ABSTRACT
OBJECTIVE: To prepare an insulin-loaded nanoparticle assembled using pH-sensitive poly(ethylene glycol)-poly(ε-caprolactone)-poly(N,N-diethylamino-2-ethylmethaerylate) (mPEG-PCL-PDEAEMA) and investigate its performance of sustained insulin release in vitro and its hypoglycemic effects in diabetic rats. METHDOS: mPEG-PCL-PDEAEMA triblock copolymers with different hydrophobic lengths were synthesized by ring opening polymerization (ROP) combined with atom transfer radical polymerization (ATRP). The copolymers were characterized using Fourier-transform Infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance spectroscopy (1H-NMR). Insulin-loaded nanoparticles were prepared by nanoprecipitation technique, in which the reversible swelling of the pH-sensitive material was used for insulin loading and release. The obtained nanoparticles were further confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The entrapment efficiency (EE%), drug loading (DL%) and in vitro release characteristics of the insulin- loaded nanoparticles were assessed using BCA protein assay kit. The hypoglycemic effects of the nanoparticles were evaluated by monitoring the glucose levels. RESULTS: The size of the nanoparticles decreased as pH value increased within the range of 1.2 to 7.4. Using copolymers mPEG5k-PCL13k- PDEAEMA10k and mPEG5k-PCL10k-PDEAEMA10k as the drug carriers, the nanoparticles prepared with an optimal insulin-coplymer mass ratio of 90% had an average size of 181.9∓6.67 nm and 169∓7.1 nm, maximal EE% of (81.99∓1.77)% and (53.12∓0.62)%, and maximal DL% of (42.46∓0.53)% and (32.34∓0.26)%, respectively. Compared with free insulin, the insulin-loaded nanoparticles was capable of sustained insulin release and the release rate was lowered as the hydrophobic length increases. In diabetic rats, the insulin-loaded nanoparticles based on mPEG5k-PCL13k- PDEAEMA10k maintained a sustained hypoglycemic effect for 48 h, which was significantly longer than the time of free insulin. CONCLUSION: The pH-sensitive triblock copolymer mPEG-PCL-PDEAEMA can serve as a promising candidate of carrier for sustained release of insulin.
ABSTRACT
BACKGROUND: It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future. MATERIALS AND METHODS: In this study, CUR-loaded methoxy polyethylene glycol-polylactide (CUR/mPEG-PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently. RESULTS: The average size of CUR/mPEG-PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067-0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG-PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG-PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG-PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG-PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax. CONCLUSION: The mPEG-PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG-PLA micelles have promising clinical potential in treating NSCLC.
