Enhanced topical delivery and anti-inflammatory activity of methotrexate from an activated nanogel
Enhanced topical delivery and anti-inflammatory activity of methotrexate from an activated nanogel
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DOI：
10.1016/j.ejpb.2010.06.014
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发表时间：
2010-10-01
影响因子：
4.9
通讯作者：
Heard, Charles M.
中科院分区：
文献类型：
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作者：
Singka, Gillian S. Leslie;Abu Samah, Nor;Heard, Charles M.
本工作检查了碳酸钠（Na 2CO 3）对甲氨蝶呤（MTX）从体外负载纳米凝胶的局部递送的影响以及对离体皮肤中前列腺素E-2（PGE（2））产生的调节。合成了N-异丙基丙烯酰胺（NIPAM）和丙烯酸丁酯（BA）共聚的纳米凝胶，对其进行了表征，并负载了MTX。然后将有限剂量应用于安装在Franz扩散池中的切除的猪表皮膜，然后加入饱和Na 2CO 3水溶液。为了比较，沿着检查半饱和Na 2CO 3的添加与单独的负载纳米凝胶。将相同的处理应用于离体的硅橡胶膜和全层猪耳皮肤，然后用放射免疫沉淀缓冲液处理，并使用商业酶免疫测定试剂盒探测PGE（2）的水平。在25-37 ℃范围内表现出7%去溶胀的载MTX纳米凝胶提供了1.4 +/- 0.3 ng cm（-2）h（-1）的MTX通量;在加入饱和Na 2CO 3水溶液后，这增加到3.1 +/- 0.22 ng cm（-2）h（-1）（p < 0.05）。滞后时间分别为6和类似于0小时。使用半饱和Na 2CO 3水溶液获得类似的结果。未检测到渗透穿过硅橡胶膜。水（对照）和饱和Na 2CO 3水溶液的PGE（2）水平相似，但当施加载有MTX的纳米凝胶时降低了33%，并且当随后施加饱和Na 2CO 3水溶液时降低了57%（p < 0.01）。提出了一种新的机制，即纳米凝胶渗透皮肤时所经历的温度变化会导致MTX原位消肿和排出。加入的Na 2CO 3导致进一步溶解和MTX释放，因此增加了浓度梯度、通量并减少了PGE（2）的产生。(C)2010 Elsevier B. V.保留所有权利。
This work examined the effect of sodium carbonate (Na2CO3) on the topical delivery of methotrexate (MTX) from a loaded nanogel in vitro and the modulation of prostaglandin E-2 (PGE(2)) production in skin ex vivo. A nanogel based on co-polymerised N-isopropylacrylamide (NIPAM) and butylacrylate (BA) was synthesized, characterized and loaded with MTX. Finite doses were then applied to excised porcine epidermal membranes mounted in Franz diffusion cells, followed by the addition of saturated aqueous Na2CO3. For comparison, the addition of half-saturated Na2CO3 was examined along with loaded nanogel alone. The same treatments were applied to Silastic membrane and full-thickness porcine ear skin ex vivo, which was then treated with radioimmunoprecipitation buffer and probed for levels of PGE(2) using a commercial enzyme immunoassay kit. The MTX-loaded nanogel, which demonstrated de-swelling by 7% over the range 25-37 degrees C, provided a MTX flux of 1.4 +/- 0.3 ng cm(-2) h(-1); this increased to 3.1 +/- 0.22 ng cm(-2)h(-1) upon the addition of saturated aqueous Na2CO3 (p < 0.05). Lag times were 6 and similar to 0 h, respectively. Similar results were obtained using half-saturated aqueous Na2CO3. No permeation was detected across Silastic membrane. PGE(2) levels for water (control) and saturated aqueous Na2CO3 were similar, but reduced by 33% when the MTX-loaded nanogel was applied, and by 57% when this was followed by the application of saturated aqueous Na2CO3 (p < 0.01). A novel mechanism is proposed whereby the change in temperature experienced by the nanogel as it penetrated skin induced de-swelling and expulsion of MTX in situ. The added Na2CO3 lead to further solubilisation and MTX release, hence increasing the concentration gradient, flux and reducing PGE(2) production. (C) 2010 Elsevier B.V. All rights reserved.