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

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.