PLGA Nanoparticles Grafted with Hyaluronic Acid to Improve Site-Specificity and Drug Dose Delivery in Osteoarthritis Nanotherapy

Luana Zerrillo; Maria Rosa Gigliobianco; Domenico D’atri; Joao Pedro Garcia; Fabio Baldazzi; Yanto Ridwan; Gastón Fuentes; Alan Chan; Laura B. Creemers; Roberta Censi; Piera Di Martino; Luis J. Cruz

doi:10.3390/nano12132248

PLGA Nanoparticles Grafted with Hyaluronic Acid to Improve Site-Specificity and Drug Dose Delivery in Osteoarthritis Nanotherapy

Luana Zerrillo, Maria Rosa Gigliobianco, Domenico D’atri, Joao Pedro Garcia, Fabio Baldazzi, Yanto Ridwan, Gastón Fuentes, Alan Chan, Laura B. Creemers, Roberta Censi, Piera Di Martino, Luis J. Cruz^*

^*Corresponding author for this work

Radiology & Nuclear Medicine

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Nanoparticles (NPs) have a tremendous potential in medicinal applications, and recent studies have pushed the boundaries in nanotherapy, including in osteoarthritis treatments. The aim of this study was to develop new poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) surfaces decorated with hyaluronic acid (HA) to enhance targeted drug specificity to the osteoarthritic knee joint. HA was selected since it binds to specific receptors expressed in many cells, such as the cluster determinant 44 (CD44), a major receptor of chondrocytes, and because of its function in the synovial fluid (SF), such as maintenance of high fluid viscosity. The PLGA polymer was grafted to sodium hyaluronate using dimethoxy-PEG (PLGA-HA) and compared with control PLGA NPs (not grafted). NPs were characterized by 1H-NMR and IR spectroscopy. Then, near-infrared (NIR) dye and gold (20 nm) were encapsulated in the formulated NPs and used to access NPs’ performance in in vitro, in vivo, and ex vivo experiments. To test the NPs’ CD44 receptor specificity, an antibody assay was performed. All NPs presented a size in the range viable for cell-uptake, no cytotoxicity to chondrocytes was registered. Although all the NPs had a high capacity to be absorbed by the cells, PLGA-HA NPs showed significantly higher affinity towards the chondrocytic C28/I2 cell line. In conclusion, PLGA NPs grafted to sodium hyaluronate showed increased binding to cartilage cells and tissue and enhanced accumulation at the target site. Thus, this study presents a safe drug-delivery system with improved receptor specificity, which may represent an advantageous alternative to current nanotherapies.

Original language	English
Article number	2248
Journal	Nanomaterials
Volume	12
Issue number	13
DOIs	https://doi.org/10.3390/nano12132248
Publication status	Published - 30 Jun 2022

Bibliographical note

Funding Information:
Conflicts of Interest: This research was fully sponsored by European Union Horizon 2020 grants. All grant agreements between the participating parties were put in place before the study was initiated. The authors declare that the work and output were not predisposed to any commercial or financial relationships, neither at the beginning nor end of the study, that could be construed as a potential conflict of interest.

Funding Information:
Funding: This work was supported by the following European Union project grants: H2020-MSCA-ITN-2014 TargetCaRe (642414), H2020-MSCA-ITN-2015 ISPIC (675743), H2020-MSCA-RISE-2016 CHARMED (734684), and H2020-MSCA-RISE-2017 CANCER (777682).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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PLGA Nanoparticles Grafted with Hyaluronic Acid to Improve Site-Specificity and Drug Dose Delivery in Osteoarthritis NanotherapyFinal published version, 3.06 MBLicence: CC BY

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Zerrillo, L., Gigliobianco, M. R., D’atri, D., Garcia, J. P., Baldazzi, F., Ridwan, Y., Fuentes, G., Chan, A., Creemers, L. B., Censi, R., Martino, P. D., & Cruz, L. J. (2022). PLGA Nanoparticles Grafted with Hyaluronic Acid to Improve Site-Specificity and Drug Dose Delivery in Osteoarthritis Nanotherapy. Nanomaterials, 12(13), Article 2248. https://doi.org/10.3390/nano12132248

