Establishing the effects of mesoporous silica nanoparticle properties on in vivo disposition using imaging-based pharmacokinetics

The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability toestablish structure-activity relationships in vivo. Here, using stable, monosized, radiolabeled,mesoporous silica nanoparticles (MSNs), we apply an integrated SPECT/CT imaging andmathematical modeling approach to understand the combined effects of MSN size, surfacechemistry and routes of administration on biodistribution and clearance kinetics in healthyrats. We show that increased particle size from ~32- to ~142-nm results in a monotonicdecrease in systemic bioavailability, irrespective of route of administration, with correspondingaccumulation in liver and spleen. Cationic MSNs with surface exposed amines (PEI)have reduced circulation, compared to MSNs of identical size and charge but with shieldedamines (QA), due to rapid sequestration into liver and spleen. However, QA show greatertotal excretion than PEI and their size-matched neutral counterparts (TMS). Overall, weprovide important predictive functional correlations to support the rational design ofnanomedicines.

纳米颗粒（nanoparticle, NP）基药物递送的发展一直受限于无法在活体环境中构建构效关系。本研究采用稳定、单分散、放射性标记的介孔二氧化硅纳米颗粒（mesoporous silica nanoparticles, MSNs），运用集成单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）成像与数学建模的一体化研究方法，探究了MSNs的粒径、表面化学性质以及给药途径对健康大鼠体内生物分布与清除动力学的综合影响。研究结果显示，当颗粒粒径从约32纳米增至约142纳米时，无论采用何种给药途径，其全身生物利用度均呈单调递减趋势，且会在肝脏与脾脏中出现相应富集。相较于粒径与表面电荷一致但氨基被遮蔽的介孔二氧化硅纳米颗粒（QA），表面暴露氨基（PEI）修饰的阳离子MSNs的循环时间更短，这是由于其会被肝脏与脾脏快速截留。不过，QA组的总排泄量高于PEI组及其粒径匹配的中性对照颗粒（TMS）。综上，本研究提供了具有重要预测价值的功能关联，可为纳米药物的合理化设计提供支撑。