Pulmonary delivery of therapeutic proteins based on zwitterionic chitosan-based nanocarriers for treatment on bleomycin-induced pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a chronically progressive interstitial lung that affects over 3 M people worldwide and rising in incidence. With a median survival of 2–3 years, IPF is consequently associated with high morbidity, mortality, and healthcare burden. Although two antifibrotic therapies, pirfenidone and nintedanib, are approved for human use, these agents reduce the rate of decline of pulmonary function but are not curative and do not reverse established fibrosis. In this review, we discuss the prevailing epithelial injury hypothesis, wherein pathogenic airway epithelial cell-state changes known as Epithelial Mesenchymal Transition (EMT) promotes the expansion of myofibroblast populations. Myofibroblasts are principal components of extracellular matrix production that result in airspace loss and mortality. We review the epigenetic transition driving EMT, a process produced by changes in histone acetylation regulating mesenchymal gene expression programs. This mechanistic work has focused on the central role of bromodomain-containing protein 4 in mediating EMT and myofibroblast transition and initial preclinical work has provided evidence of efficacy. As nanomedicine presents a promising approach to enhancing the efficacy of such anti-IPF agents, we then focus on the state of nanomedicine formulations for inhalable delivery in the treatment of pulmonary diseases, including liposomes, polymeric nanoparticles (NPs), inorganic NPs, and exosomes. These nanoscale agents potentially provide unique properties to existing pulmonary therapeutics, including controlled release, reduced systemic toxicity, and combination delivery. NP-based approaches for pulmonary delivery thus offer substantial promise to modify epigenetic regulators of EMT and advance treatments for IPF.

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An Overview on Spray-Drying of Protein-Loaded Polymeric Nanoparticles for Dry Powder Inhalation

Pharmaceutics ◽

10.3390/pharmaceutics12111032 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1032

Author(s):

Tânia Marante ◽

Cláudia Viegas ◽

Inês Duarte ◽

Ana S. Macedo ◽

Pedro Fonte

Keyword(s):

Spray Drying ◽

Polymeric Nanoparticles ◽

Therapeutic Proteins ◽

Pulmonary Delivery ◽

Non Invasive ◽

Rapid Absorption ◽

Technological Advances ◽

First Pass

The delivery of therapeutic proteins remains a challenge, despite recent technological advances. While the delivery of proteins to the lungs is the gold standard for topical and systemic therapy through the lungs, the issue still exists. While pulmonary delivery is highly attractive due to its non-invasive nature, large surface area, possibility of topical and systemic administration, and rapid absorption circumventing the first-pass effect, the absorption of therapeutic proteins is still ineffective, largely due to the immunological and physicochemical barriers of the lungs. Most studies using spray-drying for the nanoencapsulation of drugs focus on the delivery of conventional drugs, which are less susceptible to bioactivity loss, compared to proteins. Herein, the development of polymeric nanoparticles by spray-drying for the delivery of therapeutic proteins is reviewed with an emphasis on its advantages and challenges, and the techniques to evaluate their in vitro and in vivo performance. The protein stability within the carrier and the features of the carrier are properly addressed.

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Pulmonary Delivery of NLRP3 Antisense Oligonucleotides Are Effective at Preventing but Not Reversing Established Bleomycin-Induced Pulmonary Fibrosis in Mice

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a4605 ◽

2019 ◽

Author(s):

D. Bai ◽

E.R.M.A.S.G. Jeff Crosby, Chenguang Zhao, Min Zh

Keyword(s):

Pulmonary Fibrosis ◽

Antisense Oligonucleotides ◽

Pulmonary Delivery

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Microspheres containing lipid/chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins

European Journal of Pharmaceutics and Biopharmaceutics ◽

10.1016/j.ejpb.2007.10.017 ◽

2008 ◽

Vol 69 (1) ◽

pp. 83-93 ◽

Cited By ~ 111

Author(s):

Ana Grenha ◽

Carmen Remuñán-López ◽

Edison L.S. Carvalho ◽

Begoña Seijo

Keyword(s):

