Complementary\nNanoparticle Characterization by Resistive-Pulse\nSensing, Electron Microscopy, and Charge Detection Mass Spectrometry

Nanotechnology has provided novel modalities for the\ndelivery of\ntherapeutic and diagnostic agents. In particular, nanoparticles (NPs)\ncan be engineered at a low cost for drug loading and delivery. For\nexample, silica NPs have proven useful as a controlled release platform\nfor anti-inflammatory drugs. Despite the wide-ranging potential applications\nfor NPs, robust characterization across all size ranges remains elusive.\nElectron microscopy (EM) is the conventional tool for measuring NP\ndiameters. However, imitations in throughput and the inability to\nprovide comprehensive information on physical properties, such as\nmass and density, without underlying assumptions, hinder a complete\nanalysis. In addition, assessing sample heterogeneity, aggregation,\nor coalescence in solution by traditional EM analysis is not possible.\nResistive-pulse sensing (RPS) provides a high throughput, solution-phase\nmethod for characterizing particle heterogeneity based on volume.\nComplementing these methods, charge detection mass spectrometry (CD-MS),\na single particle technique, provides accurate mass information for\nheterogeneous samples including NPs. By combining EM, RPS and CD-MS,\naccurate volume, mass, and densities were obtained for silica NPs\nof various sizes. The results show that the density for 20 nm silica\nNPs is close to the density of fused silica (2.2 g/cm<sup>3</sup>).\nLarger silica NPs were found to have densities that were either smaller\nor larger, while also falling outside the range of densities usually\nfound for silica colloids and NPs (1.9–2.3 g/cm<sup>3</sup>). Lower densities are attributed to pores (i.e., porous particles).\nFor one sample, the mass distribution showed two components attributed\nto two populations of particles in the sample with different densities.\nThe synergistic combination of EM, RPS, and CD-MS measurements outlined\nhere for NP samples, allows much more extensive information to be\nobtained than from any of the techniques alone.