Label-Free Ferrocene-Loaded Nanocarrier Engineering for In Vivo Cochlear Drug Delivery and Imaging

J Pharm Sci. 2016 Oct;105(10):3162-3171. doi: 10.1016/j.xphs.2016.04.012. Epub 2016 Jul 19.


It is hypothesized that ferrocene (FC)-loaded nanocarriers (FC-NCs) are safe label-free contrast agents for cochlear biodistribution study by transmission electron microscopy (TEM). To test this hypothesis, after engineering, the poly(epsilon-caprolactone)/polyglycolide NCs are tested for stability with various types and ratios of sugar cryoprotectants during freeze-drying. Their physicochemical properties are characterized by UV-visible spectroscopy, dynamic light scattering, Fourier transform infrared spectroscopy, and scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM/EDS). The biodistribution of the FC-NCs in the cochlear tissue after intratympanic injection in guinea pigs is visualized by TEM. Auditory brainstem responses are measured before and after 4-day treatments. These FC-NCs have 153.4 ± 8.7 nm, 85.5 ± 11.2%, and -22.1 ± 1.1 mV as mean diameters, percent drug association efficiency, and zeta potential, respectively (n = 3). The incorporation of FC into the NCs is confirmed by Fourier transform infrared spectroscopy and SEM/EDS spectra. Lactose (3:1 ratio, v/v) is the most effective stabilizer after a 12-day study. The administered NCs are visible by TEM in the scala media cells of the cochlea. Based on auditory brainstem response data, FC-NCs do not adversely affect hearing. Considering the electrondense, radioactive, and magnetic properties of iron inside FC, FC-NCs are promising nanotemplate for future inner ear theranostics.

Keywords: auditory brainstem response; cochlea; cryoprotectants; electron microscopy; ferrocene; freeze-dried nanocarriers; imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bioengineering / methods*
  • Cochlea / cytology*
  • Cochlea / drug effects*
  • Cochlea / physiology
  • Drug Carriers
  • Drug Delivery Systems / methods*
  • Evoked Potentials, Auditory / drug effects
  • Evoked Potentials, Auditory / physiology
  • Female
  • Ferrous Compounds / administration & dosage*
  • Ferrous Compounds / chemistry
  • Guinea Pigs
  • Metallocenes
  • Microscopy, Electron, Scanning / methods
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Particle Size
  • Random Allocation
  • Spectroscopy, Fourier Transform Infrared / methods


  • Drug Carriers
  • Ferrous Compounds
  • Metallocenes
  • ferrocene