Therapeutic Proteins ◽

Chitosan Nanoparticles ◽

Pulmonary Delivery

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Pulmonary delivery of liposomal dry powder inhaler formulation for effective treatment of idiopathic pulmonary fibrosis

Asian Journal of Pharmaceutical Sciences ◽

10.1016/j.ajps.2017.08.005 ◽

2018 ◽

Vol 13 (1) ◽

pp. 91-100 ◽

Cited By ~ 12

Author(s):

S. Chennakesavulu ◽

A. Mishra ◽

A. Sudheer ◽

C. Sowmya ◽

C. Suryaprakash Reddy ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Effective Treatment ◽

Dry Powder Inhaler ◽

Pulmonary Delivery ◽

Dry Powder

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Quantitative Microscopic Comparison of the Organization of the Lung in Transgenic Mice Expressing Transforming Growth Factor-α (TGF-α)

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162533 ◽

1996 ◽

Vol 54 ◽

pp. 14-15

Author(s):

C. G. Plopper ◽

C. Helton ◽

A. J. Weir ◽

J. A. Whitsett ◽

T. R. Korfhagen

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Transgenic Mice ◽

Blood Vessels ◽

Lung Parenchyma ◽

Lung Maturation ◽

Alveolar Air ◽

Parenchymal Tissue ◽

Air Space ◽

Conducting Airways

A wide variety of growth factors are thought to be involved in the regulation of pre- and postnatal lung maturation, including factors which bind to the epidermal growth factor receptor. Marked pulmonary fibrosis and enlarged alveolar air spaces have been observed in lungs of transgenic mice expressing human TGF-α under control of the 3.7 KB human SP-C promoter. To test whether TGF-α alters lung morphogenesis and cellular differentiation, we examined morphometrically the lungs of adult (6-10 months) mice derived from line 28, which expresses the highest level of human TGF-α transcripts among transgenic lines. Total volume of lungs (LV) fixed by airway infusion at standard pressure was similar in transgenics and aged-matched non-transgenic mice (Fig. 1). Intrapulmonary bronchi and bronchioles made up a smaller percentage of LV in transgenics than in non-transgenics (Fig. 2). Pulmonary arteries and pulmonary veins were a smaller percentage of LV in transgenic mice than in non-transgenics (Fig. 3). Lung parenchyma (lung tissue free of large vessels and conducting airways) occupied a larger percentage of LV in transgenics than in non-transgenics (Fig. 4). The number of generations of branching in conducting airways was significantly reduced in transgenics as compared to non-transgenic mice. Alveolar air space size, as measured by mean linear intercept, was almost twice as large in transgenic mice as in non-transgenics, especially when different zones within the lung were compared (Fig. 5). Alveolar air space occupied a larger percentage of the lung parenchyma in transgenic mice than in non-transgenic mice (Fig. 6). Collagen abundance was estimated in histological sections as picro-Sirius red positive material by previously-published methods. In intrapulmonary conducting airways, collagen was 4.8% of the wall in transgenics and 4.5% of the wall in non-transgenic mice. Since airways represented a smaller percentage of the lung in transgenics, the volume of interstitial collagen associated with airway wall was significantly less. In intrapulmonary blood vessels, collagen was 8.9% of the wall in transgenics and 0.7% of the wall in non-transgenics. Since blood vessels were a smaller percentage of the lungs in transgenics, the volume of collagen associated with the walls of blood vessels was five times greater. In the lung parenchyma, collagen was 51.5% of the tissue volume in transgenics and 21.2% in non-transgenics. Since parenchyma was a larger percentage of lung volume in transgenics, but the parenchymal tissue was a smaller percent of the volume, the volume of collagen associated with parenchymal tissue was only slightly greater. We conclude that overexpression of TGF-α during lung maturation alters many aspects of lung development, including branching morphogenesis of the airways and vessels and alveolarization in the parenchyma. Further, the increases in visible collagen previously associated with pulmonary fibrosis due to the overexpression of TGF-α are a result of actual increases in amounts of collagen and in a redistribution of collagen within compartments which results from morphogenetic changes. These morphogenetic changes vary by lung compartment. Supported by HL20748, ES06700 and the Cystic Fibrosis Foundation.

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