Establishing design principles for spray dried nanofibrillar supraparticles towards modular pulmonary drug delivery systems

以乳清蛋白（β -乳球蛋白，β - lg）为原料合成淀粉样纳米原纤维（ANFs）（长约μm，宽约10 nm），并利用扫描电镜（SEM）定量分析了其对喷雾干燥超颗粒（SPs）形貌的影响。SP纳米颗粒部分采用二氧化硅纳米颗粒（SNPs；直径为10、50、100 nm）或软多糖纳米颗粒（植物糖原；直径为~50 nm）和银纳米线（SNWs）。我们发现，与βLG对照相比，ANFs增强了SP的形态皱缩，这表明由于ANFs的高纵横比，在SP固结过程中，结构停滞的发生速度更快。通过超声波将ANFs分解成更短的长度（更低的宽高比），可以进一步调制褶皱转变。当ANF含量较高时，随着SNP大小的增加，SP形状会发生皱缩，而在ANF含量较低时，软纳米颗粒会阻碍皱缩。中空的SP形状没有被观察到，可能是由于大的干燥应力和ANFs提供的塑性有利于皱缩。对含雪SPs的研究结果过于初步，无法得出结论。喷雾干燥后ANFs的结构完整性仍不清楚。场发射扫描电镜不能识别SP表面的ANFs。未干燥的SPs的透射电镜不确定ANF的存在，而水分散的SPs显示较短的ANF片段。这些结果通过阐明SP形状/表面积的控制，直接与SP颗粒的相互作用、空气动力学/药物释放特性和清除有关，并间接与SP颗粒的内聚性有关。

Amyloid nanofibrils (ANFs) were synthesized (few μm length, ~10 nm width) from whey protein (beta-lactoglobulin, βLG) and their influence on the morphology of spray-dried supraparticles (SPs) was analyzed quantitatively with scanning electron microscopy (SEM). Silica nanoparticles (SNPs; 10, 50, 100 nm diameter) or soft polysaccharide nanoparticles (phytoglycogen; ~50 nm diameter) and silver nanowires (SNWs) were used as the SP nanoparticle fraction. We found that ANFs enhance the morphological crumpling of SPs compared to βLG control, indicating faster onset of structural arrest during the SP consolidation due to the high aspect-ratio of ANFs. The crumpling transition could be further modulated by ultrasonic breakup of ANFs to shorter lengths (lower aspect-ratio). Crumpled SP shapes occurred at higher ANF content with increasing SNP size, while soft nanoparticles impeded crumpling at low ANF content. Hollow SP shapes were not observed likely due to crumpling being favored by large drying stresses and plasticity afforded by ANFs. Results on SNW-containing SPs are too preliminary to draw conclusions.Structural integrity of ANFs after spray drying remains unclear. Field-emission SEM could not discern ANFs on SP surfaces. Transmission electron microscopy of never-dried SPs were inconclusive on the presence of ANFs, while water-dispersed SPs displayed short ANF segments.These results have direct relevance to SP particle interactions, aerodynamic/drug release properties and clearance by illuminating the control of SP shape/surface area, and indirectly, their cohesiveness.