The in vivo fate of nanocrystals is a controversial topic, i.e. dissolving versus integral absorption through the intestinal membrane. This is due to the lack of functional strategies to identify integral nanocrystals. In this study, the in vivo fate of quercetin hybrid nanocrystals (QT-HNCs) via the oral route is explored by physically embedding an environment-responsive probe in the crystal lattices of quercetin. The specific property of the probe is the water-initiated aggregation-caused quenching (ACQ) ability, by which integral QT-HNCs can be self-discriminated. Instead of dissolving instantly, QT-HNCs can be retained in the gastrointestinal tract for 12–16 h, and can then be absorbed and distributed into various organs with the liver as the primary terminal. The ileum provides better absorption than the jejunum. Cellular studies prove that both trans-epithelial and M cell-mediated routes are involved in the absorption of integral QT-HNCs, which may be impeded by the mucous layer. Moreover, the particle size affects the in vivo behavior and the ex vivo cellular interaction of QT-HNCs, with moderate size, such as 550 nm, being preferred. The results not only validate the idea of using ACQ fluorophores for bioimaging of integral nanocrystals but also support the intestinal absorption of nanocrystals.

Paeoniflorin (Pae), a water-soluble monoterpene glucoside, has high potential clinical value in autoimmune and inflammatory diseases. However, the extremely low oral bioavailability of Pae (approxi...

In this study, self-discriminating hybrid nanocrystals was utilized to explore the biological fate of quercetin hybrid nanocrystals (QT-HNCs) with diameter around 280 nm (QT-HNCs-280) and 550 nm (QT-HNCs-550) following oral and intravenous administration and the contribution of integral nanocrystals to oral bioavailability enhancement of QT was estimated by comparing the absolute exposure of integral QT-HNCs and total QT in the liver. Results showed that QT-HNCs could reside in vivo as intact nanocrystals for as long as 48 h following oral and intravenous administration. A higher accumulation of integral QT-HNCs in liver and lung was observed for both oral and intravenous administration of QT-HNCs. The particle size affects the absorption and biodistribution of integral QT-HNCs and total QT. As compared to QT-HNCs-550, QT-HNCs-280 with smaller particle size is more easily absorbed, but dissolves faster in vivo, leading to higher distribution of QT (146.90 vs. 117.91 h·μg/mL) but lower accumulation of integral nanocrystals (6.8 2e10 vs. 15.27e10 h·[p/s]/[µW/cm²]) in liver following oral administration. Due to its slower dissolution and enhanced recognition by RES, QT-HNCs-550 with larger diameter shows higher liver distribution for both of QT (1015.80 h·μg/mL) and integral nanocrystals (259.63e10 h·[p/s]/[µW/cm²]) than those of QT-HNCs-280 (673.82 & 77.66e10 h·[p/s]/[µW/cm²]) following intravenous administration. The absolute exposure of integral QT-HNCs in liver following oral administration of QT-HNCs are 8.78% for QT-HNCs-280 and 5.88% for QT-HNCs-550, while the absolute exposure of total QT for QT-HNCs-280 and QT-HNCs-550 are 21.80% and 11.61%, respectively. Owing to imprecise quantification method, a surprisingly high contribution of integral QT-HNCs to oral bioavailability enhancement of QT (40.27% for QT-HNCs-280 and 50.65% for QT-HNCs-550) was obtained. These results revealed significant difference in absorption and biodistrbution between integral nanocrystals and overall drugs following oral and intravenous administration of QT-HNCs, and provided a meaningful reference for the contribution of integral nanocrystals to overall bioavailability enhancement.