Potential Use of Polymersomes & Lipid Nanocapsules
as Therapeutic Carriers in the Rat Inner Ear
By Ya Zhang
Tampere University Press
Distributed by Coronet Books Inc.
$92.50 Paper original
The traditional treatment strategies for sensorineural hearing loss (SNHL) have not been very satisfied. A cure for SNHL would thus depend on new technologies such as gene or drug delivery using nanocarriers to achieve an ideal effect. Nanocarriers are used as vectors in controlling drug release, protecting gene degradation by enzymes, and targeting therapeutic delivery. Nanocarriers, such as hyperbranched polylysine, liposomes and poly(lactide-co-glycolide) (PLGA) carrying genes, drugs and fluorophores, have been investigated in the inner ear. However there is no literature report on targeted inner ear drug or gene delivery using nanocarriers. In this study, potential use of polymersomes (PMs) and lipid nanocapsules (LNCs) as nanocarriers in rat inner ear respect to the inner ear distribution, targetability and biocompatibility was investigated. Firstly, quenching effect of copper sulfate (CuSO4) on autofluorescence and 1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine-perchlorate (DiI)-encapsulated PMs were investigated. Then the distribution of PMs and TAT (TAT-PMs) or Tet1 (Tet1-PMs) peptide functionalized PMs in rat inner ear was detected; the effect of delivery methods on PM entering into the inner ear was evaluated; and the distribution and biocompatibility of the LNCs in rat inner ear were investigated.
In whole mounted specimens, autofluorescence was observed in the subcuticular cytoplasm of inner hair cells (IHCs), the OHCs, the SGCs, the strial marginal cells, the spiral ligament fibrocytes, the mesothelial cells of the scala tympani below the basilar membrane, and the epithelial cells of the Reissner’s membrane. This autofluorescence could be quenched by treatment of 1 mM CuSO4 (pH 5.0). At the same time the CuSO4 treatment did not affect the fluorescence of DiI encapsulated in the PMs (p > 0.05, Kruskal-Wallis test). Different delivery methods induced different distribution pattern of the PMs: cochleostomy resulted in distribution of the PMs in the spiral ligament (SL), mesothelial cells beneath Corti’s organ, supporting cells in Corti’s organ, and spiral ganglion cells (SGCs); transtympanic injection induced uptake of the PMs in the SL and mesothelial cells beneath Corti’s organ; topical round window membrane (RWM) surface administration showed distribution of the PMs only in SL. In the vestibulum, transtympanic injection and cochleostomy induced more distribution of the PMs than did topical RWM surface delivery (p < 0.05, Kruskal-Wallis test). TAT-PMs exhibited more intense fluorescence signals in the RWM cells, spiral ligament fibrocytes, and mesothelial cells beneath Corti’s organ than the scrTAT-PMs and the unlabelled PMs. Tet1-PMs were detected in nerve fibers identified by the fact that Tet1-PMs were co-localized with NF-200 immunostaining; however the ScrTet1-PMs and unlabelled PMs were remote from the NF-200. LNCs were shown to pass though the RWM and reached the Corti’s organ, strial vascularis and spiral ligament fibrocytes. No sigh of increased toxicity was observed in the in vivo study.
Both PMs and LNCs can pass through the RWM and internalized by the cochlear cells. Study of PMs showed that delivery methods affect the distribution of the PMs in the inner ear cells. After transtympanic injection, more PMs were detected in the vestibulum than in the cochlea, indicating that the PMs entered the vestibulum through the oval window. Administration via cochleostomy displayed the broadest distribution of PMs in the inner ear, because this method avoids the barriers between the middle ear and the inner ear. So it is necessary to choose optimal delivery method according to the purpose of treatment. The results suggest that enhanced permeability through the RWM can also be achieved by using TAT peptide functionalized PMs. Further more specific targeting to the cochlear nerve can be achieved by functionalizing the PMs with Tet1 peptides. Both PMs and LNCs are potential nanocarriers to carry drugs and genes in the future to perform inner ear therapeutics. The study of PMs and LNCs is still in its initial stage. More investigation of the PMs and LNCs is needed in the future work.
Acta Universitatis Tamperensis No. 1685
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