Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

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.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Availability of data and materials

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.

References

  1. Mitchell MJ, et al. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20(2):101–24.

    Article  CAS  PubMed  Google Scholar 

  2. Fan YN, et al. Progress in nanoparticle-based regulation of immune cells. Med Rev (Berl). 2023;3(2):152–79.

    Article  Google Scholar 

  3. Zhang P, et al. Nbtxr3 radiotherapy-activated functionalized hafnium oxide nanoparticles show efficient antitumor effects across a large panel of human cancer models. Int J Nanomed. 2021;16:2761–73.

    Article  CAS  Google Scholar 

  4. Guo B, et al. Cuproptosis induced by ROS responsive nanoparticles with elesclomol and copper combined with αPD-L1 for enhanced cancer immunotherapy. Adv Mater. 2023;35(22):e2212267.

    Article  PubMed  Google Scholar 

  5. Rao Z, et al. Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination. J Nanobiotechnol. 2023;21(1):265.

    Article  CAS  Google Scholar 

  6. Tenchov R, et al. Lipid nanoparticles─from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano. 2021;15(11):16982–7015.

    Article  CAS  PubMed  Google Scholar 

  7. Park H, Otte A, Park K. Evolution of drug delivery systems: From 1950 to 2020 and beyond. J Control Release. 2022;342:53–65.

    Article  CAS  PubMed  Google Scholar 

  8. Liu Y, et al. Nanoparticles advanced from preclinical studies to clinical trials for lung cancer therapy. Cancer Nanotechnol. 2023;14(1):28.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ta HT, et al. The effects of particle size, shape, density and flow characteristics on particle margination to vascular walls in cardiovascular diseases. Expert Opin Drug Deliv. 2018;15(1):33–45.

    Article  CAS  PubMed  Google Scholar 

  10. Li X, et al. Design of Smart Size-, Surface-, and Shape-Switching Nanoparticles to Improve Therapeutic Efficacy. Small. 2022;18(6):e2104632.

    Article  PubMed  Google Scholar 

  11. Gamble JF, et al. Morphological distribution mapping: Utilisation of modelling to integrate particle size and shape distributions. Int J Pharm. 2023;635:122743.

    Article  CAS  PubMed  Google Scholar 

  12. Sivadasan D, et al. Polymeric lipid hybrid nanoparticles (PLNs) as emerging drug delivery platform-a comprehensive review of their properties, preparation methods, and therapeutic applications. Pharmaceutics. 2021;13(8):1291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jain S, et al. Lipid-polymer hybrid nanosystems: a rational fusion for advanced therapeutic delivery. J Funct Biomater. 2023;14(9):437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. He C, Lu J, Lin W. Hybrid nanoparticles for combination therapy of cancer. J Control Release. 2015;219:224–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dehaini D, et al. Erythrocyte-platelet hybrid membrane coating for enhanced nanoparticle functionalization. Adv Mater. 2017;29(16):10.1002.

  16. Ferreira Soares DC, et al. Polymer-hybrid nanoparticles: Current advances in biomedical applications. Biomed Pharmacother. 2020;131:110695.

    Article  CAS  PubMed  Google Scholar 

  17. Dhiman N, et al. Lipid nanoparticles as carriers for bioactive delivery. Front Chem. 2021;9:580118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yun P, Devahastin S, Chiewchan N. Microstructures of encapsulates and their relations with encapsulation efficiency and controlled release of bioactive constituents: A review. Compr Rev Food Sci Food Saf. 2021;20(2):1768–99.

    Article  CAS  PubMed  Google Scholar 

  19. Barenholz Y. Doxil®–the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34.

    Article  CAS  PubMed  Google Scholar 

  20. Adams D, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21.

    Article  CAS  PubMed  Google Scholar 

  21. Schoenmaker L, et al. mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. Int J Pharm. 2021;601:120586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jia Y, et al. Lipid nanoparticles optimized for targeting and release of nucleic acid. Adv Mater. 2024;36(4):2305300.

    Article  CAS  Google Scholar 

  23. Crommelin DJA, van Hoogevest P, Storm G. The role of liposomes in clinical nanomedicine development. What now? Now what? J Control Release. 2020;318:256–63.

    Article  CAS  PubMed  Google Scholar 

  24. Hald Albertsen C, et al. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv Drug Deliv Rev. 2022;188:114416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ding D, Zhu Q. Recent advances of PLGA micro/nanoparticles for the delivery of biomacromolecular therapeutics. Mater Sci Eng C Mater Biol Appl. 2018;92:1041–60.

    Article  CAS  PubMed  Google Scholar 

  26. Idrees H, et al. A review of biodegradable natural polymer-based nanoparticles for drug delivery applications. Nanomater (Basel). 2020;10(10):1970.

    Article  CAS  Google Scholar 

  27. Khalili L, et al. Smart active-targeting of lipid-polymer hybrid nanoparticles for therapeutic applications: Recent advances and challenges. Int J Biol Macromol. 2022;213:166–94.

    Article  CAS  PubMed  Google Scholar 

  28. Ghitman J, et al. Review of hybrid PLGA nanoparticles: Future of smart drug delivery and theranostics medicine. Mater Des. 2020;193:108805.

    Article  CAS  Google Scholar 

  29. Arpicco S, et al. Hyaluronic acid-coated liposomes for active targeting of gemcitabine. Eur J Pharm Biopharm. 2013;85(3 Pt A):373–80.

    Article  CAS  PubMed  Google Scholar 

  30. Zeng X, et al. pH-Responsive hyaluronic acid nanoparticles for enhanced triple negative breast cancer therapy. Int J Nanomedicine. 2022;17:1437–57.

