Polymer Science Division, BMT Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695012, Kerala, India.
Polymer Science Division, BMT Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695012, Kerala, India.
J Colloid Interface Sci. 2017 Apr 15;492:61-72. doi: 10.1016/j.jcis.2016.12.070. Epub 2016 Dec 31.
We report a new prodrug micelle-based approach in which a model hydrophobic non-steroidal anti-inflammatory drug (NSAID), ibuprofen (Ibu), is tethered to amphiphilic methoxy polyethylene glycol-polypropylene fumarate (mPEG-PPF) diblock copolymer via hydrolytic anhydride linkages for potential controlled release applications of NSAIDs. Synthesized mPEG-PPF-Ibu polymer drug conjugates (PDCs) demonstrated high drug conjugation efficiency (∼90%) and self-assembled to form micellar nanostructures in aqueous medium with critical micelle concentrations ranging between 16 and 30μg/mL. The entrapment efficiency of Ibu in prepared PDC micelles was as high as 18% (w/w). Crosslinking of prodrug micelles with N,N'-dimethylaminoethyl methacrylate conferred pH-responsive characteristics. pH-responsive PDC micelles averaged 100nm in size at pH 7.4 and exhibited concomitant changes in size upon incubation in physiologically relevant mildly acidic conditions. Ibu release was observed to increase with increasing acidic conditions and could be controlled by varying the amount of crosslinker used. Furthermore, the prepared mPEG-PPF-based micelles demonstrated excellent cytocompatibility and cellular internalization in vitro. More importantly, PDC micelles exerted anti-inflammatory effects by significantly decreasing monosodium urate crystal-induced prostaglandin E2 levels in rabbit synoviocyte cultures in vitro. Cumulatively, our results indicate that this new prodrug micelle approach is promising for NSAID-based therapies in the treatment of arthritis and cancer.
我们报告了一种新的前药胶束方法，其中将模型疏水性非甾体抗炎药（NSAID）布洛芬（Ibu）通过水解酸酐键连接到两亲性甲氧基聚乙二醇-聚（富马酸）（mPEG-PPF）嵌段共聚物上，用于 NSAID 的潜在控制释放应用。合成的 mPEG-PPF-Ibu 聚合物药物偶联物（PDC）表现出高药物偶联效率（约 90%），并在水介质中自组装形成胶束纳米结构，临界胶束浓度在 16 至 30μg/mL 之间。在制备的 PDC 胶束中，Ibu 的包封效率高达 18%（w/w）。用 N,N'-二甲氨基乙基甲基丙烯酸酯交联前药胶束赋予其 pH 响应特性。在 pH 7.4 时，PDC 胶束的平均粒径为 100nm，并在生理相关的轻度酸性条件下孵育时表现出相应的粒径变化。观察到 Ibu 的释放随着酸性条件的增加而增加，并可以通过改变使用的交联剂的量来控制。此外，所制备的基于 mPEG-PPF 的胶束在体外表现出优异的细胞相容性和细胞内化。更重要的是，PDC 胶束通过显著降低兔滑膜细胞培养物中单钠尿酸盐晶体诱导的前列腺素 E2 水平发挥抗炎作用。总之，我们的结果表明，这种新的前药胶束方法有望用于治疗关节炎和癌症的 NSAID 治疗。