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abstract = "Nanoparticles (NPs) have a tremendous potential in medicinal applications, and recent studies have pushed the boundaries in nanotherapy, including in osteoarthritis treatments. The aim of this study was to develop new poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) surfaces decorated with hyaluronic acid (HA) to enhance targeted drug specificity to the osteoarthritic knee joint. HA was selected since it binds to specific receptors expressed in many cells, such as the cluster determinant 44 (CD44), a major receptor of chondrocytes, and because of its function in the synovial fluid (SF), such as maintenance of high fluid viscosity. The PLGA polymer was grafted to sodium hyaluronate using dimethoxy-PEG (PLGA-HA) and compared with control PLGA NPs (not grafted). NPs were characterized by 1H-NMR and IR spectroscopy. Then, near-infrared (NIR) dye and gold (20 nm) were encapsulated in the formulated NPs and used to access NPs{\textquoteright} performance in in vitro, in vivo, and ex vivo experiments. To test the NPs{\textquoteright} CD44 receptor specificity, an antibody assay was performed. All NPs presented a size in the range viable for cell-uptake, no cytotoxicity to chondrocytes was registered. Although all the NPs had a high capacity to be absorbed by the cells, PLGA-HA NPs showed significantly higher affinity towards the chondrocytic C28/I2 cell line. In conclusion, PLGA NPs grafted to sodium hyaluronate showed increased binding to cartilage cells and tissue and enhanced accumulation at the target site. Thus, this study presents a safe drug-delivery system with improved receptor specificity, which may represent an advantageous alternative to current nanotherapies.",

author = "Luana Zerrillo and Gigliobianco, {Maria Rosa} and Domenico D{\textquoteright}atri and Garcia, {Joao Pedro} and Fabio Baldazzi and Yanto Ridwan and Gast{\'o}n Fuentes and Alan Chan and Creemers, {Laura B.} and Roberta Censi and Martino, {Piera Di} and Cruz, {Luis J.}",

note = "Funding Information: Conflicts of Interest: This research was fully sponsored by European Union Horizon 2020 grants. All grant agreements between the participating parties were put in place before the study was initiated. The authors declare that the work and output were not predisposed to any commercial or financial relationships, neither at the beginning nor end of the study, that could be construed as a potential conflict of interest. Funding Information: Funding: This work was supported by the following European Union project grants: H2020-MSCA-ITN-2014 TargetCaRe (642414), H2020-MSCA-ITN-2015 ISPIC (675743), H2020-MSCA-RISE-2016 CHARMED (734684), and H2020-MSCA-RISE-2017 CANCER (777682). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - D’atri, Domenico

AU - Garcia, Joao Pedro

AU - Baldazzi, Fabio

AU - Ridwan, Yanto

AU - Fuentes, Gastón

AU - Chan, Alan

AU - Creemers, Laura B.

AU - Censi, Roberta

AU - Martino, Piera Di

AU - Cruz, Luis J.

N1 - Funding Information: Conflicts of Interest: This research was fully sponsored by European Union Horizon 2020 grants. All grant agreements between the participating parties were put in place before the study was initiated. The authors declare that the work and output were not predisposed to any commercial or financial relationships, neither at the beginning nor end of the study, that could be construed as a potential conflict of interest. Funding Information: Funding: This work was supported by the following European Union project grants: H2020-MSCA-ITN-2014 TargetCaRe (642414), H2020-MSCA-ITN-2015 ISPIC (675743), H2020-MSCA-RISE-2016 CHARMED (734684), and H2020-MSCA-RISE-2017 CANCER (777682). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/6/30

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N2 - Nanoparticles (NPs) have a tremendous potential in medicinal applications, and recent studies have pushed the boundaries in nanotherapy, including in osteoarthritis treatments. The aim of this study was to develop new poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) surfaces decorated with hyaluronic acid (HA) to enhance targeted drug specificity to the osteoarthritic knee joint. HA was selected since it binds to specific receptors expressed in many cells, such as the cluster determinant 44 (CD44), a major receptor of chondrocytes, and because of its function in the synovial fluid (SF), such as maintenance of high fluid viscosity. The PLGA polymer was grafted to sodium hyaluronate using dimethoxy-PEG (PLGA-HA) and compared with control PLGA NPs (not grafted). NPs were characterized by 1H-NMR and IR spectroscopy. Then, near-infrared (NIR) dye and gold (20 nm) were encapsulated in the formulated NPs and used to access NPs’ performance in in vitro, in vivo, and ex vivo experiments. To test the NPs’ CD44 receptor specificity, an antibody assay was performed. All NPs presented a size in the range viable for cell-uptake, no cytotoxicity to chondrocytes was registered. Although all the NPs had a high capacity to be absorbed by the cells, PLGA-HA NPs showed significantly higher affinity towards the chondrocytic C28/I2 cell line. In conclusion, PLGA NPs grafted to sodium hyaluronate showed increased binding to cartilage cells and tissue and enhanced accumulation at the target site. Thus, this study presents a safe drug-delivery system with improved receptor specificity, which may represent an advantageous alternative to current nanotherapies.

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PLGA Nanoparticles Grafted with Hyaluronic Acid to Improve Site-Specificity and Drug Dose Delivery in Osteoarthritis Nanotherapy

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