Study On Surface Modification And Microwave-responsive Controlled Drug Release Of Fe₃O₄-based Nanocomposite With Magnetic-fluorescence-microwave Absorbing Properties

The use of nanotechnology in drug delivery is a rapidly expanding field. Recent research has focused on developing structurally stable, biocompatible, and nontoxic drug delivery systems that are able to deliver a relatively large amount of drug molecules and targeted controllable release. Not only because of the size and morphology, specific surface area of the multifunctional inorganic nanoparticles is big, which is easy to surface modification. But it also have unique optical, electrical, magnetic, microwave absorpting properties, which are suitable for used as a carrier of antitumor drug molecules. It is beneficial to improve the therapeutic effect of antitumor drug and reduce the side effects.As outlined below, several perquisites need to be incorporated into such a material in order to serve as efficient drug delivery systems:(1) The carrier material should be biocompatible.(2) High loading/encapsulation of desired drug molecules.(3) High stability in blood circulation.(4) Controlled release of drug molecules with a proper rate of release to achieve an effective local concentration. In order to improve the therapeutic effect of antitumor drug, to building an efficient, safe drug controlled release system is very important.Under this background, the article have prepared magnetic-luminescent bifunctional nanocomposites Fe3O4@Gd2O3/YF3:Eu3+using hydrothermal method and precipitation method, respectively. And the advantages and disadvantages of the two methods are compared. Based on this study, multifunctional nano-carrier (Fe3O4@MOn:Re3+(M=Zn, Ti, Sn; n=1,2; Re=Er,Yb)) which has magnetic, luminescence and microwave absorbing simultaneously were synthesised for the first time. In order to achieve the purpose of drug loaded efficiently, the surface are modified by organic molecules (Polyacrylic acid (PAA),β-cyclodextrin (β-CD), Glycine (Gly),3-ammonia propyl triethoxy silane (APTES)) and introduced the active groups (carboxyl (-COOH) and amino (-NH2)). Ibuprofen (IBU) with carboxyl groups and Etoposide (VP-16) with hydroxyl group and carbonyl oxygen as a model drug to achieved the drug loading by intermolecular force and hydrogen bond. Eventually, the interaction force between drug and nanoparticals was breaked by microwave-thermal conversion of nanoparticles, in order to realize the controlled drug delivery, so as to achieve the purpose to treat cancer efficiently. The main results were listed as follows:(1) Bifunctional magnetic-luminescent Fe3O4@Gd2O3:Eu3+nanoparticles have been successfully prepared using hydrothermal method and homogeneous precipitation method, respectively. The nanocomposites simultaneously exhibit excellent magnetic and luminescence properties (5Do-7F2electron dipole transition of Eu3+) as well as can be easily separated from solution using an externally applied magnetic field. Fe3O4@Gd2O3:Eu3+that prepared by homogeneous precipitation method have the uniformity of size distribution and coating layer is superior to the hydrothermal method. The homogeneous precipitation method can proceed well at ambient temperature and atmospheric pressure, so it is easy to achieve batch synthesis. And it can overcome the local inhomogeneity of precipitant, more suitable for the preparation of Fe3O4-based nanoparticles with core-shell structure.(2) PAA-functionalized Fe3O4@YF3:Eu3+bifunctional nanocomposites were prepared using an easy direct precipitation method and in situ polymerization method which have introduced reactive carboxyl groups at their surfaces to improve its biocompatible and drug loading property. The nanocomposites simultaneously possess strong magnetic behavior (38.3emu/g) and unique europium fluorescence properties with high emission intensity (Eu3+,5D0→77F1). A cytotoxicity assay indicated low toxicity of the Fe3O4@YF3:Eu3+-PAA nanoparticles to MCF-7cells. In addition, the introduction of reactive carboxyl groups made the nanoparticles more biocompatible than the unmodified Fe3O4@YF3:Eu3+nanoparticles, which is a significant step in improving the functionalization of these materials for potential use as a targeted drug-delivery system.(3)(β-CD)-functionalized Fe3O4@ZnO:Er3+,Yb3+multifunctional nanocomposites with magnetic, luminescence and microwave absorbing simultaneously were prepared using an easy direct precipitation method. The nanoparticles can achieve magnetic targeting, up-conversion luminescence monitoring and microwave-absorption controlled release drug. The ZnO:Er3+, Yb3+shell gives up-conversion fluorescence and excellent microwave thermal response property. The cavity of β-cyclodextrin is chemically inert which can store etoposide molecules (VP-16) by means of hydrophobic interactions. Drug-loading rate is approximately70%. Release of etoposide was triggered when the hydrophobic interaction was weakened under microwave stimulation, and the release profile could be controlled by the duration and cycle numbers of microwave application. The nanocarrier showed little cytotoxicity and few side effects in the living cells, but that the released drug caused significant mortality of the targeted cells. This confirmed that the release of drug molecules could be controlled using the microwave irradiation and the released drug can kill the cancer cells effectively.(4) The nanocarrier consists of a Fe3O4nanoparticles core and TiO2:Er3+, Yb33+shell, has been introduced reactive amino groups by glycine at their surfaces, subsequent etoposide (VP-16) conjugation was achieved. The multifunctional nanocarrier has a spherical shape and a mean diameter of40nm. The TiO2:Er3+, Yb3+shell exhibit both excellent luminescence properties and microwave thermal response property for microwave triggered drug release. Drug-loading rate is approximately70%. The release amount of the drug can be controlled precisely by adjusting the irradiation time and the microwave on-off cycles. The nanocarrier showed little cytotoxicity and few side effects for the living cells, but that the released drug caused significant mortality of the targeted cells. This confirmed that the release of drug molecules containing hydroxyl or amino could be controlled using the microwave irradiation.(5) An efficient microwave/pH triggered controlled release carrier system was successfully fabricated using3-aminopropyltriethoxysilane (APTES) functionalized Fe3O4@SnO2:Er3+,Yb3+nanoparticles with a spherical shape and a mean diameter of45nm. The Fe3O4core functioned successfully for magnetic property (41.2emu/g). The SnO2:Er3+, Yb3+shell gives up-conversion fluorescence and excellent absorbing microwave property. Fe3O4@SnO2:Er3+,Yb3+@APTES have greatly drug loading capacity, drug-loading rate is approximately47%. The release profile could be controlled by the duration and cycle numbers of microwave application. Approximately71%IBU was released after four cycles. The amount of VP-16content released at pH=5was estimated to be54%suggesting that the pH plays a critical role in controlling the release. This indicates that the system can realize microwave/pH dual stimuli-responsive controlled release.