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Targeting pentamidine towards CD44-overexpressing cells using hyaluronated lipid-polymer hybrid nanoparticles

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Abstract

Biodegradable nanocarriers possess enormous potential for use as drug delivery systems that can accomplish controlled and targeted drug release, and a wide range of nanosystems have been reported for the treatment and/or diagnosis of various diseases and disorders. Of the various nanocarriers currently available, liposomes and polymer nanoparticles have been extensively studied and some formulations have already reached the market. However, a combination of properties to create a single hybrid system can give these carriers significant advantages, such as improvement in encapsulation efficacy, higher stability, and active targeting towards specific cells or tissues, over lipid or polymer-based platforms. To this aim, this work presents the formulation of poly(lactic-co-glycolic) acid (PLGA) nanoparticles in the presence of a hyaluronic acid (HA)-phospholipid conjugate (HA-DPPE), which was used to anchor HA onto the nanoparticle surface and therefore create an actively targeted hybrid nanosystem. Furthermore, ionic interactions have been proposed for drug encapsulation, leading us to select the free base form of pentamidine (PTM-B) as the model drug. We herein report the preparation of hybrid nanocarriers that were loaded via ion-pairing between the negatively charged PLGA and HA and the positively charged PTM-B, demonstrating an improved loading capacity compared to PLGA-based nanoparticles. The nanocarriers displayed a size of below 150 nm, a negative zeta potential of -35 mV, a core-shell internal arrangement and high encapsulation efficiency (90%). Finally, the ability to be taken up and exert preferential and receptor-mediated cytotoxicity on cancer cells that overexpress the HA specific receptor (CD44) has been evaluated. Competition assays supported the hypothesis that PLGA/HA-DPPE nanoparticles deliver their cargo within cells in a CD44-dependent manner.

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All data generated or analyzed during this study are included in this published article. Additional data related to this paper may be requested from the authors.

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Acknowledgements

The authors thank ESRF for financial support and beamtime (https://doi.org/10.15151/ESRF-ES-1351189712), ID02 staff for technical support and PSCM facility (Grenoble) for allowing on-site sample preparation. E.D.F. thanks BIOMETRA Dept. for partial support (PSR2021_DEL_FAVERO). This work benefited from the use of the SasView application.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino, Italy

    Ilaria Andreana, Marta Chiapasco, Valeria Bincoletto, Maela Manzoli, Silvia Arpicco & Barbara Stella

  2. Dipartimento di Oncologia, Università di Torino, Torino, Italy

    Sabrina Digiovanni & Chiara Riganti

  3. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università di Milano, Milano, Italy

    Caterina Ricci & Elena Del Favero

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  1. Ilaria Andreana
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Contributions

Conceptualization: Chiara Riganti, Silvia Arpicco, Barbara Stella; Methodology: Elena Del Favero, Chiara Riganti, Silvia Arpicco, Barbara Stella; Formal analysis and investigation: Ilaria Andreana, Marta Chiapasco, Valeria Bincoletto, Sabrina Digiovanni, Maela Manzoli, Caterina Ricci, Elena Del Favero; Writing - original draft preparation: Ilaria Andreana; Writing - review and editing: Sabrina Digiovanni, Maela Manzoli, Caterina Ricci, Elena Del Favero, Chiara Riganti, Silvia Arpicco, Barbara Stella; Supervision: Barbara Stella.

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Correspondence to Barbara Stella.

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Andreana, I., Chiapasco, M., Bincoletto, V. et al. Targeting pentamidine towards CD44-overexpressing cells using hyaluronated lipid-polymer hybrid nanoparticles. Drug Deliv. and Transl. Res. 14, 2100–2111 (2024). https://doi.org/10.1007/s13346-024-01617-7

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