Hollow manganese oxide nanoparticles as multifunctional agents for magnetic resonance imaging and drug delivery.

Nanometer-sized colloidal particles with small size and large surface area have many superior properties when used as magnetic resonance imaging (MRI) contrast agents, such as their ability to carry large payloads of active magnetic centers, easy penetration of biological membranes, long blood circulation times, and efficient conjugation to affinity molecules. Thus, they have the potential to allow us to visualize targets at low imaging-agent concentration with high sensitivity and sepcificity. Furthermore, nanoparticles can be used in combination with therapeutic agents as bifunctional medical systems that enable simultaneous MRI diagnosis and drug treatment. For example, superparamagnetic iron oxide nanoparticles have been developed as efficient T2 contrast agents and employed to image tumors, stem cell migration, and cancer metastases. Some colloidal nanoparticles containing gadolinium(III) or manganese(II) have recently been reported as potent T1 MRI contrast agents. [4] Very recently, some of the present authors developed MnO nanoparticles as T1 contrast agents for MRI signal enhancement of the anatomic brain structure. The further development of nanoparticle MRI contrast agents will require materials with higher relaxivity than the current state of the art that can operate at much lower concentrations of potentially toxic metal ions such as Gd and Mn. In this context, hollow nanoparticles with interior void spaces are attractive candidates owing to their large water-accessible surface areas, which are able to carry high payloads of MR-active magnetic centers, and because they can take up a large amount of therapeutic drug within the interior void. While hollow nanoparticles containing magnetic ions have recently been prepared through several synthetic strategies, there are few examples of the investigation of their medical applications. Herein, we report a novel and facile synthesis of hollow manganese oxide nanoparticles (HMONs) and their potential application as multifunctional agents for simultaneous MR imaging and drug delivery. We demonstrate the greatly improved relaxivities of the hollow nanoparticles along with their efficient cellular uptake and drug loading capacities. These properties allow us to develop these particles for the delivery of therapeutic drugs as well as for diagnostic imaging. Manganese oxide nanoparticles with a diameter of 20 nm stabilized by oleic acid (MONs) as well as water-dispersible manganese oxide nanoparticles (WMONs) were prepared using a reported procedure involving the thermal decomposition of a manganese oleate complex and encapsulation with poly(ethylene glycol) phospholipid. The powder X-ray diffraction (XRD) patterns revealed that MnO is the main component of both MONs and WMONs and showed an increase of the Mn3O4 fraction in the WMONs. The analysis of the surface composition with X-ray photoelectron spectroscopy (XPS) indicated the presence of Mn and Mn (see the Supporting Information). On the basis of these observations, it was presumed that the as-synthesized MONs were passivated with Mn3O4 formed by their contact with air, even under an organic solvent, and that further oxidation occurred to form a thicker Mn3O4 shell when they were transferred into water. Very recently, the oxidation of the surface of MnO nanoparticles in air was also reported. The hollow interior of the HMONs was created by selective removal of the core MnO phase from the WMONs in acidic solution (Scheme 1). After being stirred at room