Self-assembly of diclofenac prodrug into nanomicelles for enhancing the anti-inflammatory activity.
Self-assembly of diclofenac prodrug into nanomicelles for enhancing the anti-inflammatory activity.
复制标题
作者：
非甾体抗炎药（NSAID）被广泛用于治疗各种类型的炎症。双氯芬酸是一种非常常见的NSAID，用于缓解疼痛和减少发热，最重要的是，炎症。然而，其具有低水溶性和低溶解特性。因此，我们的目标是开发一种新的药物传递系统的基础上合成的两亲性结构，能够自组装成纳米胶束，这将是一个水溶性的双氯芬酸的传递系统。两亲性结构由三甘醇（TEG）、聚乙二醇PEG 400或PEG 600的亲水部分通过酯键与疏水性药物双氯芬酸连接组成。核磁共振证实双氯芬酸衍生物合成成功。此外，通过原子力显微镜证实了所合成的两亲性衍生物的胶束结构的形成，获得了平均直径为200 nm的Dic-PEG 400-Dic和110 nm的Dic-PEG 600-Dic的球形胶束。Dic-PEG 400-Dic的临界胶束浓度为2.7 × 10−3 mg mL−1，Dic-PEG 600-Dic的临界胶束浓度为1 × 10−4 mg mL−1。通过酯酶进行了体外双氯芬酸释放曲线，结果表明，在Dic-PEG 400-Dic胶束和85%以上的Dic-PEG 600-Dic胶束中，在35 h内几乎完全转化为游离双氯芬酸。通过检测LPS刺激的Balb/c小鼠TNF-α的产生来确定其抗炎活性。给予5 mg kg−1剂量后，双氯芬酸胶束显著抑制TNF-α的产生。在Dic-PEG 400-Dic和Dic-PEG 600-Dic胶束的情况下，所开发的胶束在处理48小时后分别显示出高达87.4%和84%的TNF-α抑制，而在双氯芬酸单独给药的情况下为42.3%。Dic-PEG 400-Dic胶束显示出最有效的抗炎活性，随着时间的推移，TNF-α抑制作用得到改善。因此，开发的纳米胶束提供了一种简便的合成方法，以提高双氯芬酸的水溶性，改善抗炎作用，并实现缓释特性，以获得更好的患者依从性。成功合成了两亲性双氯芬酸前药，并将其自组装成纳米胶束结构，提高了体内抗炎活性。
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for the treatment of various types of inflammatory conditions. Diclofenac is a very common NSAID that is utilized to relieve pain and reduce fever and, most importantly, inflammation. However, it suffers from low water solubility and a low dissolution profile. Therefore, we aim to develop a new drug delivery system based on the synthesis of amphiphilic structures that are capable of self assembling into nano-micelles which will be a water-soluble delivery system for the diclofenac. The amphiphilic structure consists of a hydrophilic moiety of triethylene glycol (TEG), polyethylene glycol PEG 400, or PEG 600 linked with the hydrophobic drug diclofenac through an ester linkage. The diclofenac derivatives were successfully synthesized as confirmed by nuclear magnetic resonance. Moreover, the formation of the micellar structure of the synthesized amphiphilic derivatives was confirmed by atomic force microscopy obtaining a spherical shape of the micelles with average diameters of 200 nm for Dic-PEG400-Dic, and 110 nm for Dic-PEG600-Dic. The critical micelle concentration has been determined as 2.7 × 10−3 mg mL−1 for Dic-PEG400-Dic, and 1 × 10−4 mg mL−1 for Dic-PEG600-Dic. The in vitro diclofenac release profile by esterase enzyme was conducted and showed almost complete conversion to free diclofenac within 35 h in the case of Dic-PEG400-Dic micelles and more than 85% of Dic-PEG600-Dic micelles. Then the anti-inflammatory activity was determined by testing the TNF-α production in LPS-stimulated Balb/c mice. Diclofenac micelles significantly suppressed TNF-α production after a 5 mg kg−1 dose was given. The developed micelles showed TNF-α inhibition up to 87.4% and 84% after 48 hours of treatment in the case of Dic-PEG400-Dic and Dic-PEG600-Dic micelles respectively in comparison to 42.3% in the case of diclofenac alone. Dic-PEG400-Dic micelles showed the most potent anti-inflammatory activity with improved TNF-α suppression through time progress. Therefore, the developed nano-micelles provide a facile synthetic approach to enhance diclofenac water solubility, improve the anti-inflammatory effect and achieve a sustained release profile to get better patient compliance. Amphiphilic diclofenac prodrugs were successfully synthesized and self-assembled into the nano-micellar structures that have improved the anti-inflammatory activity in vivo.
登录
查看更多内容
影响因子：
2.1
作者：
Assali, Mohyeddin;Joulani, Maysa;Zaid, Abdel Naser
通讯作者：
Zaid, Abdel Naser
DOI：
10.2217/nnm.15.45
发表时间：
2015
期刊：
Nanomedicine (London, England)
影响因子：
--
作者：
Prasad LK;O'Mary H;Cui Z
通讯作者：
Cui Z
DOI：
10.1080/00914037.2016.1263951
发表时间：
2017-01-01
影响因子：
3.2
作者：
Assali, Mohyeddin;Zaid, Abdel Naser;Sawalha, Hassan
通讯作者：
Sawalha, Hassan
影响因子：
5.8
作者：
Jukanti, Raju;Devaraj, Gopinath;Apte, Shashank
通讯作者：
Apte, Shashank
影响因子：
4.6
作者：
Assali, Mohyeddin;Shawahna, Ramzi;Alhimony, Imad-Aldin
通讯作者：
Alhimony, Imad-Aldin