Hyaluronic Acid-Decorated Chitosan Nanoparticles for CD44-Targeted Delivery of Everolimus.

Enrica Chiesa,Tiziana Modena,Bice Conti,Ida Genta,Rossella Dorati,Emanuela Cova,Federica Meloni

doi:10.3390/ijms19082310

Abstract

Bronchiolitis obliterans syndrome (BOS), caused by lung allograft-derived mesenchymal cells’ abnormal proliferation and extracellular matrix deposition, is the main cause of lung allograft rejection. In this study, a mild one-step ionotropic gelation method was set up to nanoencapsulate the everolimus, a key molecule in allograft organ rejection prevention, into hyaluronic acid-decorated chitosan-based nanoparticles. Rationale was the selective delivery of everolimus into lung allograft-derived mesenchymal cells; these cells are characterized by the CD44-overexpressing feature, and hyaluronic acid has proven to be a natural selective CD44-targeting moiety. The optimal process conditions were established by a design of experiment approach (full factorial design) aiming at the control of the nanoparticle size (≤200 nm), minimizing the size polydispersity (PDI 0.171 ± 0.04), and at the negative ζ potential maximization (−30.9 mV). The everolimus was successfully loaded into hyaluronic acid-decorated chitosan-based nanoparticles (95.94 ± 13.68 μg/100 mg nanoparticles) and in vitro released in 24 h. The hyaluronic acid decoration on the nanoparticles provided targetability to CD44-overexpressing mesenchymal cells isolated from bronchoalveolar lavage of BOS-affected patients. The mesenchymal cells’ growth tests along with the nanoparticles uptake studies, at 37 °C and 4 °C, respectively, demonstrated a clear improvement of everolimus inhibitory activity when it is encapsulated in hyaluronic acid-decorated chitosan-based nanoparticles, ascribable to their active uptake mechanism.

Highlights

Everolimus (EVE), a macrocyclic lactone derivative of Sirolimus, has recently emerged as a key maintenance immunosuppressive molecule in therapies for preventing acute and chronic allograft organ rejection [1,2,3]
Rationale was the selective delivery of everolimus into lung allograft-derived mesenchymal cells; these cells are characterized by the CD44-overexpressing feature, and hyaluronic acid has proven to be a natural selective CD44-targeting moiety
For these patients, survival continues to be challenged by chronic allograft dysfunctions, such as obliterative bronchiolitis or its clinical correlate bronchiolitis obliterans syndrome (BOS), a fibrous obliteration of small airways caused by mesenchymal cells (MSc) abnormal proliferation, and extracellular matrix deposition causing bronchiolar occlusion and organ rejection [8,9,10,11]

Summary

Introduction

Everolimus (EVE), a macrocyclic lactone derivative of Sirolimus, has recently emerged as a key maintenance immunosuppressive molecule in therapies for preventing acute and chronic allograft organ rejection [1,2,3]. EVE is successfully used in combination with cyclosporine and corticosteroids both in adult and paediatric population of renal- and cardiac-transplant recipients, but far less often for lung-transplant recipients [4,5,6,7] For these patients, survival continues to be challenged by chronic allograft dysfunctions, such as obliterative bronchiolitis or its clinical correlate bronchiolitis obliterans syndrome (BOS), a fibrous obliteration of small airways caused by mesenchymal cells (MSc) abnormal proliferation, and extracellular matrix deposition causing bronchiolar occlusion and organ rejection [8,9,10,11]. The unsatisfactory clinical response could be partially due to the EVE systemic toxicity and its insufficient accumulation at the target tissues [14,17]

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Conclusion