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.

Preparation and evaluation of 2-methoxyestradiol-loaded pH-sensitive liposomes

The development and clinical application of 2-methoxyestradiol (2-ME) as a new type of antitumor drug are limited due to its poor solubility, rapid metabolism in vivo, and large oral dosage. 2-ME-loaded pH-sensitive liposomes (2-ME-PSLs) was prepared containing the lipids, Lipoid E-80 (E-80), cholesteryl hemisuccinate (CHEMS), and cholesterol (CHOL) via thin-film ultrasonic dispersion. First, preparation conditions of 2-ME-PSLs were optimized by orthogonal test. Then 2-ME-PSL was characterized, and the release behavior and stability of 2-ME-PSL in vitro were evaluated. The optimal preparation conditions for 2-ME-PSLs were as follows: 2-ME : E-80+CHEMS 1:15; CHOL : E-80+CHEMS 1:5; ultrasonication time 20 minutes. The mean particle size, PDI, zeta potential, and entrapment efficiency (EE) of 2-ME-PSLs were 116 ± 9 nm, 0.161 ± 0.025, −22.4 ± 1.7 mV, and 98.6 ± 0.5%, respectively. As viewed under a transmission electron microscope, 2-ME-PSLs were well dispersed and almost spherical. They exhibited significant pH-sensitive properties and were fairly stable when diluted with a physiological solution. In conclusion, 2-ME-PSLs were successfully prepared and possessed a favorable pH sensitivity and good dissolution stability with a normal solution