Nanocarriers with long-term retention in the respiratory system for prolonged drug exposure

Abstract

This study was the first attempt to visualize pulmonary retention of nanocarriers (NCs) with the use of the P2 probe, a new water-initiated aggregation-caused fluorescent-quenching (ACQ) dye, for the development of NCs with long-lasting retention in the respiratory system (RS). Flash nanoprecipitation was used to fabricate mucopenetrating NCs (MP/NCs) and mucoadhesive NCs (MA/NCs). Both NCs were labeled with the P2 probe, and their distribution and retention in RS were visualized after intratracheal administration to rats. MP/NCs and MA/NCs had a mean diameter below 200 nm and ζ-potential of 0 and 48 mV, respectively. MA/NCs showed three times stronger interactions with mucin than MP/NCs, resulting in significantly lower diffusiveness in mucus. The P2 probe exhibited an ACQ effect with negligible rekindling in simulated lung fluid, and the spectroscopic data suggested applicability to reliable imaging of insufflated NCs. In confocal laser scanning microscopic and in vivo imaging system images of the rat RS, MA/NCs were locally deposited in the respiratory tract and transported toward the pharynx by mucocilliary clearance (MCC). In contrast, MP/NCs diffused in the respiratory mucus were less subject to the influence of MCC. Based on the results from the bioimaging study using the P2 probe, MP/NCs could offer enhanced pulmonary retention of drugs compared with MA/NCs.

Keywords:

• Aggregation-caused fluorescent-quenching dye
• flash nanoprecipitation
• mucoadhesive nanocarriers
• mucopenetrating nanocarriers
• pulmonary retention

Acknowledgments

Special thanks are due to Wei Wu, a professor in the Key Laboratory of Smart Drug Delivery of MOE & PLA at Fudan University (Shanghai, China), for providing the P2 probe and giving advice regarding bioimaging studies. The authors wish to thank Robert K. Prud’homme, a professor in the Department of Chemical & Biological Engineering at Princeton University (Princeton, NJ, USA).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported in part by JSPS KAKENHI [Grant-in-Aid for Scientific Research (C) (No. 20K07158: S. Onoue; and No. 20K07180: H. Sato)].