mesenchymal stem cells
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MDPI and ACS Style

Chiesa, E.; Riva, F.; Dorati, R.; Greco, A.; Ricci, S.; Pisani, S.; Patrini, M.; Modena, T.; Conti, B.; Genta, I. On-Chip Synthesis of Hyaluronic Acid-Based Nanoparticles for Selective Inhibition of CD44+ Human Mesenchymal Stem Cell Proliferation. Pharmaceutics 2020, 12, 260.

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