Formulation and Characterization of Solid Lipid Nanoparticles Loading RF22-c, a Potent and Selective 5-LO Inhibitor, in a Monocrotaline-Induced Model of Pulmonary Hypertension

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Pulmonary arterial hypertension (PAH) is a rare but fatal disease characterized by persistent elevated blood pressure in the pulmonary circulation, due to increased resistance to blood flow, through the lungs. Advances in the understanding of the pathobiology of PAH clarify the role of leukotrienes (LTs) that appear to be an exciting new target for disease intervention. Over the years, our group has long investigated this field, detecting the 1,2-benzoquinone RF-22c as the most powerful and selective competitive inhibitor of the enzyme 5-lipoxygenase (5-LO). With the aim to improve the bioavailability of RF-22c and to confirm the role of 5-LO as therapeutic strategy for PAH treatment, we developed a solid lipid nanoparticle (SLN) loaded with drug. Therefore, in monocrotaline (MCT) rat model of PAH, the role of 5-LO has been investigated through the formulation of RF-22c-SLN. The rats were randomly grouped into control group, MCT group, and MCT + RF22-c group. After 21 days, all the animals were sacrificed to perform functional and histological evaluations. RF22-c-SLN treatment was able to significantly reduce the mean pulmonary arterial pressure (mPAP) and precapillary resistance (R-pre) compared to the MCT group. The MCT induced rise in medial wall thickness of pulmonary arterioles, and the cardiomyocytes width were significantly attenuated by RF22-c-SLN formulation upon treatment. The results showed that the selective inhibition of 5-LO improved hemodynamic parameters as well as vascular and cardiac remodeling by preventing induced pulmonary hypertension. The improved sustained release properties and targeting abilities achieved with the innovative nanotechnological approach may be therapeutically beneficial for PAH patients as a consequence of the increase of pharmacological effects and of the possible reduction and/or optimization of the drug frequency of administration.

Related collections

Most cited references 54

Record: found
Abstract: found
Article: not found

Inflammation, growth factors, and pulmonary vascular remodeling.

Paul Hassoun, Luc Mouthon, Joan Barberà … (2009)

Inflammatory processes are prominent in various types of human and experimental pulmonary hypertension (PH) and are increasingly recognized as major pathogenic components of pulmonary vascular remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the vascular lesions of PH, whether in idiopathic pulmonary arterial hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef), and increased expression of growth (such as vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary vascular remodeling. Thus, the recognition of complex inflammatory disturbances in the vascular remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy.

0 comments Cited 196 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Inflammation in pulmonary arterial hypertension.

Laura Price, S. John Wort, Frédéric Perros … (2012)

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. Although the exact pathophysiology remains unknown, there is increasing evidence to suggest an important role for inflammation. Firstly, pathologic specimens from patients with PAH reveal an accumulation of perivascular inflammatory cells, including macrophages, dendritic cells, T and B lymphocytes, and mast cells. Secondly, circulating levels of certain cytokines and chemokines are elevated, and these may correlate with a worse clinical outcome. Thirdly, certain inflammatory conditions such as connective tissue diseases are associated with an increased incidence of PAH. Finally, treatment of the underlying inflammatory condition may alleviate the associated PAH. Underlying pathologic mechanisms are likely to be "multihit" and complex. For instance, the inflammatory response may be regulated by bone morphogenetic protein receptor type 2 (BMPR II) status, and, in turn, BMPR II expression can be altered by certain cytokines. Although antiinflammatory therapies have been effective in certain connective-tissue-disease-associated PAH, this approach is untested in idiopathic PAH (iPAH). The potential benefit of antiinflammatory therapies in iPAH is of importance and requires further study.

0 comments Cited 136 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Inflammation in pulmonary arterial hypertension.

F Perros, M. Humbert, P. Dorfmüller … (2003)

Inflammatory mechanisms appear to play a significant role in some types of pulmonary hypertension (PH), including monocrotaline-induced PH in rats and pulmonary arterial hypertension of various origins in humans, such as connective tissue diseases (scleroderma, systemic lupus erythematosus, mixed connective disease), human immunodeficiency virus infection, or plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal (M) protein and skin changes (POEMS) syndrome. Interestingly, some patients with severe pulmonary arterial hypertension associated with systemic lupus erythematosus have experienced significant improvements with immunosuppressive therapy, emphasising the relevance of inflammation in a subset of patients presenting with PH. Patients with primary PH (PPH) also have some immunological disturbances, suggesting a possible role for inflammation in the pathophysiology of this disease. A subset of PPH patients have been shown to have circulating autoantibodies, including antinuclear antibodies, as well as elevated circulating levels of the pro-infammatory cytokines, interleukins -1 and -6. Lung histology has also revealed inflammatory infiltrates in the range of plexiform lesions in patients displaying severe PPH, as well as an increased expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and fractalkine. Further analysis of the role of inflammatory mechanisms is necessary to understand whether this component of the disease is relevant to its pathophysiology.

0 comments Cited 111 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Angela Liparulo: URI : https://loop.frontiersin.org/people/804241/overview

Renata Esposito: URI : https://loop.frontiersin.org/people/803815/overview

Alejandra Muñoz-Ramírez: URI : https://loop.frontiersin.org/people/876927

Giuseppe Spaziano: URI : https://loop.frontiersin.org/people/500492

Carmelo Puglia: URI : https://loop.frontiersin.org/people/526247

Liberato Berrino: URI : https://loop.frontiersin.org/people/548949

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 28 February 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 83

Affiliations

[1] ¹ Department of Experimental Medicine, Section of Pharmacology “L. Donatelli,” University of Campania “L. Vanvitelli,” Naples, Italy

[2] ² Department of Drug Sciences, University of Catania , Catania, Italy

[3] ³ Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago, Casilla , Correo, Chile

[4] ⁴ Institute of Food Safety and Nutrition, Jinan University , Guangzhou, China

[5] ⁵ Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli,” Naples, Italy

[6] ⁶ Consorzio Sannio Tech-AMP Biotec , Apollosa, Italy

Author notes

Edited by: Salvatore Cuzzocrea, University of Messina, Italy

Reviewed by: Loredana Serpe, University of Turin, Italy; Francesca Ungaro, University of Naples Federico II, Italy

*Correspondence: Giuseppe Spaziano, giuseppe.spaziano@ 123456unicampania.it ; Rosanna Filosa, rosanna.filosa@ 123456unicampania.it

This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

†These authors have contributed equally to this work

Article

DOI: 10.3389/fphar.2020.00083

PMC ID: 7059131

SO-VID: 3562f45e-2212-4008-ae16-4add813a58b6

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 28 October 2019

Date accepted : 27 January 2020

Page count

Figures: 7, Tables: 0, Equations: 5, References: 56, Pages: 9, Words: 4475

Funding

Funded by: Comisión Nacional de Investigación Científica y Tecnológica 10.13039/501100002848

Award ID: 2014-21140089

Formulation and Characterization of Solid Lipid Nanoparticles Loading RF22-c, a Potent and Selective 5-LO Inhibitor, in a Monocrotaline-Induced Model of Pulmonary Hypertension

Read this article at

Abstract

Related collections

Nanoparticles to cross the blood-brain barrier (BBB)

Most cited references 54

Inflammation, growth factors, and pulmonary vascular remodeling.

Inflammation in pulmonary arterial hypertension.

Inflammation in pulmonary arterial hypertension.

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 286

Most referenced authors 642