Nanostructured lipid carrier mediates effective delivery of methotrexate to induce apoptosis of rheumatoid arthritis via NF-κB and FOXO1

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• 作者：Neeraj K. Garg^a ; ¹ ; Rajeev K. Tyagi^b ; ^c ; ¹ ; Bhupinder Singh^a ; ^d ; Gajanand Sharma^a ; Pradip Nirbhavane^a ; Varun Kushwah^e ; Sanyog Jain^e ; Om Prakash Katare^a ; ^{drkatare@yahoo.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Nanostructured lipid carriers (NLCs) ; Methotrexate ; Rheumatoid Arthritis ; Apoptosis ; NF-κB-IkB ; FOXO1 ; RT-PCR ; α-Terpineol ; Phospholipids S-100 ; Gelucire 50/13 ; Transcutol P ; Transdermal delivery
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：29 February 2016
• 年：2016
• 卷：499
• 期：1-2
• 页码：301-320
• 全文大小：7154 K

文摘

Present study was designed to develop novel nano-structured lipid carriers (NLCs) formulated by lipid mixture and chemical permeation enhancer-based hydrogel for an effective transdermal delivery of methotrexate (MTX). The prepared NLCs were optimized with different preparative variables such as particle size <200 nm, poly-dispersity index (PDI) <0.2, and entrapment efficiency ∼85%. The drug incorporated into NLCs-gel base showed excellent spread ability without any grittiness during rheological behavior and texture profile analysis. The in vitro release showed biphasic release pattern with initial fast release of drug (>50%) in 8 h followed by sustained release (up to 85%) by the end of 48th h. NLCs showed greater uptake in human hyper-proliferative keratinocyte cell line (HaCaT). NLCs showed increased expression of inflammatory mediators as well asapoptosis in U937 monocytic cells. The greater expression of pro-apoptotic gene Bim regulated by NF-κB-IkB and FOXO1 is supported by fold regulations calculated for various apoptotic and pro-inflammatory biomarkers carried out by RT-PCR. The immunocytochemistry to detect IL-6 expression and immunofluorescence assay suggested that induced apoptosis occurs in experimentally induced in vitro arthritis model treated with NLCs-MTX. We saw reduced inflammation and triggered apoptosis through NF-κB & FOXO1 pathways induced by MTX loaded NLCs in rheumatoid arthritic cells. In addition, formulated NLCs exhibit better skin permeation with higher permeation flux & enhancement ratio as shown by confocal laser scanning microscopy (CLSM). Moreover, histopathological examinations of skin are suggestive of safety potential of NLCs.