Understanding the translocation mechanism of PLGA nanoparticles across round window membrane into the inner ear: a guideline for inner ear drug delivery based on nanomedicine

Abstract

Background The round window membrane (RWM) functions as the primary biological barrier for therapeutic agents in the inner ear via local application. Previous studies on inner ear nano-drug delivery systems mostly focused on their pharmacokinetics and distribution in the inner ear, but seldom on the interaction with the RWM. Clarifying the transport mechanism of nanoparticulate carriers across RWM will shed more light on the optimum design of nano-drug delivery systems intended for meeting demands for their clinical application. Methods The poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) encapsulating coumarin-6 were prepared by emulsifying solvent evaporation method. We utilized confocal laser scanning microscope (CLSM) in combination with transmission electron microscope to investigate the transport pathway of PLGA NPs in the RWM. Simultaneously, the concentration and time dependence of NPs across the RWM were also determined. The endocytic mechanism of NPs through this membrane interface was classically analyzed by means of various endocytic inhibitors. The intracellular location of NPs into lysosomes was evaluated using CLSM scanning microscope colocalization analysis. The Golgi-related inhibitors were employed to probe into the function of Golgi and endoplasmic reticulum (ER) in the discharge of NPs out of cells. Results PLGA NPs were herein transported through the RWM of a sandwich-like structure into the perilymph via the transcellular pathway. NPs were internalized predominantly via macropinocytosis and caveolin-mediated endocytic pathways. After being internalized, the endocytosed cargos were entrapped within the lysosomal compartments and/or the endoplasmic reticulum/Golgi apparatus which mediated the exocytotic release of NPs. Conclusion For the first time, we showed the translocation itinerary of NPs in RWM, providing a guideline for the rational fabrication of inner ear nanoparticulate carriers with better therapeutic effects.

Uptake and transport of pullulan acetate nanoparticles in the BeWo b30 placental barrier cell model

“…The caveolin-1 signaling pathway is known for its role in regulating cellular functions, including signal transduction and endocytosis. 26 Zhang et al 27 prepared PLGA NPs encapsulating coumarin-6 and analyzed the endocytic mechanism of NPs through this membrane interface by means of various endocytic inhibitors. The results showed that NPs were internalized predominantly via macropinocytosis and caveolin-mediated endocytic pathways.…”

Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug delivery

“…Moreover, the drug will accumulate in cochlea at only a low concentration; therefore, many methods are currently being investigated to improve the permeability of the RWM for local drug delivery. Some efficient carriers such as poly (lactic-co-glycolic acid) nanoparticles and phospholipid-based nanoparticles are used as inner ear nanoparticulate carriers to produce better therapeutic effects and to maintain long-term particle circulation in the perilymph (4,5).…”

A Review on Recent Advancement on Age-Related Hearing Loss: The Applications of Nanotechnology, Drug Pharmacology, and Biotechnology

“…Permeability was increased by a factor of 2–3 for the higher drug concentration [ 111 ]. This behaviour has also been presented in Poly (lactic- co -glycolic acid) (PLGA) nanoparticles [ 116 ]. An increased contact duration of a solution with the RWM subsequently increases its permeability, as shown with PLGA nanoparticles [ 116 ] and TMPA solution [ 111 ].…”