Challenges and opportunities in developing targeted molecular imaging to determine inner ear defects of sensorineural hearing loss

Abstract

The development of inner ear gene carriers and delivery systems has enabled genetic defects to be repaired and hearing to be restored in mouse models. Today, promising advances in translational therapies provide confidence that targeted molecular therapy for inner ear diseases will be developed. Unfortunately, the currently available non-invasive modalities, such as Computerized Tomography scan or Magnetic Resonance Imaging provide insufficient resolution to identify most pathologies of the human inner ear, even when the current generation of contrast agents is utilized. The development of targeted contrast agents may play a critical role in determining the cause of, and treatment for, sensorineural hearing loss. Such agents should be able to pass through the cochlea barriers, possess minimal cytotoxicity, and easily conjugate to a targeting agent, without distorting the anatomic details. This review focuses on a series of contrast agents which may fit these criteria for potential clinical application.

Keywords: Inner ear imaging; Molecular imaging; Targeted nano particles.

Figure 1. Contrast Agent delivery to the inner ear

There are two routes available for the delivery of contrast agents. (Figure A) Systemic delivery is inefficient with the distribution problems being exacerbated by the blood labyrinth barrier. This can impede contrast agent delivery and may result in insufficient amounts of the agent reaching the inner ear. Transtympanic, (Figure B) local delivery efficiently delivers the contrast agent into the cochlea.

Figure 2. Enhancement mouse cochlea MR image using a Gadolinium contrast agent

Mouse cochlear structures in MPR multi view of T1-weighted images with IT administration of Gd-DOTA (23 mm coil) (180 min time point). Gelfoam soaked with 5 μL, 500 mmol/L Gd-DOTA was placed into the left ear. In the enlarged window A, LW and Mod are slightly highlighted by Gd-DOTA uptake in addition to more pronounced enhancement in ST and SV. The structure adjacent to ST is suspected to be CA with signal intensity similar to ST. LW demonstrated brighter signal than SM. A dark border appeared between ST and LW in the basal turn near the hook region. OSL is seen as a sharp dark line. Small window B is a relative perpendicular cut through the center of plane A. Small window C is a relative axial cut through the center of the cochlea in window A. Small window D is the minimized image of window A. CA, cochlear aqueduct; LW, lateral wall; Mod, modiolus; MPR, multiplanar reconstruction; OSL, osseous spiral lamina; SM, the scala media; ST, the scala tympani; SV, the scala vestibuli; 1st, the basal turn; 2nd, the second turn. Reprinted from Zou et al (2010).

Figure 3. Enhancement of the Rat cochlea CT image using an Iodine contrast agent

The heterogeneous fine structures of rat inner ear were demonstrated using iodine-contrasted micro CT (BM: basilar membrane; CN: cochlear nerve; RM: Reissner's membrane; SA: stapedial artery; SFP: stapes footplate; ST: scala tympani; SV: scala vestibuli; Vest: vestibule.) scale bar = 500 μm. Reprinted from Zou et al (2015).

Figure 4. The chemical structure of two commonly used contrast agents

(A) The chemical structure of DOTAREM (gadoterate meglumine) (Guerbet, Aulnaysous-Bois, France), the Gadolinium contrast agent used in the MRI study shown in Figure 2. (B) The chemical structure of VISIPAQUE (iodixanol) (GE Healthcare, Helsinki, Finland), the Iodine based contrast agent used in the CT scan Image illustrated in Figure 3.