Biomaterials. 2016. 101: 165-175

Magnetically Softened Iron Oxide (MSIO) Nanofluid and Its Application to Thermally-induced Heat Shock Proteins for Ocular Neuroprotection

Seongtae Bae1, Jin Wook Jeoung2, Minhong Jeun3, Jung-tak Jang1, Joo Hyun Park2, Yu Jeong Kim2, Kwan Lee1,5, Minkyu Kim4,5, Jooyoung Lee4,5, Hey Min Hwang4,5, Sun Ha Paek4,5, and Ki Ho Park2

1 Department of Electrical Engineering, University of South Carolina, Columbia, SC, 29208, USA 2 Department of Ophthalmology, Seoul National University College of Medicine, Seoul 110-744, South Korea

3 Department of Electrical and Computer Engineering, National University of Singapore, Singapore, 117576, Singapore

4 Biomedical Research Institute, Cancer Research Institute, and Ischemic/Hypoxic Disease Institute, Department of Neurosurgery, Seoul National University College of Medicine Seoul, 110-744, South Korea

5 Department of Neurosurgery, Seoul National University College of Medicine, Seoul, 110-744, South Korea

 

Abstract

We successfully developed Magnetically Softened Iron Oxide (MSIO) nanofluid, PEGylated (Mn0.5Zn0.5)Fe2O4, for local induction of heat shock proteins (HSPs) 72 in retinal ganglion cells (RGCs) for ocular neuroprotection. The obtained MSIO nanofluid showed significantly enhanced alternating current (AC) magnetic heat induction characteristics including exceptionally high SLP (Specific Loss Power, > 2000 W/g). This phenomenon was resulted from the dramatically improved AC magnetic softness of MSIO caused by the magnetically tailored Mn2+ and Zn2+ distributions in Fe3O4. In addition, the MSIO nanofluid with ultra-thin surface coating layer thickness and high monodispersity allowed for a higher cellular uptake up to a 52.5% with RGCs and enhancing “relaxation power” for higher AC heating capability. The RGCs cultured with MSIO nanofluid successfully induced HSPs 72 by magnetic nanofluid hyperthermia (MNFH). Moreover, it was interestingly observed that systematic control of “AC magnetically-induced heating up rate” reaching to a constant heating temperature of HSPs 72 induction allowed to achieve maximized induction efficiency at the slowest AC heating up rate during MNFH. In addition to in-vitro experimental verification, the studies of MSIO infusion behavior using animal models and a newly designed magnetic coil system demonstrated that the MSIO has promising biotechnical feasibility for thermally-induced HSPs agents in future glaucoma clinics.

PMID: 27294536

 

Supplement

Glaucoma is considered as a well-known neurodegenerative disease, in which the progressive loss or death of retinal ganglion cells (RGCs) due to the increased intraocular pressure (IOP). Although there are many clinical treatment methods to reduce IOP by taking a medicine or doing surgery, these treatments have been revealed not to be effective for ocular neuroprotection. For the past few decades, a great deal of research has been undertaken to develop biotechnical approaches that will protect the damaged optic nerve. Eventually, it was discovered that neuroprotection of the optic nerve is effectively made by heat shock proteins (HSPs). Particularly, the induction of HSPs 70 family has been recently considered as a new powerful clinical modality for ocular neuroprotection to treat glaucoma. However, although the research efforts made so far had demonstrated to successfully identify the induction of HSPs 72 in RGCs, these biotechnical approaches were found to cause systemic or chemical side effects. Therefore, to settle down these current biotechnical challenges, the development of a new biomedical engineering approaches enabling to provide highly efficient local induction of HSPs in RGCs is inevitably required for the effective and safe ocular neuroprotection in glaucoma clinics.

 

 

Figure 1Figure 1. (A) Sketch of MSIO nanoparticles dispersed in organic solution. (B) Low magnetification transmission electron microscopy (TEM) image of obtained MSIO nanoparticles. (C) Alternating Current (AC) hysteresis loops measured at a fappl = 140 kHz and Happl = ±140 Oe of obtained MSIO and conventional Fe3O4 nanoparticles at powder state. (D) AC heating characteristics measured at a fappl = 140 kHz and Happl = ±140 Oe of obtained MSIO and conventional Fe3O4 nanoparticles at powder state.

 

In this study, we have made a possible breakthrough and have developed a new biotechnical approach that induces HSPs in the optic nerve by magnetic nanofluid hyperthermia (MNFH) using Magnetically Softened Iron Oxide (MSIO) nanoparticles that have very promising self-heating, temperature rising and superior biocompatible characteristics. The MSIO nanoparticles were prepared using one-pot thermal decomposition method (Fig. 1A and 1B) and showed an exceptionally high AC magnetic softness than that of conventional Fe3O4 (Fig. 1C) which is directly proportional to the AC hysteresis loss as well as to the total heating power of AC magnetically induced heat generation. The newly developed MSIO nanoparticles showed a significantly higher TAC, mag compared to that of conventional Fe3O4 nanoparticles (Fig. 1D) and MSIO nanoparticles successfully induced HSPs 72 in the RGCs at the biologically and physiologically safe range of AC magnetic field.

 

 

Figure 2 

Figure 2. (A) A schematic diagram of our newly designed DC magnetic coil system to externally apply the magnetic field to the infused MSIO nanoparticles. (B) before and (C) after magnetic nanofluid hyperthermia using MSIO nanoparticles.

 

In addition, we have developed a new infusion technique of MSIO nanoparticles to the retina through the vitreous body. Specifically, we have deveopled a direct current (DC) magnetic coil system to externally apply magnetic field to the infused MSIO nanoparticles in order to improve the diffusion behavior of infused MSIO nanoparticles (Fig. 2A). The external magnetic field was designed to provide driving force to the infused MSIO nanoparticles started to move inside the vitereous body of eyeball. With this DC maganetic coil system, we have made success to infuse our MSIO nanoparticles to the surface of retina (Fig. 2B and 2C). Our group’s main goal is to develop a complete in-vivo hyperthermia system using our newly developed MSIO nanoparticles and DC maganetic coil system.

 

Figure 3Contact: Seongtae Bae, Ph.D. Assistant Professor

Department of Electrical Engineering

University of South Carolina

Swearingen Room 3A31, 301 Main Street, Columbia, Sc 229208

bae4@cec.sc.edu

 

 

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