PDF(Pubmed)
Abstract：
Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice.
摘要：
雷帕霉素减缓多囊肾病（PKD）小鼠模型的膀胱形成，但在临床试验中失败，可能是由于药物剂量不足。为了在不增加剂量的情况下提高药物效率，可以使用肾脏特异性药物递送。中尺度纳米颗粒(MNP)选择性地靶向啮齿动物的近端小管。我们探讨了MNPs是否可以靶向囊性肾小管，以及雷帕霉素包裹的MNPs（RapaMNPs）是否可以减缓Pkd1基因敲除（KO）小鼠的囊肿生长。在成年Pkd1KO小鼠中静脉内施用MNP。在8、24、48或72小时后收集血清和器官以测量MNP定位，mTOR水平,和雷帕霉素浓度。然后将Pkd1KO小鼠每两周注射一次RapaMNP，持续6周，雷帕霉素,或载体，以确定药物对肾囊肿生长的疗效。单次注射MNP导致肾脏优先于其他器官的积累，特别是在小管和囊肿中。同样，与肝脏相比，一次RapaMNP注射导致更高的药物递送到肾脏，并表现出持续的mTOR抑制。每两周注射RapaMNP，雷帕霉素或载体6周导致mTOR抑制不一致，囊肿指数变化不大，however.MNPs作为一个有效的短期，肾脏特异性输送系统，但长期RapaMNP未能减缓Pkd1KO小鼠的囊肿进展。
