James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Cancer Lett. 2012 Dec 29;326(1):33-40. doi: 10.1016/j.canlet.2012.07.017. Epub 2012 Jul 20.
Poor oral bioavailability limits the use of many chemopreventives in the prevention and treatment of cancer. To overcome this limitation, we report an improvised implant formulation ("coated" implants) using curcumin, individual curcuminoids, withaferin A and oltipraz. This method involves the coating of blank polycaprolactone implants with 20-30 layers of 10-20% polycaprolactone solution in dichloromethane containing 0.5-2% of the test agent. The in vitro release showed that while oltipraz was released with almost zero-order kinetics over 8 weeks, curcumin, individual curcuminoids and withaferin A were released with some initial burst. The in vivo release was determined by grafting implants subcutaneously in A/J mice. When delivered by coated implants, oltipraz significantly diminished lung DNA adducts in mice treated with dibenzo[a,l]pyrene compared with sham treatment (28 ± 7 versus 54 ± 17 adducts/10(9) nucleotides). Withaferin A also diminished DNA adducts, but it was insignificant. Curcumin and individual curcuminoids were ineffective. Analysis of lung, liver and brain by UPLC-fluorescence showed the presence of the three test curcuminoids indicating effectiveness of the implant delivery system. Further, based on its known antitumor activity in vivo, withaferin A given via the implants significantly inhibited human lung cancer A549 xenograft in athymic nude mice, while it was ineffective when the same total dose was administered i.p. and required over 2-fold higher dose to elicit effectiveness. Together, our data suggest that coated polymeric implants can accommodate heat-labile compounds, can furnish sustained release for long duration, and elicit DNA damage-inhibiting and anti-tumor activities.
较差的口服生物利用度限制了许多化学预防药物在癌症预防和治疗中的应用。为了克服这一限制，我们报告了一种改良的植入剂配方（“包衣”植入剂），该配方使用姜黄素、单独的姜黄素类化合物、虎杖苷和奥替普拉。该方法涉及用 20-30 层 10-20%的聚己内酯溶液在二氯甲烷中包被空白聚己内酯植入物，其中含有 0.5-2%的测试剂。体外释放结果表明，奥替普拉几乎以零级动力学在 8 周内释放，而姜黄素、单独的姜黄素类化合物和虎杖苷则有初始突释。体内释放通过将植入物皮下植入 A/J 小鼠中进行测定。与假手术相比，用包衣植入物给药时，奥替普拉显著减少了二苯并[a,l]芘处理的小鼠肺 DNA 加合物（28±7 与 54±17 加合物/10(9) 核苷酸）。虎杖苷也减少了 DNA 加合物，但无统计学意义。姜黄素和单独的姜黄素类化合物无效。用 UPLC-荧光法对肺、肝和脑进行分析表明，存在三种测试的姜黄素类化合物，表明植入物递送系统有效。此外，基于其在体内已知的抗肿瘤活性，虎杖苷通过植入物给药显著抑制了裸鼠中人类肺癌 A549 异种移植物，而当相同的总剂量腹腔内给药时无效，并且需要高出 2 倍的剂量才能发挥作用。总之，我们的数据表明，包衣聚合物植入物可以容纳热敏化合物，可以提供长时间的持续释放，并引发 DNA 损伤抑制和抗肿瘤活性。
