Synthesis Of Mn-Zn Ferrite Nanostructures With High Performance And Their Applications In Cancer Targeted Magnetic Hyperthermia

Magnetic ferrite nanostructure with high performance is of great scientific interest for researchers from a wide range of biomedicine applications, including clinical magnetic resonance imaging (MRI), cancer magnetic hyperthermia, triggered drug release, and catalysis. Specially, the high performance of these magnetic nanostructure, such as controllable size and morphology, superior magnetism, high magnetically induced heating effects, favorable biocompatibility, accurate targeting ability and long circulation, is crucial for their effective application in clinical diagnosis and therapy of disease. High-quality magnetic nanostructure is typically prepared through a thermal decomposition of organometallic compounds in high-boiling organic solvent containing surfactants, in which the shape, size, composition, surface states and some other important features are synthetically controlled.In this study, we had successfully synthesized doped Mn-Zn ferrite nanostructure with excellent magnetic property via thermal decomposition of metal acetylacetonate, and more importantly, a systematic study on the shape-controlled growth mechanism of magnetic nanostructure based on the classical crystallization and nonclassical oriented attachment theories was presented here. In the classical crystal nucleation/growth process, differential stabilization of the surfactant (e.g. oleic acid, OA) on specific crystal facets could alter relative crystal growth rates, resulting in the formation of zero-dimensional (0-D) spherical, cubical and starlike nanocrystals (ca.9,11,16nm), respectively. Moreover, by shortening nucleation duration time, the starlike nanocrystals with larger size (ca.23nm) were firstly obtained and subsequently tended to form the highly assembled three-dimensional (3-D) nanoclusters with sharp-or obtuse-edges (ca. 45,50nm) to minimize their magnetostatic energy due to the strong magnetic dipolar interactions. Our study revealed the transformation process of 0-D nanocrystals to 3-D nanoclusters as well as the formation mechanism, which provided a versatile synthetic strategy for the shape-controlled nanostructure. The two representative "muti-branched" nanoclusters were proved to have higher magnetization and magnetically heating effects in an alternating current magnetic field (ACMF), which could be used as promising heating agents for biomedical application.For further cancer theranostics, we had successfully developed an effective high-quality Mn-Zn ferrite magnetic nanocrystals (MNCs)-mediated cancer theranostics strategy as a combination of simultaneous diagnostics and hyperthermia treatment of mice tumor by using MRI and ACMF. In this strategy, we had firstly synthesized a well-established spherical Mn-Zn ferrite MNCs (14nm,115emu/g Fe) coated with PEG-phospholipids (MNCs@PEG) through hydrophobic interactions. The obtained MNCs@PEG with representative core-shell structure could drastically minimize the recognition and phagocytosis of macrophages, simultaneously improved their biocompatibility in vitro. These advantages endowed them with efficient passive targeting ability in vivo for prominent tumor MRI and magnetically induced heating in an ACMF, based on enhanced permeability and retention (EPR) effects. In succession, a specific cyclic Arg-Gly-Asp (RGD) peptide, which was widely used to actively accumulate in tumor blood vessels, was firmly attached to the surface of MNCs@PEG. In comparison, the MNCs@PEG and RGD-coated MNCs (MNCs@RGD) exhibited excellent specific absorption rate (SAR) values of 498 and 532 W/g Fe, respectively, which were potentially used for passive or active cancer targeted magnetic hyperthermia (TMH) in vivo. To ensure sufficient accumulation of MNCs within tumors for TMH, we described the use of MNCs with well-tolerated repeatedly intravenous injection and magnetically hyperthermia within a subcutaneous cell carcinoma mouse model in an ACMF. The tumor surface sites were heated to approximately 42～44℃ based on the long-lasting hyperthermia, which could effectively induce the apoptosis of tumor cells, inhibit the angiogenesis of tumor vessels, and finally suppress the tumor growth within a certain period of time. Furthermore, we had loaded targeted anticancer drugs (e.g., paclitaxe, PTX) in the surface hydrophobic aliphatic chain of obtained MNCs@RGD, leading to the formation of PTX-loaded MNCs (MNCs@PTX@RGD). Based on the cancer active TMH and the efficient heating-induced drug delivery, the MNCs@PTX@RGD could promote the synergistic magnetic hyperthermia and chemotherapy, which had more promising clinical cancer theranostics applications.