New Co-Spray-Dried Tobramycin Nanoparticles-Clarithromycin Inhaled Powder Systems for Lung Infection Therapy in Cystic Fibrosis Patients

Pilcer, Gabrielle; Rosière, Rémi; Traina, Karl; Sebti, Thami; Vanderbist, Francis; Amighi, Karim

doi:10.1002/jps.23525

Cited by 47 publications

(20 citation statements)

References 29 publications

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“…We encourage more clinical trials to assess the effectiveness of this therapy, which gain particular interest when considering the possibility of local aerosol administration; indeed, its formulation as dry powder inhaler is currently under investigation [28]. To our knowledge, CLM treatment has never been tested in patients that already showed no improvement under AZM therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, CLM treatment was shown to decrease lung inflammatory processes and chronic airways hypersecretion in non-CF patients with bronchiectasis [24,25]. Pertaining to its anti-pseudomonal effects, CLM has no bactericidal activity against P. aeruginosa , like other macrolides, but can interfere with protein synthesis and inhibit protease expression, twitching motility and biofilm maturation, promoting biofilm permeability and favoring penetration of other antimicrobial agents like ciprofloxacin and tobramycin, also used in CF therapy [26–28]. …”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

et al. 2018

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Background: Cystic fibrosis (CF) lung infection is a complex condition where opportunistic pathogens and defective immune system cooperate in developing a constant cycle of infection and inflammation. The major pathogen, Pseudomonas aeruginosa, secretes a multitude of virulence factors involved in host immune response and lung tissue damage. In this study, we examined the possible anti-inflammatory effects of molecules inhibiting P. aeruginosa virulence factors.Methods: Pyocyanin, pyoverdine and proteases were measured in bacterial culture supernatant from different P. aeruginosa strains. Inhibition of virulence factors by sub-inhibitory concentrations of clarithromycin and by protease inhibitors was evaluated. Lung inflammatory response was monitored by in vivo bioluminescence imaging in wild-type and CFTR-knockout mice expressing a luciferase gene under the control of a bovine IL-8 promoter.Results: The amount of proteases, pyocyanin and pyoverdine secreted by P. aeruginosa strains was reduced after growth in the presence of a sub-inhibitory dose of clarithromycin. Intratracheal challenge with culture supernatant containing bacteria-released products induced a strong IL-8-mediated response in mouse lungs while lack of virulence factors corresponded to a reduction in bioluminescence emission. Particularly, sole inactivation of proteases by inhibitors Ilomastat and Marimastat also resulted in decreased lung inflammation.Conclusions: Our data support the assumption that virulence factors are involved in P. aeruginosa pro-inflammatory action in CF lungs; particularly, proteases seem to play an important role. Inhibition of virulence factors production and activity resulted in decreased lung inflammation; thus, clarithromycin and protease inhibitors potentially represent additional therapeutic therapies for P. aeruginosa-infected patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

et al. 2018

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“…Recently, easily dispersible and porous antibiotics-conjugated nanoparticles have been utilized to produce formulations for treating lung infection [24]. Kanamycin, an aminoglycoside antibiotic, potentiates the antibacterial effect of gold nanoparticles [25], therefore, kanamycin-capped gold particles were produced through a simple, biofriendly reaction to yield stable and monodispersed particles.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Unifying in vitro and in vivo IVT mRNA expression discrepancies in skeletal muscle via mechanotransduction

et al. 2018

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The translational efficiency of an in vitro transcribed (IVT) mRNA was measured upon delivery to primary skeletal muscle cells and to a mouse model system, towards the development of a predictive in vitro assay for the screening and validation of intramuscular mRNA-based vaccines. When IVT mRNA was delivered either naked or complexed with novel aminoglycoside-based delivery vehicles, significant differences in protein expression in vitro and in vivo were observed. We hypothesized that this previously anticipated discrepancy was due to differences in the mechanism of IVT mRNA endosomal entry and release following delivery. To address this, IVT mRNA was fluorescently labeled prior to delivery, to visualize its distribution. Colocalization with endosomal markers indicated that different entry pathways were utilized in vivo and in vitro, depending on the delivery vehicle, resulting in variations in protein expression levels. Since extracellular matrix stiffness (ECM) influences mRNA entry, trafficking and release, the effect of mechanotransduction on mRNA expression was investigated in vitro upon delivery of IVT mRNA alone, and complexed with delivery vehicles to skeletal muscle cells grown on ∼10 kPa hydrogels. This in vitro hydrogel model more accurately recapitulated the results obtained in vivo upon IM injection, indicating that this approach may assist in the characterization of mRNA based vaccines.

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“…Radiography-confirmed diagnosis, low FEV 1 and presence of PA in sputum were the only criteria for inclusion. Using a measure such as the recently widely Aminoglycoside Gentamicin Dry powder [84] Tobramycin PLGA z dry powder [85] Tobramycin Liposomal z dry powder [86,87] Macrolide Clarithromycin Sprayed liquid [43] Clarithromycin PLGA z dry powder [44] Clarithromycin Liposomal z suspension * [88] Telithromycin Sprayed liquid [45] Azithromycin Nebulised solution [46] Azithromycin Dry powder [89] Fluoroquinolone Ciprofloxacin Dry powder [90] Ciprofloxacin PLGA z dry powder [91] Ciprofloxacin Liposomal z suspension * [92] Polymyxins Colistin (colistimethate sodium) Liposomal z suspension * [93] Polymyxin B Liposomal z suspension * [54] Combination Doxycycline and ciprofloxacin Dry powder [94,95] Ciprofloxacin and gatifloxacin (with ambroxol) Dry powder [82,96] Vancomycin and clarithromycin Dry powder [97] Tobramycin and clarithromycin Dry powder [98] validated bronchiectasis severity index (BSI) [58] may help stratify patients' disease severities, which may allow degree of benefit to be more accurately determined. This measure is described more thoroughly in Section 4.1.…”

Section: Methodsmentioning

confidence: 99%

Inhaled antibiotics in the treatment of non-cystic fibrosis bronchiectasis: clinical and drug delivery perspectives

Sugianto

Chan

2015

Expert Opinion on Drug Delivery

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The evidence base of the clinical efficacy of inhaled antibiotics in NCFB is limited and the degrees of reported clinical benefits have been modest and conflicting. Challenges surrounding inhaled antibiotics application and development include the lack of knowledge of disease factors and optimum management strategies, unreceptive lung pathophysiology and the lack of factors that support compliance and tolerability. Nonetheless, research continues to give birth to new clinical findings and novel formulations such as combination antibiotics and sustained-release formulations, which add great value to the development of efficacious, safe and convenient inhalable antibiotics of the future.

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New Co-Spray-Dried Tobramycin Nanoparticles-Clarithromycin Inhaled Powder Systems for Lung Infection Therapy in Cystic Fibrosis Patients

Cited by 47 publications

References 29 publications

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

Unifying in vitro and in vivo IVT mRNA expression discrepancies in skeletal muscle via mechanotransduction

Inhaled antibiotics in the treatment of non-cystic fibrosis bronchiectasis: clinical and drug delivery perspectives

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