Biodegradable Electrospun Nanofibers: A New Approach For Rhinosinusitis Treatment
Graphical Abstract
Introduction
Rhinosinusitis (RS) is characterized by inflammation of the nasal and paranasal sinuses mucosa, classified as acute and chronic. Chronic rhinosinusitis (CRS) is a significant health problem that affects between 5 and 12% of the general population, constituting one of the most prevalent upper airway disorders (Fokkens et al., 2020). The disease has a meaningful broad reporting on direct and indirect costs, whereas the patients need a high healthcare service use, health-related quality of life, and productivity loss (Wahid et al., 2020). CRS (with or without nasal polyps) shows two or more symptoms, one of which should be either nasal blockage, obstruction, congestion or nasal discharge (anterior/posterior nasal drip), facial pain, and/or pressure; anosmia for at least 12 weeks (Bachert et al., 2020).
CRS's new classification considers anatomic distribution (primary or secondary sinus pathologic characteristics), endotype dominance, and phenotypes (Grayson et al., 2020). The CRS's pathophysiology is multifactorial, including environmental and genetic factors, anatomical variations, immunodeficiency, and mucociliary clearance disorders (Bachert and Holtappels, 2015). With a level of evidence-based medicine IA, the CRS treatment is endoscopic sinus surgery, long-term antibiotics, nasal corticosteroids, corticosteroid-eluting implants, systemic corticosteroids, and nasal irrigation with saline (Fokkens et al., 2020; Potter and Pawankar, 2012).
Electrospun polymeric nanofibers loaded with drugs provide exceptional control over the release kinetics by the characteristics of morphology, diameter, porosity, polymer and drug composition, and a larger surface area. (Chou et al., 2015; Meinel et al., 2012; Thakkar and Misra, 2017; Tseng et al., 2013).This scaffold allows for carrying hydrophilic or hydrophobic drugs, selecting different polymers with burst or sustained-release (Balusamy et al., 2020; Chou et al., 2015).
Mometasone furoate (MF) is a glucocorticoid with local anti-inflammatory properties, with effects on several cells such as mast cells, eosinophils, neutrophils, macrophages, lymphocytes, and also on mediators involved in the inflammatory process (Bousquet, 2009; Hochhaus, 2008; Van Drunen et al., 2005). MF is structurally similar to cortisol, diverging by the presence of groups that increase affinity for the glucocorticoid receptor and shows more potent inhibition of IL-1, IL-4, IL-5, IL-6, IFN-γ, and TNF-α synthesis/release. (Barton et al., 1991; He et al., 2014; Onrust and Lamb, 1998). A recent study developed by Matera and collaborators (2019) suggests that MF does not show systemic effects and is safe when inhaled on dosage of 1600 mg (Matera et al., 2019). Moreover, a work carried out by Han and Kern (2019) showed a minimal steroid sinus penetration when administered by spray. Thus, new drug delivery systems become an interesting substitute for obtaining the best local steroid application (Sofi et al., 2020; Thakkar and Misra, 2017).
Biodegradable polymeric systems allow constant in vivo degradation kinetics and, consequently, a controlled release of the drug dispersed in its polymeric matrix, capable of increasing the residence time (Fialho and Da Silva Cunha, 2005; Taherali et al., 2017). The poly-lactic-co-glycolic acid (PLGA) presents biocompatibility, biodegradation kinetics, mechanical resistance and, naturally excretion from the body; which are desirable characteristics for drugs' controlled release (Fialho and Da Silva Cunha, 2005; Jain et al., 1998; Jain, 2000; Makadia and Siegel, 2011; Uhrich et al., 1999). Furthermore, we aimed to determine the best conditions using Design of Experiment (DoE) to produce electrospun mometasone furoate nanofibers and analyze their morphology, chemical interaction, and release profile. This statistical tool reduces significant cost processes by designing more efficient products (Grangeia et al., 2020). In vivo, the rabbits are the most suitable for studies involving surgery or other invasive procedures. The safety assessment of nanofibers containing mometasone furoate was performed by the examination of rabbits' maxillary sinuses mucosa after insertion of the system (Costantino et al., 2007; Kara, 2004; Li et al., 2009; Parikh et al., 2014; Perez et al., 2014, 2012).
The present study was designed to reach a nanostructured drug delivery system that enables the increase of mometasone furoate bioavailability, assuring a potentially effective therapy for CRS, using electrospinning to incorporate a glucocorticoid into polymer chains of the PLGA nanofibers.
Section snippets
Materials
Mometasone furoate (MF) reference standard was purchased from United States Pharmacopeia (batch I0L395, with a value of 0.993 mg of mometasone furoate per mg of material as the basis). Mometasone furoate active pharmaceutical ingredient was purchased from Unimax Laboratories Ltd. India (batch MTF/1115005M2). Poly lactic-co-glycolic acid (PLGA) 75:25 with inherent viscosity from 0.50 to 0.70 dl/g, Boehringer Ingelheim Pharma GmbH & Co (Ingelheim, Germany). Ultra-pure water from a Millipore
Optimization studies of mometasone furoate nanofibers
A two-factor five-level central composite design was chosen to evaluate the best condition, and eleven experimental runs with independent variables were realized, and the nanofiber diameters were measured for the 11 formulations (Table 3 and Fig. 2). The statistical evaluation of experimental design, considering the nanofiber diameters' response, suggested a quadratic model by Design-Expert® Version 12 software (Statease, Minneapolis, USA).
The model ignored two points for the statistical
Conclusion
In the present study, we successfully developed biodegradable polymeric nanofibers containing mometasone furoate, a glucocorticoid widely used in CRS treatment, by the traditional electrospinning method. The nanofibers of poly-lactic-co-glycolic acid incorporated the drug in its polymeric chain provide controlled release of the drug for 60 days and have shown safety after insertion into the maxillary sinuses of rabbits. Its safety corroborates with the potential application as a carrier for the
CRediT author statement
Graziella Gomes Rivelli: Methodology, Investigation, Data curation, Writing - Original draft preparation, Writing - review & editing. André Coura Perez: Methodology, Investigation, Data curation. Pedro Henrique Reis Silva: Methodology, Investigation, Validation. Elionai Cassiana de Lima Gomes: Methodology, Validation, Data curation. Carolina Paula de Souza Moreira: Methodology, Investigation. Edwin Tamashiro: Conceptualization, Methodology, Data curation, Writing - review & editing. Fabiana
Declaration of Competing Interest
The authors report no conflicts of interest. The authors are responsible for the content of this article.
Acknowledgments
The authors would like to thank CAPES/MEC (Brazil), CNPq (Brazil), and UFMG (Brazil) for the financial support. The authors would like to acknowledge the Ezequiel Dias Foundation (Brazil) for chromatography and X-ray diffraction equipment and technical support.
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