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Chronic rhinosinusitis (CRS) is a chronic inflammatory condition affecting the nasal and paranasal sinuses of approximately 11.5% of the United States adult population. Oral corticosteroids are effective in controlling sinonasal inflammation in CRS, but the associated adverse effects limit their clinical use. Topical budesonide has demonstrated clinical efficacy in patients with CRS. Herein, we investigated the systemic delivery of liposomes tethered with poly(ethylene glycol) (PEG) and loaded with budesonide in a murine model of CRS. PEGylated liposomes encapsulated with budesonide phosphate (L-BudP) were administered via tail vein injection, and the feasibility of L-BudP to reduce sinonasal inflammation was compared to that of free budesonide phosphate (F-BudP) and topical budesonide phosphate (T-BudP) treatment over a 14-day study period. Compared to a single injection of F-BudP and repeat T-BudP administration, a single injection of L-BudP demonstrated increased and prolonged efficacy, resulting in the significant improvement of sinonasal tissue histopathological scores (p < 0.05) with decreased immune cell infiltration (p < 0.05). Toxicities associated with L-BudP and T-BudP treatment, assessed via body and organ weight, as well as peripheral blood liver enzyme and differential white blood cell analyses, were transient and comparable. These data suggest that systemic liposomal budesonide treatment results in improved efficacy over topical treatment., (Copyright © 2023. Published by Elsevier B.V.)

Chronic rhinosinusitis (CRS) is a debilitating inflammatory disorder of the sinonasal mucosa that substantially diminishes patient quality of life. Progress surrounding management of this disease has been crippled by a lack of therapeutic innovation. It has been posited that increased vascularity within the diseased sinuses of patients with CRS may allow for improved systemic drug delivery via nanoscale liposomal carriers. Such a system could enhance drug distribution, accumulation, and retention within the sinuses, ultimately leading to improved patient outcomes. PEGylated liposomes loaded with indocyanine green (ICG) were synthesized, characterized and systemically administered in a mouse model of CRS. Accumulation and retention of ICG in sinonasal tissue were evaluated. Compared to healthy controls, CRS mice showed significant sinonasal tissue accumulation and retention of PEGylated liposomal ICG for up to 21 days (P < 0.001). Conversely, free ICG was eliminated from the body after 24 h in both groups., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Altered neovascularity is typically observed in chronic inflammatory diseases with overlapping pathophysiology to that observed in chronic rhinosinusitis (CRS). However, characterization of these inflammatory-induced vascular-mediated changes in CRS is limited. Understanding the underlying vascular changes in CRS will allow for strategic design and development of new drug-delivery technologies that exploit vascular permeability for increased extravasation into the target sinonasal tissues., Methods: Patients with CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) and non-CRS controls were enrolled in this prospective, observational study. The extent of angiogenesis in tissue was characterized using immunohistochemical and multiplex gene expression analyses. Vascular permeability, interendothelial junction structures, and endothelial barrier morphology were evaluated using transmission electron microscopy., Results: Sinonasal vascularity was increased significantly in CRSsNP and CRSwNP (p < 0.05) when compared with controls, as assessed by enumerating the platelet endothelial cell adhesion molecule (PECAM-1)-positive blood vessels. Pro-angiogenic gene expression, including PECAM1 and platelet-activating factor receptor, was elevated significantly in patients with CRSwNP when compared with controls (p < 0.05). The fenestration sizes between endothelial cells (17-280 nm) were larger in CRSwNP compared with CRSsNP (10-33 nm) patients and controls (4-12 nm). Global thinning of the endothelial cell lining was observed in CRS patients but not in controls., Conclusion: Significant increases in vascularity, the pro-angiogenic gene, and protein expression and blood vessel morphogenesis were observed in CRS patients compared with controls. In addition, fenestration sizes between interendothelial junction structures were larger in CRS patients than in controls, suggesting inflammation-driven vascular dysregulation in CRS pathology., (© 2020 ARS-AAOA, LLC.)

Background: Chronic inflammation is known to cause alterations in vascular homeostasis that directly affects blood vessel morphogenesis, angiogenesis, and tissue permeability. These phenomena have been investigated and exploited for targeted drug delivery applications in the context of cancers and other disease processes. Vascular pathophysiology and its associated genes and signaling pathways, however, have not been systematically investigated in patients with chronic rhinosinusitis (CRS). Understanding the interplay between key vascular signaling pathways and top biomarkers associated with CRS may facilitate the development of new targeted delivery strategies and treatment paradigms. Herein, we report findings from a gene meta-analysis to identify key vascular pathways and top genes involved in CRS., Methods: Proprietary software (Illumina BaseSpace Correlation Engine) and open-access data sets were used to perform a gene meta-analysis to systematically determine significant differences between key vascular biomarkers and vascular signaling pathways expressed in sinonasal tissue biopsies of controls and patients with CRS., Results: Thirteen studies were initially identified, and then reduced to five after applying exclusion principle algorithms. Genes associated with vasculature development and blood vessel morphogenesis signaling pathways were identified to be overexpressed among the top 15 signaling pathways. Out of many significantly upregulated genes, the levels of pro angiogenic genes such as early growth response (EGR3), platelet endothelial cell adhesion molecule (PECAM1) and L-selectin (SELL) were particularly significant in patients with CRS compared to controls., Discussion: Key vascular biomarkers and signaling pathways were significantly overexpressed in patients with CRS compared to controls, suggesting a contribution of vascular dysfunction in CRS pathophysiology. Vascular dysregulation and permeability may afford opportunities to develop drug delivery systems to improve efficacy and reduce toxicity of CRS treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chronic rhinosinusitis (CRS) is a debilitating inflammatory disorder of the sinonasal mucosa that substantially diminishes patient quality of life. Progress surrounding management of this disease has been crippled by a lack of therapeutic innovation. It has been posited that increased vascularity within the diseased sinuses of patients with CRS may allow for improved systemic drug delivery via nanoscale liposomal carriers. Such a system could enhance drug distribution, accumulation, and retention within the sinuses, ultimately leading to improved patient outcomes. PEGylated liposomes loaded with indocyanine green (ICG) were synthesized, characterized and systemically administered in a mouse model of CRS. Accumulation and retention of ICG in sinonasal tissue were evaluated. Compared to healthy controls, CRS mice showed significant sinonasal tissue accumulation and retention of PEGylated liposomal ICG for up to 21 days (P < 0.001). Conversely, free ICG was eliminated from the body after 24 h in both groups. The extravasation mechanism of PEGylated liposomal ICG into the sinonasal mucosa through interendothelial tight junctions, which are widened in the context of CRS. This phenomenon leads to the increased sinonasal tissue accumulation and retention of liposomal drug carriers. [Display omitted] [ABSTRACT FROM AUTHOR]