Preparation, characterization, biotoxicity, and biodistribution of thermo-responsive magnetic complex micelles formed by Mn0.6Zn0.4Fe2O4 and a PCL/PEG analogue copolymer for controlled drug delivery

Abstract

A thermo-responsive PCL/PEG analogue copolymer (PCL-[b-P(MEO₂MA-co-OEGMA)]₂) with a lower critical solution temperature (LCST) of 40.4 °C at an MEO₂MA/OEGMA molar ratio of 87 : 13 was designed and synthesized. The copolymer was subsequently labeled by coupling with fluorescein isothiocyanate (FITC). Thermo-responsive magnetic PCL-[b-P(MEO₂MA-co-OEGMA)]₂/Mn_0.6Zn_0.4Fe₂O₄ (MZF) complex micelles were prepared by a self-assembly method. Doxorubicin (DOX) was loaded into the magnetic complex micelles as a model drug, and the DOX-MZF-micelles showed well-controlled thermo-responsive release both at externally fixed temperatures and in the presence of an alternating magnetic field (AMF). Both the blank polymer micelles and the magnetic complex micelles exhibited excellent stability in normal saline and serum. Based on the detection of the FITC fluorescence signal, the micelles were found to be effectively labeled by FITC. Furthermore, the biological toxicity of micelles was studied in vitro and in vivo. In vitro toxicity studies to evaluate cell viability and cell toxicity were performed by employing WST-1 and LDH release assays using HL7702 cells, respectively. In vivo biotoxicity studies were conducted in ICR mice through a series of tests: general conditions, body weight shifts, serum biochemistry profiles, and organ coefficient tests. All the biological toxicity results obtained from the blank polymer micelles and the magnetic complex micelles indicated their good biocompatibility and nontoxicity. The in vivo biodistribution studies of the FITC-labeled magnetic complex micelles were performed in the ICR mice. The copolymer was cleared by the kidney and spleen, while the MZF nanoparticles were cleared by the liver in time, causing no adverse effects on organisms. The thermo-responsive magnetic complex micelles were shown to be an ideal nanocarrier for anticancer drug delivery in terms of controlled release, stability, biocompatibility and safety.