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已发表论文
耦合甲氨蝶呤脂质体微泡用于穿过血脑屏障的甲氨蝶呤超声介导递送
Authors Wang X, Liu P, Yang W, Li L, Li P, Liu Z, Zhuo Z, Gao Y
Published Date October 2014 Volume 2014:9(1) Pages 4899—4909
DOI http://dx.doi.org/10.2147/IJN.S69845
Received 23 June 2014, Accepted 3 September 2014, Published 23 October 2014
Approved for publication by Professor Thomas J. Webster
Abstract: Methotrexate (MTX) is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 µm in diameter) was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 µg/g) > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 µg/g) > MTX alone (6.97±0.75 µg/g) > MTX-liposome-coupled microbubbles (2.92±0.39 µg/g). Therefore, treatment with MTX-liposome-coupled microbubbles and ultrasound resulted in a significantly higher brain MTX concentration than all other treatments (P <0.01). These results suggest that MTX-liposome-coupled microbubbles may hold great promise as new and effective therapies for primary central nervous system lymphoma and other central nervous system malignancies.
Keywords: methotrexate, microbubbles, ultrasound, liposomes, blood–brain barrier
Keywords: methotrexate, microbubbles, ultrasound, liposomes, blood–brain barrier
