Spermidine-mediated poly(lactic-co-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

International Journal of Nanomedicine, Sep 2017

Spermidine-mediated poly(lactic-co-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis Jing Tang,1 Jianming Li,2 Guo Li,2 Haitao Zhang,2 Ling Wang,3 Dai Li,4 Jinsong Ding2 1School of Pharmaceutical Sciences, Changsha Medical University, 2Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 3Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, 4Xiangya Hospital, Central South University, Changsha, China 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. Keywords: idiopathic pulmonary fibrosis, fluorofenidone, spermidine, polyamine transport system, nanoparticles

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Spermidine-mediated poly(lactic-co-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

International Journal of Nanomedicine spermidine-mediated poly(lactic- co-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis Jing Tang 2 Jianming li 1 guo li 1 Haitao Zhang 1 ling Wang 0 Dai li 3 Jinsong Ding 1 0 Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University , Chengdu 1 Xiangya School of Pharmaceutical Sciences, Central South University , Changsha 2 School of Pharmaceutical Sciences, Changsha Medical University 3 Xiangya Hospital, Central South University , Changsha , China 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-Cou6-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 0.49fold 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. - reflux disease, commonly prescribed drugs, diabetes mellitus, infectious agents, and genetic factors.1,6,7 Despite IPF being classified as a rare disease, its health-care costs and social burden are significant.8 Over the last few decades, many conventional therapeutic concepts on IPF have proved to be unsuccessful. 18 Corticosteroids and immunosuppressants are usually the l-20 main treatment for IPF, but the therapeutic benefits of these -J3u agents are limited, with poor final outcome.9 Immunomoduon1 lation by azathioprine and cyclophosphamide did not show 027 sufficient benefit.8 Lung transplantation may be the final ..46 choice of medical therapy for refractory patients with IPF.10 .795 Despite the majority of therapies so far having disappointing yb3 results, there is a new antifibrotic drug, pirfenidone (PD), /om which has shown positive effects on reducing mortality in .ssc IPF patients.3,11 PD (5-methyl-1-phenyl-2-[1H]-pyridone) rep was the first antifibrotic drug tested specifically for use in ve IPF, starting in 1999.12 It has been approved in multiple .doww l.yno countries and regions (including Europe, Japan, Canada, and //ttsphw lseauno tdhreugUsSf)o.r13IIPtFi.s14p,1r5esumed that pyridone agents are effective : from rspe Fluorofenidone (AKF; 5-methyl-1-[3-fluorophenyl]-2ded roF [1H]-pyridone) which has been synthesized by the Departlao ment of Pharmacochemistry, School of Pharmaceutical onw Sciences, Central South University (Changsha, China), has a iicedend sgirmowilatrhcahnemdiccoalllsatgruecntusryenttohPeDsi.s16,o17fItdcifafnerreednutcoerfgiabnrosb.1l8a–s21t nom Furthermore, AKF is able to attenuate bleomycin-induced faN experimental IPF by reducing inflammation, accelerating loa the production of caveolin 1, inhibiting the phosphorylated ronu MAPK-signaling pathway, and limiting the fibrosis cytokine lJa TGF-β.22 However, the curative power of AKF in the lung itnoa has been limited by its unsatisfactory pharmacokinetic trne properties, which include a short half-life (2 hours), as well In as rapid absorption and extensive distribution.17 Therefore, improvement of AKF lung concentration is a high-priority requirement in treating IPF. 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Jing Tang, Jianming Li, Guo Li, Haitao Zhang, Ling Wang, Dai Li, Jinsong Ding. Spermidine-mediated poly(lactic-co-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis, International Journal of Nanomedicine, 2017, pp. 6687-6704, DOI: 10.2147/IJN.S140569