A Composite Nanosystem as a Potential Tool for the Local Treatment of Glioblastoma: Chitosan-Coated Solid Lipid Nanoparticles Embedded in Electrospun Nanofibers.

Barbara Vigani,Roberta Listro,Francesca Fagiani,Caterina Valentino,Silvia Rossi,Maria Cristina Bonferoni,Cristina Lanni,Franca Ferrari,Carla M Caramella,Giuseppina Sandri,Simona Collina

doi:10.3390/polym13091371

Abstract

Glioblastoma multiforme (GBM) is one of the most prevalent and aggressive brain tumors for which there is currently no cure. A novel composite nanosystem (CN), consisting of chitosan-coated Solid Lipid Nanoparticles (c-SLN) embedded in O-carboxymethyl chitosan (O-CMCS)-containing nanofibers (NFs), was proposed as a potential tool for the local delivery of lipophilic anti-proliferative drugs. Coacervation was selected as a solvent-free method for the preparation of stearic acid (SA) and behenic acid (BA)-based SLN (SA-SLN and BA-SLN respectively). BA-SLN, containing 0.75% w/w BA sodium salt and 3% w/w poly(vinyl alcohol) (PVA), were selected for the prosecution of the work since they are characterized by the lowest size functional to their subsequent coating and incorporation in nanofibers. BA-SLN were coated with chitosan (CS) by means of a two-step coating method based on the physical absorption of positively charged CS chains on the SLN negative surface. Nile Red (NR), chosen as the hydrophobic model dye, was dissolved in a micellar solution of BA sodium salt and then added with a coacervating solution until pH ≅ 2.5 was reached. Immunocytochemistry analyses highlighted that CS-coated BA-SLN (c-BA-SLN) exhibited a higher accumulation in human glioblastoma cells (U-373) after 6 h than CS-free BA-SLN. Finally, the c-BA-SLN dispersion was blended with a solution consisting of freely soluble polymers (O-CMCS, poly(ethylene oxide) and poloxamer) and then electrospun to obtain NFs with a mean diameter equal to 850 nm. After the NFs dissolution in an aqueous media, c-BA-SLN maintained their physicochemical properties and zeta potential.

Highlights

Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults, whose prognosis currently remains very poor.The intratumoral heterogeneity of GBM leads it to be classified by the World Health Organization (WHO) as a grade IV astrocytoma
Coacervation was selected as a solvent-free method for the preparation of SLN containing fatty acids by acidifying a hot micellar solution of fatty acid sodium salts in the presence of an appropriate polymeric stabilizer. pH lowering was responsible for SLN precipitation due to proton exchange between the coacervating solution and fatty acid sodium salts [24,27,30,31]
Such a method should allow the entrapment of hydrophobic drugs within SLN by drug dissolution in the micellar solution prior to acidification

Summary

Introduction

Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults, whose prognosis currently remains very poor (median survival less than 15 months).The intratumoral heterogeneity of GBM leads it to be classified by the World Health Organization (WHO) as a grade IV astrocytoma. Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults, whose prognosis currently remains very poor (median survival less than 15 months). The rapid proliferation and high capability of tumor cells to infiltrate healthy brain parenchyma explain the high rate of GBM recurrence and the lack of an effective therapeutic approach [1,2,3]. After surgical resection of the primary tumor, GBM patients are subjected to standard therapeutic regimens, including radiotherapy and adjuvant oral chemotherapy. The GBM anatomical localization interferes with both its complete surgical excision and the chemotherapy success. The remaining tumor cells rapidly diffuse and form satellite tumors, at the resection border margins, while the blood–

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