Feng Lan, Benhabbour Soumya R, Mumper Russell J
Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Adv Healthc Mater. 2013 Nov;2(11):1451-7. doi: 10.1002/adhm.201300017. Epub 2013 Apr 19.
A docetaxel (DX) lipid conjugate 2'-(2-bromohexadecanoyl)-docetaxel (2-Br-C16-DX) is synthesized to enhance the drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The conjugate is successfully entrapped in the previously optimized NPs with an entrapment efficiency of 56.8%. In-vitro release studies in 100% mouse plasma show an initial 45% burst release with no additional release within 8 h. The conjugate is able to be hydrolyzed to release DX by esterases in-vitro. The conjugate is less potent than unmodified DX in DU-145 and 4T1 cells. However, NPs containing the conjugate show significantly higher cytotoxicity compared to its free form especially in 4T1 cells. In-vivo, the AUC0-∞ value of NP-formulated 2-Br-C16-DX is about 100-fold higher than DX formulated in Taxotere. Furthermore, 2-Br-C16-DX NPs improve DX AUC 4.3-fold compared to Taxotere. The high concentration and prolonged exposure of both 2-Br-C16-DX and DX from 2-Br-C16-DX NPs in circulation result in a 10-fold and 1.5-fold higher accumulation of 2-Br-C16-DX and DX, respectively, in tumors compared to Taxotere. In mice bearing syngeneic 4T1 tumors, 2-Br-C16-DX NPs show markedly greater anticancer efficacy, as well as survival benefit over all controls. The results of these studies support that the oil-filled NPs containing hydrolyzable lipophilic DX prodrug 2-Br-C16-DX improve the therapeutic index of DX and are more efficacious in the treatment of breast cancer.
合成了一种多西他赛（DX）脂质偶联物2'-（2-溴十六烷酰基）-多西他赛（2-Br-C16-DX），以提高药物在填充液体油的脂质纳米颗粒（NPs）中的负载、包封和保留。该偶联物成功包封在先前优化的纳米颗粒中，包封效率为56.8%。在100%小鼠血浆中的体外释放研究表明，最初有45%的突释，8小时内无额外释放。该偶联物能够在体外被酯酶水解以释放DX。在DU-145和4T1细胞中，该偶联物的效力低于未修饰的DX。然而，含有该偶联物的纳米颗粒与其游离形式相比显示出显著更高的细胞毒性，尤其是在4T1细胞中。在体内，纳米粒制剂2-Br-C16-DX的AUC0-∞值比泰索帝制剂的DX高约100倍。此外，与泰索帝相比，2-Br-C16-DX纳米粒使DX的AUC提高了4.3倍。循环中2-Br-C16-DX和来自2-Br-C16-DX纳米粒的DX的高浓度和长时间暴露导致2-Br-C16-DX和DX在肿瘤中的积累分别比泰索帝高10倍和1.5倍。在携带同基因4T1肿瘤的小鼠中，2-Br-C16-DX纳米粒显示出明显更大的抗癌疗效，以及优于所有对照组的生存益处。这些研究结果支持，含有可水解亲脂性DX前药2-Br-C16-DX的油填充纳米粒提高了DX的治疗指数，在乳腺癌治疗中更有效。
