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A novel phenolic propanediamine moiety-based lung-targeting therapy for asthma
- Source :
- Drug Delivery, Vol 25, Iss 1, Pp 1117-1126 (2018), Drug Delivery
- Publication Year :
- 2018
- Publisher :
- Taylor & Francis Group, 2018.
-
Abstract
- Asthma is one of the most prevalent chronic inflammatory diseases of lung. Current asthma therapy using inhaled corticosteroid often results in undesired treatment outcome due to poor compliance and drugs’ lack of tissue specificity. N,N,N’-trimethyl-N’-(2-hydroxyl-3-methyl-5-123Iiodobenzyl)-1,3-propanediamine (HIPD), a phenolic propanediamine derivative, has been used as an imaging agent for localized pulmonary diseases. Inspired by this, N,N,N’-trimethyl-N’-(4-hydroxyl-benzyl)-1,3-propanediamine (TPD), a new HIPD analog, was proposed as a lung-targeting ligand and covalently conjugated to an anti-inflammatory compound Rhein for asthma therapy. Cellular uptake efficiency of TPD-Rhein by A549 cells was significantly enhanced compared with Rhein. The enhanced cellular uptake was mainly mediated by organic cation transporters (OCTs) in an active manner, showing concentration- and energy-dependent. After systemic administration in rats, TPD-Rhein specifically distributed to lungs, displaying the highest Cmax and AUC0−t values of all tested tissues and resulting in a 13-fold increase in Cmax and a 103-fold increase in AUC0−t for lung compared with Rhein. Also, TPD-Rhein remarkably decreased serum histamine levels, serum IL-5 levels as well as bronchoalveolar lavage fluid IL-5 levels in lungs of asthmatic rats challenged by ovalbumin (OVA). Accordingly, histological examinations demonstrated that TPD-Rhein attenuated lung inflammation in rats, with no apparent toxicity against major organs. Together, phenolic propanediamine-based lung-targeting approach represents an efficient and safe strategy for asthma therapy.
- Subjects :
- 0301 basic medicine
Male
medicine.drug_class
lung-targeting
Anti-Inflammatory Agents
Pharmaceutical Science
Anthraquinones
Pharmacology
asthma therapy
rhein
03 medical and health sciences
Mice
phenolic propanediamine
Cell Line, Tumor
medicine
Moiety
Animals
Humans
Anti-Asthmatic Agents
Sulfhydryl Compounds
Rats, Wistar
Lung
A549 cell
Organic cation transport proteins
biology
Chemistry
lcsh:RM1-950
General Medicine
Ligand (biochemistry)
Imaging agent
Asthma
Rats
respiratory tract diseases
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
lcsh:Therapeutics. Pharmacology
small ligand
A549 Cells
Systemic administration
biology.protein
Corticosteroid
Bronchoalveolar Lavage Fluid
HeLa Cells
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 15210464 and 10717544
- Volume :
- 25
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Drug Delivery
- Accession number :
- edsair.doi.dedup.....4f2214c3c1d03a75003628bae30c216e