Optimization, Characterization and in vivo Evaluation of Paclitaxel-Loaded Folate-Conjugated Superparamagnetic Iron Oxide Nanoparticles
Gang Gui, Ziqi Fan, Yihuan Ning, Can‐Can Yuan, Baolin Zhang, Qin Xu
Abstract
Background: Paclitaxel (PTX) has interesting anticancer activity. However, it is insoluble in water, which seriously hinders its use in clinical. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as an ideal drug delivery system. Therefore, we proposed a folic acid (FA) targeting drug-loaded SPIONs to reduce its adverse reaction. Methods: To improve the hydrophilicity of PTX, the structure of PTX was modified by succinic anhydride to obtain 2ʹ-succinate paclitaxel (SPTX). FA conjugated Polyethylene glycol (PEG)/polyethyleneimine (PEI)-SPIONs SPTX-loaded nanoparticles ( [email protected] @PEG/PEI-SPIONs) were prepared by solvent volatilization and hydrogen bond adsorption, and the nano-formulation was optimized by response surface methodology (RSM). The characteristics, antitumor effect in vitro, pharmacokinetics, and biodistribution of [email protected] @PEG/PEI-SPIONs were evaluated. Results: SPTX was successfully loaded on the surface of [email protected] /PEI-SPIONs. The formation of [email protected] @PEG/PEI-SPIONs was exhibited water-dispersive monodispersity with high stability by RSM, and dynamic light scattering (DLS) was 178.1± 3.12 nm, particle size observed in the transmission electron microscope (TEM) was 13.01± 1.10 nm, and the encapsulation efficiency (EE) and loading efficiency (LE) were 81.1± 1.66% and 14.8± 1.46%, respectively. It enhanced the stability in normal physiological condition, accelerated drug release at tumorous pH, and preferentially prolonged the circulation time. In vitro, the [email protected] @PEG/PEI-SPIONs significantly targeted to folate receptor (FR) positive cancers cell (HNE-1) via the receptor-ligand mediated pathway, resulting in effective cytotoxic activity. Pharmacokinetic results demonstrated that [email protected] @PEG/PEI-SPIONs (t 1/2 =3.41 h) had longer than free SPTX or PTX (t 1/2 =1.67 h) in rats in vivo. Tissue distribution studies showed that [email protected] @PEG/PEI-SPIONs were present at high levels in the liver and help in targeting the folate receptors present on the kidneys. Conclusion: These results suggest that [email protected] @PEG/PEI-SPIONs offer a highly promising approach to control drug release, improve drug pharmacokinetics and actively target the nasopharyngeal carcinoma. Keywords: paclitaxel, folic acid, superparamagnetic iron oxide nanoparticles, targeted drug delivery, response surface methodology, anti-nasopharyngeal carcinoma