In Vitro Evaluation of the Efficient Passage of PLGA-Formulated Trastuzumab for Nose-to-Brain Delivery.

in Pharmaceutics by Léa Kengne Kamkui, Clémence Disdier, Amaury Herbet, Narciso Costa, Anne-Cécile Guyot, Didier Boquet, Aloïse Mabondzo

TLDR

  • A study developed nanoparticles to deliver the medicine trastuzumab (TZB) directly to the brain, bypassing the blood-brain barrier, and showed promising results in a lab setting.
  • The nanoparticles carried the medicine across the nasal epithelium, but not across the blood-brain barrier, suggesting the nose-brain route may be a more effective delivery method.

Abstract

: The limited permeability of the blood-brain barrier (BBB) to biotherapeutics is a major challenge in the treatment of brain tumors. The nose-to-brain (N2B) delivery approach, which bypasses the BBB, offers a promising alternative way to treat these tumors. The aim of this work was to develop PLGA nanoparticles for N2B delivery of biodrugs using trastuzumab (TZB) as a paradigm.: An in vitro model was used to evaluate the ability of PLGA nanoparticles to enhance passage through the nasal epithelium. We also compared the passage of loaded TZB versus unencapsulated TZB across an in vitro BBB model simulating systemic administration of TZB. TZB-loaded PLGA nanoparticles (NP-TZBs) were prepared using a double emulsion method followed by solvent evaporation and characterized for various properties, including particle size, polydispersity index, zeta potential, morphology, encapsulation efficiency, and drug loading capacity and release kinetics. TZB functionality was assessed after release from NP or passage through an in vitro barrier model. The permeability of TZB and NP-TZBs through in vitro models of nasal epithelium and BBB was investigated.: NP-TZBs exhibited an average size of about 200 nm with a polydispersity index of less than 20%, neutral charge, and a loading efficiency of 67%. Transmission electron microscopy revealed spherical nanoparticles with a smooth surface. Importantly, the TZB released from the nanoparticles retained all of its physicochemical properties and functionality. We observed that the NP-TZB formulation results in at least a nine-fold increase in TZB permeability across the nasal epithelium 24 h post-exposure, depending on the exposure conditions, but shows no significant improvement across the BBB model. The TZB released in the basal compartment is fully functional and able to recognize HER2 expressed on the surface of breast tumor BT474 cells.: Using compounds already validated for clinical use, we were able to develop a formulation that allowed efficient passage of TZB across an in vitro nasal epithelial model. In contrast, no passage was observed across the BBB, supporting the notion of the superiority of the nose-brain route over systemic injection for in vivo delivery of TZB to the central nervous system.

Overview

  • The study aims to develop PLGA nanoparticles for nose-to-brain (N2B) delivery of biodrugs using trastuzumab (TZB) as a paradigm to treat brain tumors.
  • The study investigates the ability of PLGA nanoparticles to enhance passage through the nasal epithelium and the blood-brain barrier (BBB) using an in vitro model.
  • The primary objective is to develop a formulation that allows efficient passage of TZB across the nasal epithelium and BBB.

Comparative Analysis & Findings

  • NP-TZBs exhibited improved permeability across the nasal epithelium, with a nine-fold increase in TZB permeability 24 h post-exposure, depending on the exposure conditions.
  • However, no significant improvement was observed in TZB permeability across the BBB model, suggesting that the nasal epithelium is a more permeable barrier than the BBB.
  • TZB released from the nanoparticles retained all of its physicochemical properties and functionality, and was able to recognize HER2 expressed on the surface of breast tumor BT474 cells.

Implications and Future Directions

  • The study suggests that the nose-brain route may be superior to systemic injection for in vivo delivery of TZB to the central nervous system.
  • Future studies should investigate the efficacy and safety of NP-TZBs in preclinical models of brain tumors.
  • Novel approaches, such as optimizing the nanoparticle size and surface modification, may further enhance the permeability and functionality of NP-TZBs.
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