    Article  PubMed  PubMed Central  Google Scholar 

  31. de Paula MC, et al. The role of hyaluronic acid in the design and functionalization of nanoparticles for the treatment of colorectal cancer. Carbohydr Polym. 2023;320:121257.

    Article  PubMed  Google Scholar 

  32. Stella B, et al. Pentamidine-loaded lipid and polymer nanocarriers as tunable anticancer drug delivery systems. J Pharm Sci. 2020;109(3):1297–302.

    Article  CAS  PubMed  Google Scholar 

  33. Andreana I, et al. Selective delivery of pentamidine toward cancer cells by self-assembled nanoparticles. Int J Pharm. 2022;625: 122102.

    Article  CAS  PubMed  Google Scholar 

  34. Andreana I, et al. Nanotechnological approaches for pentamidine delivery. Drug Deliv Transl Res. 2022;12(8):1911–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Peretti E, et al. Strategies to obtain encapsulation and controlled release of pentamidine in mesoporous silica nanoparticles. Pharmaceutics. 2018;10(4):195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fessi H, et al. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55(1):R1–4.

    Article  CAS  Google Scholar 

  37. Mandal TK, et al. Poly(D, L-lactide-co-glycolide) encapsulated poly(vinyl alcohol) hydrogel as a drug delivery system. Pharm Res. 2002;19(11):1713–9.

    Article  CAS  PubMed  Google Scholar 

  38. Doucet M, et al. SasView version 5.0.3. Zenodo. 2020. https://doi.org/10.5281/zenodo.3930098.

    Article  Google Scholar 

  39. Franze S, et al. Hyaluronan-decorated liposomes as drug delivery systems for cutaneous administration. Int J Pharm. 2018;535(1–2):333–9.

    Article  CAS  PubMed  Google Scholar 

  40. Cannito S, et al. Hyaluronated and PEGylated liposomes as a potential drug-delivery strategy to specifically target liver cancer and inflammatory cells. Molecules. 2022;27(3):1062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Franze S, et al. Rationalizing the design of hyaluronic acid-decorated liposomes for targeting epidermal layers: a combination of molecular dynamics and experimental evidence. Mol Pharm. 2021;18(11):3979–89.

    Article  CAS  PubMed  Google Scholar 

  42. Pandolfi L, et al. Liposomes loaded with everolimus and coated with hyaluronic acid: a promising approach for lung fibrosis. Int J Mol Sci. 2021;22(14):7743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Andreana I, et al. Freeze drying of polymer nanoparticles and liposomes exploiting different saccharide-based approaches. Mater (Basel). 2023;16(3):1212.

    Article  CAS  Google Scholar 

  44. Camara CI, et al. Hyaluronic acid-dexamethasone nanoparticles for local adjunct therapy of lung inflammation. Int J Mol Sci. 2021;22(19):10480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Di Cola E, et al. Novel O/W nanoemulsions for nasal administration: Structural hints in the selection of performing vehicles with enhanced mucopenetration. Colloids Surf B Biointerfaces. 2019;183:110439.

    Article  PubMed  Google Scholar 

  46. d’Angelo I, et al. Hybrid lipid/polymer nanoparticles for pulmonary delivery of siRNA: development and fate upon in vitro deposition on the human epithelial airway barrier. J Aerosol Med Pulm Drug Deliv. 2018;31(3):170–81.

    Article  CAS  PubMed  Google Scholar 

  47. Clementino AR, et al. Structure and fate of nanoparticles designed for the nasal delivery of poorly soluble drugs. Mol Pharm. 2021;18(8):3132–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li W, et al. Hyaluronic acid ion-pairing nanoparticles for targeted tumor therapy. J Control Release. 2016;225:170–82.

    Article  CAS  PubMed  Google Scholar 

  49. Chang G, et al. CD44 targets Na(+)/H(+) exchanger 1 to mediate MDA-MB-231 cells’ metastasis via the regulation of ERK1/2. Br J Cancer. 2014;110(4):916–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Corsetto PA, et al. Effects of n-3 PUFAs on breast cancer cells through their incorporation in plasma membrane. Lipids Health Dis. 2011;10:73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cano ME, et al. Synthesis of defined oligohyaluronates-decorated liposomes and interaction with lung cancer cells. Carbohydr Polym. 2020;248: 116798.

    Article  CAS  PubMed  Google Scholar 

  52. Nedeljković M, Damjanović A. Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge. Cells. 2019;8(9):957.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Muley H, et al. Drug uptake-based chemoresistance in breast cancer treatment. Biochem Pharmacol. 2020;177:113959.

    Article  CAS  PubMed  Google Scholar 

  54. Wang L, et al. Gold nanomaterial system that enables dual photothermal and chemotherapy for breast cancer. Pharmaceutics. 2023;15(9):2198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mirzaei S, et al. Dual-targeted delivery system using hollow silica nanoparticles with H(+)-triggered bubble generating characteristic coated with hyaluronic acid and AS1411 for cancer therapy. Drug Dev Ind Pharm. 2023;49(10):648-57.

    Article  Google Scholar 

  56. Abduh MS. Anticancer analysis of CD44 targeted cyclosporine loaded thiolated chitosan nanoformulations for sustained release in triple-negative breast cancer. Int J Nanomedicine. 2023;18:5713–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Spini A, et al. Repurposing of drugs for triple negative breast cancer: an overview. Ecancermedicalscience. 2020;14:1071.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.

Funding

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

Author information

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

Authors
  1. Ilaria Andreana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Chiapasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valeria Bincoletto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabrina Digiovanni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maela Manzoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Caterina Ricci
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elena Del Favero
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chiara Riganti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Silvia Arpicco
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Barbara Stella
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Barbara Stella.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors approved the version to be published.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 134 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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. (2024). https://doi.org/10.1007/s13346-024-01617-7

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13346-024-01617-7

Keywords

Search

Navigation