Spermidine-mediated poly(lactic-<em>co</em>-glycolic acid)&nbsp;nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis is a progressive, fatal lung disease with poor survival. The advances made in deciphering this disease have led to the approval of different antifibrotic molecules, such as pirfenidone and nintedanib. An increasing number of studies with particles (liposomes, nanoparticles [NPs], microspheres, nanopolymersomes, and nanoliposomes) modified with different functional groups have demonstrated improvement in lung-targeted drug delivery. In the present study, we prepared, characterized, and evaluated spermidine (Spd)-modified poly(lactic- co -glycolic acid) (PLGA) NPs as carriers for fluorofenidone (AKF) to improve the antifibrotic efficacy of this drug in the lung. Spd-AKF-PLGA NPs were prepared and functionalized by modified solvent evaporation with Spd and polyethylene glycol (PEG)-PLGA groups. The size of Spd-AKF-PLGA NPs was 172.5±4.3 nm. AKF release from NPs was shown to fit the Higuchi model. A549 cellular uptake of an Spd–coumarin (Cou)-6-PLGA NP group was found to be almost twice as high as that of the Cou-6-PLGA NP group. Free Spd and difluoromethylornithine (DFMO) were preincubated in A549 cells to prove uptake of Spd-Cou-6-PLGA NPs via a polyamine-transport system. As a result, the uptake of Spd-Cou-6-PLGA NPs significantly decreased with increased Spd concentrations in incubation. At higher Spd concentrations of 50 and 500 µM, uptake of Spd-Cou-6-PLGA NPs reduced 0.34- and 0.49-fold from that without Spd pretreatment. After pretreatment with DFMO for 36 hours, cellular uptake of Spd-Cou-6-PLGA NPs reached 1.26-fold compared to the untreated DFMO group. In a biodistribution study, the drug-targeting index of Spd-AKF-PLGA NPs in the lung was 3.62- and 4.66-fold that of AKF-PLGA NPs and AKF solution, respectively. This suggested that Spd-AKF-PLGA NPs accumulated effectively in the lung. Lung-histopathology changes and collagen deposition were observed by H&E staining and Masson staining in an efficacy study. In the Spd-AKF-PLGA NP group, damage was further improved compared to the AKF-PLGA NP group and AKF-solution group. The results indicated that Spd-AKF-PLGA NPs are able to be effective nanocarriers for anti–pulmonary fibrosis therapy.

Tailoring of silica-based nanoporous pod by spermidine multi-activity

“…The OS reduction is followed by a decrease of cytotoxicity from (22.4 ± 3.8)% to (7 ± 2.9)%, confirming the role of PTS in spd-SNPs internalization. These experiments suggest that spermidine functionalization selectively acts on particle transport into MeWo cells by a PTS-mediated endocytosis process, resulting fully consistent with data reported by recent studies 70 , 71 .…”

“…Specifically, if PTS selectively takes part to particle uptake, it is expected that, after blocking its function, cellular uptake would quantitatively decrease. Data confirm PTS involvement in particle internalization, mainly for spd-SNPs, indicating an active uptake via spermidine-PTS affinity 70,71 .…”

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

“…This method provides the ability to specifically deliver antiproteases to the luminal surface of the respiratory epithelium within the airway surface fluid. The amount of antiprotease delivered to the apical surface would be protective in the early stages of CF, but it may not be sufficient to prevent the late‐stage CF lung's (Tang et al, ).…”

Fibrogenic Disorders in Human Diseases: From Inflammation to Organ Dysfunction

“…Drug-delivering nanoparticles displaying at their 57 surface reconnaissance molecules for overexpressed targets in fibrosis-associated cells may represent another approach to solve some of the problems of off-target side-effects, as shown in a rat model of pulmonary fibrosis. 196 Drugs able to modulate physiological pathways other than the TGF-β, such as oxidative stress, lipids, enzymes, kinases or peptide receptors, have been evaluated. Most clinical trials were disappointing, although the molecules had shown efficacy in preclinical animal models of the diseases.…”