TY - JOUR
T1 - Enhanced Bioavailability by Orally Administered Sirolimus Nanocrystals
AU - Kong, Jianglong
AU - Wu, Kai
AU - Ji, Ying
AU - Chen, Kui
AU - Zhang, Jiaxin
AU - Sun, Hui
AU - Liang, Yuelan
AU - Liang, Wei
AU - Chang, Yanan
AU - Cheng, Jenny
AU - Tong, Junmao
AU - Li, Juan
AU - Xing, Gengmei
AU - Chen, Guogang
N1 - Funding Information:
This work was supported financially by the National Basic Research Program of China (973 Program) (2015CB932104), National Natural Science Foundation of China (31571028).
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/10/21
Y1 - 2019/10/21
N2 - Nanocrystallization can improve the dissolvability of insoluble medicines in water, making them easier to administer. In the present study, sirolimus (SRL) was nanocrystallized, and the transport mechanism and efficacy of both formulations were compared in vitro and in vivo. The results showed that the 120 nm sirolimus nanocrystals (SRL NCs) had better ability to pass through the Caco-2 cell monolayer. SRL NCs were uptaken by Caco-2 cells via multiple endocytosis pathways, and the endoplasmic reticulum (ER), Golgi apparatus, and microtubules were identified as vital organelles for expelling SRL NCs out of the cells. SRL NCs decreased CD4+/CD8+ in normal mice after 14 days of daily gavage administration. Furthermore, SRL NCs enhanced the immune tolerance in an ovalbumin (OVA)-sensitized mouse model. SRL NCs significantly increased the percentage of Tregs (CD25+Foxp3+) among CD4+T cells. Collectively, these findings demonstrate that nanocrystallization of SRL enhances oral bioavailability, transcytosis, and prolongs drug residence time in vivo, while also enhancing SRL efficacy.
AB - Nanocrystallization can improve the dissolvability of insoluble medicines in water, making them easier to administer. In the present study, sirolimus (SRL) was nanocrystallized, and the transport mechanism and efficacy of both formulations were compared in vitro and in vivo. The results showed that the 120 nm sirolimus nanocrystals (SRL NCs) had better ability to pass through the Caco-2 cell monolayer. SRL NCs were uptaken by Caco-2 cells via multiple endocytosis pathways, and the endoplasmic reticulum (ER), Golgi apparatus, and microtubules were identified as vital organelles for expelling SRL NCs out of the cells. SRL NCs decreased CD4+/CD8+ in normal mice after 14 days of daily gavage administration. Furthermore, SRL NCs enhanced the immune tolerance in an ovalbumin (OVA)-sensitized mouse model. SRL NCs significantly increased the percentage of Tregs (CD25+Foxp3+) among CD4+T cells. Collectively, these findings demonstrate that nanocrystallization of SRL enhances oral bioavailability, transcytosis, and prolongs drug residence time in vivo, while also enhancing SRL efficacy.
KW - bioavailability
KW - immune tolerance
KW - oral administration
KW - sirolimus nanocrystals
KW - transport mechanisms
UR - http://www.scopus.com/inward/record.url?scp=85072915750&partnerID=8YFLogxK
U2 - 10.1021/acsabm.9b00695
DO - 10.1021/acsabm.9b00695
M3 - Journal article
AN - SCOPUS:85072915750
SN - 2576-6422
VL - 2
SP - 4612
EP - 4621
JO - ACS Applied Bio Materials
JF - ACS Applied Bio Materials
IS - 10
ER -