Nanoparticle Functionalization for Blood-Brain Barrier

• Applicants: Professor Dr. Bernhard A. Sabel; Professorin Dr. Franziska Scheffler, since 3/2016
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Mechanical Process Engineering ; Medical Physics, Biomedical Technology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251953791

Although there is a great need for new drug treatments for various brain diseases (Stroke, Alzheimer, traumatic brain injury), drug development is severely hampered by the fact that 98% of potential hit substances fail to reach the brain tissue because they cannot cross the BBB. Here, nanoparticles have been proposed to offer a solution as they may be used as a CNS drug delivery tool. Therefore, much effort has been invested for more than a decade into such particles systems, but unfortunately, successful pharmaceutical developments are still rare. The main stumbling blocks are that (i) toxicity is insufficiently addressed, (ii) in vitro models of the BBB still cannot be directly translated to clinical applications, and (iii) in vivo models for testing BBB passage are quite complex, elaborate and costly. In this interdisciplinary project proposal we wish to combine our expertise of nanoparticle engineering (Prof. Tomas group) with a unique neurobiological in vivo imaging system of the BBB (Prof. Sabel group) to study NPs in vivo with live recording of NP kinetic across the mammalian BBB to address the following issues: Evaluating process-parameters for tailor-made, well-defined NPs (core, surface, size, zeta-potential), defining galenic parameters for BBB passage, diffusion and permeation through the extracellular matrix and neuronal uptake, determining the transport and interaction mechanisms of BBB passage of NP. We plan to produce NPs in defined sizes (50-500 nm) approaching monodispersity; positive or negative zeta potential; anionic, non-ionic, cationic surfactants and test size, influence of temperature, zeta potential and pH value and determine the BBB passage of these nanoparticles. This is of major importance for developing a general drug delivery solution to transport drugs into the CNS but also identifying nanoparticles that have an unwanted effect on the brain which are potentially released into the environment. The unique challenge is to combine microscopic analysis of transport and interaction mechanisms with an in vivo system for the biological testing which avoids the drawbacks of in vitro testing systems (no blood proteins presents, BBB culture is not as tight as in the living organisms). Our project will provide parallel information about (i) BBB-passage kinetic (speed and amount), (ii) the spatial and statistical distribution of nano-carriers in the brain tissue (intra-/extracellular), and (iii) adverse effects (door-opener, neurotoxicity, neuronal stress; quantification of survival and neuroactivity). After having characterized the critical process parameters and material properties of NP crossing the BBB we will investigate the underlying mechanisms. Our hypothesis is that NPs with positive and negative zeta potential cross the BBB and we will be able to distinguish receptor-mediated transcytosis vs. adsorption-mediated transcytosis for individual NP formulations.

• DFG Programme: Research Grants
• Participating Persons: Privatdozentin Dr. Petra Henrich-Noack, Ph.D.; Dr. Werner Hintz
• Ehemaliger Antragsteller: Professor Dr.-Ing. Jürgen Tomas, until 2/2016 (†)