Lipid-based liquid crystalline nanoparticles as oral drug delivery vehicles for poorly water-soluble drugs: cellular interaction and in vivo absorption

Ni Zeng,^1,3,* Xiaoling Gao,^2,* Quanyin Hu,¹ Qingxiang Song,² Huimin Xia,¹ Zhongyang Liu,¹ Guangzhi Gu,¹ Mengyin Jiang,^1,4 Zhiqing Pang,¹ Hongzhuan Chen,² Jun Chen,¹ Liang Fang^3
1Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, ²Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, ³Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, ⁴School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong People's Republic of China,
^*These authors contributed equally to this work

Background: Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as novel drug-delivery systems for improving the bioavailability of both hydrophilic and hydrophobic drugs. However, their cellular interaction and in vivo behavior have not been fully developed and characterized.
Methods: In this study, self-assembled LCNPs prepared from soy phosphatidylcholine and glycerol dioleate were developed as a platform for oral delivery of paclitaxel. The particle size of empty LCNPs and paclitaxel-loaded LCNPs was around 80 nm. The phase behavior of the liquid crystalline matrix was characterized using crossed polarized light microscopy and small-angle X-ray scattering, and showed both reversed cubic and hexagonal phase in the liquid crystalline matrix. Transmission electron microscopy and cryofield emission scanning electron microscopy analysis revealed an inner winding water channel in LCNPs and a "ball-like"/"hexagonal" morphology.
Results: Cellular uptake of LCNPs in Caco-2 cells was found to be concentration-dependent and time-dependent, with involvement of both clathrin and caveolae/lipid raft-mediated endocytosis. Under confocal laser scanning microscopy, soy phosphatidylcholine was observed to segregate from the internalized LCNPs and to fuse with the cell membrane. An in vivo pharmacokinetic study showed that the oral bioavailability of paclitaxel-loaded LCNPs (13.16%) was 2.1 times that of Taxol® (the commercial formulation of paclitaxel, 6.39%).
Conclusion: The findings of this study suggest that this LCNP delivery system may be a promising candidate for improving the oral bioavailability of poorly water-soluble agents.

Keywords: soy phosphatidylcholine, glycerol dioleate, liquid crystalline nanoparticles, paclitaxel, cellular interaction