PEG-PCL modification and intestinal sustained-release of solid lipid nanoparticles for improving oral bioavailability of 2-methoxyestradiol

The primary purpose of the present study was to design and optimize a solid lipid nanoparticle (SLN) formulation of the poorly water-soluble drug 2-methoxyestradiol (2-ME) to improve its oral bioavailability and prolong the duration of therapeutic drug level. SLN was modified by amphipathic PEG-PCL (PLN) and then encapsulated in pH-sensitive microparticles (MP) by spray drying technology. Several properties of 2-ME PLN-MP were characterized including particle size, drug loading, and drug or PLN release. After oral administration of 2-ME PLN-MP, retention time in mice was evaluated by in vivo imaging technology and the pharmacokinetic parameters in rats were determined by HPLC. The results demonstrated that PEG-PCL modification of 2-ME SLN significantly decreased particle size and delayed drug release without influencing IC50 in 4T1 cells. 2-ME PLN in the microparticles showed significant pH-sensitive release in the simulated gastrointestinal fluid and controlled release in the intestine. The PLN (labelled with IR-780 iodide) prolonged significantly fluorescence duration time compared to the SLN and the prolongation was further enhanced by the PLN-MP formulation. Furthermore, compared with the suspension, the PLN-MP formulation showed a 56.66-fold delay in Tmax, a 10.36-fold extension in MRT and a 140.86-fold increase in the relative bioavailability in the rat. The research work in the paper suggests that the PLN-MP could serve as a practical oral preparation for 2-ME in future cancer therapy.