Targeted Delivery of Contrast Agents to the Tympanic Medial Wall at Minimum Amount and the Efficient Uptake in the Inner Ear through Oval and Round Windows

Review Article

Austin J Radiol. 2015; 2(6): 1034.

Targeted Delivery of Contrast Agents to the Tympanic Medial Wall at Minimum Amount and the Efficient Uptake in the Inner Ear through Oval and Round Windows

Zou J1,2*, Ostrovsky S³, Israel LL³, Lellouche JP³ and Pyykkö I¹

¹Hearing and Balance Research Unit, Field of Otolaryngology, School of Medicine, University of Tampere, Finland

²Department of Otolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, China

³Institute of Nanotechnology & Department of Chemistry, Bar-Ilan University, Israel

*Corresponding author: Zou J, Hearing and Balance Research Unit, Field of Oto-laryngology, School of Medicine, University of Tampere, Medisiinarinkatu 3, 33520 Tampere, Finland

Received: August 05, 2015; Accepted: September 02, 2015; Published: September 03, 2015


Inner ear MRI after intratympanic administration of Gadolinium chelate (GdC) has become a valuable method in detecting endolymphatichy drops attributing to the efficient uploading in the inner ear while avoiding high dose intravenous application that can cause renal injury. In addition to the well-accepted round window pathway, the oval window was discovered as a dominant approach for the agents to move from the middle ear into the inner ear. In order to fine-tune this method, a targeted delivery of GdC to the medial wall of the middle ear cavity was developed in a minimally invasive way. The targeted tympanic medial wall administration was expended in the topical tympanic application of super paramagnetic iron oxide nanoparticles and manganese as contrast agents in the inner ear MRI. This review provides an overview of the developments in the field.

Keywords: Contrast agent; MRI; Middle ear; Targeting


Gadolinium-enhanced inner ear MRI became a valuable diagnostic tool in inner ear diseases after two milestone studies showed that the cochlear scalae were distinguishable, and that the experimental endolymphatichy drops was visible in vivo in 4.7 T MRI after intravenous injection of Gadolinium Diethylenetriaminepentaacetic Acid Bismethylamide (Gd-DTPA-BMA) in guinea pigs [1-3]. In the studies, high-dose Gadolinium chelate (GdC) was applied intravenously to induce enough distribution in the inner ear because GdC has poor transport efficacy across the blood-perilymph barrier [4-6]. However, high doses of GdC can cause renal injury and even nephrogenic systemic fibrosis.

High contrast images of all cochlear turns were obtained after placing GdC on the round window membrane. Auditory brainstem response measurements showed no significant threshold shifts after the application, indicating that gadolinium is non-toxic to the guinea pig cochlea [7]. In 2005, the perilymphatic and endolymphatic spaces were first demonstrated separately in humans using a 1.5 T machine after transtrympanic injection of GdC [8]. In 2007, clear visualization of endolymphatic hydrops in patients with Meniere’s disease was demonstrated on a 3.0 T machine with Three-Dimensional Fluid-Attenuated Inversion Recovery (3D-FLAIR) sequence after transtymanic injection of GdC diluted eightfold with saline [9]. In order to further reduce the amount of contrast agent applied to the body, a targeted delivery of GdC to the medial wall of the middle ear cavity was developed in a minimally invasive way and generated efficient uptake of GdC in the inner ear in 2011 [10].

Novel contrast agents, such as manganese and Super Paramagnetic Iron Oxide Nanoparticles (SPIONs), were also tested in targeted delivery system and demonstrated efficient uptake in the inner ear (see following text). Pautler et al. first reported that Manganese-Enhanced MRI (MEMRI) was capable of tracking neuronal connections in vivo in the nose and eyes of mice after topical administration [11]. The mechanism underlying the analysis is that the Mn++ acts as a Ca++ agonist in addition to its T1 contrast effect. MEMRI was used to trace the central auditory pathway in the living animals after either topical or systemic administration because Mn++ ions enter excitable cells through voltage-gated calcium channels [12-14]. Recently, alterations in calcium handling (possibly due to Ca++-ATPase dysfunction) in preclinical models of cardiac hypertrophy were visualized using MEMRI [15]. That report broadened the application of MEMRI from detecting neuronal activities to monitoring Ca++ homeostatic maintenance. It is important to trace the Ca++ transport in the inner ear in vivo using MEMRI.

SPIONs have been proven to be highly efficient MRI contrast agents, and several SPION formulations such asFerridex I.V.® for liver and spleen imaging and Combidex® for imaging lymph node metastases have been approved for clinical use. In inner ear imaging, SPIONs hierarchically coated with oleic acid and Pluronic F127 copolymers demonstrated a high contrast effect and were capable of singling out the bright endolymph from the dark perilymph distributed with SPIONs using MRI [16]. SPIONs have attracted considerable attention for the early detection of diseases including inflammatory and tumor markers due to their specific physicochemical properties and molecular imaging capabilities [17- 19]. Recently, pre-formed Massart magnetite (Fe3O4) Nanoparticles (NPs) have been modified by positively charged lanthanide Ce (III/IV) cations/[CeLn]3/4+ complexes by using a strong mono-electronic Ceric Ammonium Nitrate oxidant (CAN) as Ce donor. The doping process is promoted by high-power ultrasonic irradiation [20]. The reaction has been statistically optimized by Design of Experiments (DoE, MINITAB® 16 DoE software) to afford globally optimized, magnetically responsive ultra-small 6.61±2.04 nm-sized CANDOE-γ- Fe3O4 NPs that are highly positively charged (ξ potential: +45.7 mV) (Figure 1). This innovative inorganic DoE-optimized NP platform technology paves an efficient way for the successful development of a wide range of biomedicine and diagnostic-related applications.