Delivering Enhanced Testosterone Replacement Therapy through Nanochannels
Delivering Enhanced Testosterone Replacement Therapy through Nanochannels
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DOI：
10.1002/adhm.201400348
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发表时间：
2015-02-18
影响因子：
10
通讯作者：
Grattoni, Alessandro
中科院分区：
文献类型：
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作者：
Ferrati, Silvia;Nicolov, Eugenia;Grattoni, Alessandro
原发性或继发性性腺功能减退症会导致一系列影响生活质量的体征和症状，需要终生睾丸素替代疗法。在这项研究中，一种可植入的纳米通道系统被作为一种替代的给药策略来长期持续和持续地释放睾酮。体外释放试验使用溶出仪，睾酮和testosterone:2-hydroxypropyl-beta-cyclodextrin(TES：HPCD)1：1和1：2摩尔比的络合物从可植入的纳米通道系统中释放，并用高效液相色谱法进行定量。1：2TES：HPCD络合物稳定地达到10-15倍的睾酮溶解度和25-30倍的体外释放。通过LNCaP/Luc细胞发光实验验证了所释放的睾酮的生物活性。采用液-质联用技术和多重分析技术，对去势大鼠体内睾酮、黄体生成素和卵泡刺激素水平进行了检测，并用纳米通道植入物或可降解睾酮微丸进行治疗。1：2TES：HPCD纳米通道植入物表现出持续的和临床相关的体内释放动力学，并达到生理稳定的血浆睾酮、黄体生成素和卵泡刺激素水平。总之，通过提供长期稳定释放的1：2TES：HPCD纳米通道植入物可能是治疗男性性腺功能减退的一个重大突破。
Primary or secondary hypogonadism results in a range of signs and symptoms that compromise quality of life and requires life-long testosterone replacement therapy. In this study, an implantable nanochannel system is investigated as an alternative delivery strategy for the long-term sustained and constant release of testosterone. In vitro release tests are performed using a dissolution set up, with testosterone and testosterone:2-hydroxypropyl-beta-cyclodextrin (TES:HPCD) 1:1 and 1:2 molar ratio complexes release from the implantable nanochannel system and quantify by HPLC. 1:2 TES:HPCD complex stably achieve 10-15 times higher testosterone solubility with 25-30 times higher in vitro release. Bioactivity of delivered testosterone is verified by LNCaP/LUC cell luminescence. In vivo evaluation of testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels by liquid chromatography mass spectrometry (LC/MS) and multiplex assay is performed in castrated Sprague-Dawley rats over 30 d. Animals are treated with the nanochannel implants or degradable testosterone pellets. The 1:2 TES:HPCD nanochannel implant exhibits sustained and clinically relevant in vivo release kinetics and attains physiologically stable plasma levels of testosterone, LH, and FSH. In conclusion, it is demonstrated that by providing long-term steady release 1:2 TES:HPCD nanochannel implants may represent a major breakthrough for the treatment of male hypogonadism.