The treatment of brain disorders is extremely challenging as the blood-brain barrier (BBB), the brain's own defence system, actively blocks or expels curative drugs from entering the brain. Currently, nanotechnology is being applied to generate innovative delivery devices, collectively called nanocarriers, to overcome this major hurdle. One of the most promising nanocarriers to enhance delivery of drugs to the brain is currently in clinical phase II/III, being developed by the Dutch SME to-BBB (applicant). Still, in order to gain maximal benefit from these novel developments and to enable improved delivery of drugs to the brain, we need to understand more on the working mechanisms of such brain-targeting technologies, the topic of the current application. The BrainTrain project will offer three early stage researchers (ESRs) the opportunity to thoroughly investigate the different underlying aspects of BBB traversal. This will allow them to discover and improve nanocarriers for treatment of central nervous system (CNS) related diseases. All ESRs will be trained on state of the art technologies to study BBB transport. All will receive onsite, in-depth training on to-BBB's G-Technology® and the ESR will match this knowledge with the specific and complementary knowledge on mechanisms involved in brain delivery from the three academic institutions involved in BrainTrain. Brain delivery will be tested in vitro on 3D BBB models developed within this project and subsequently in animal models to show in vivo proof of concept. The work will lead to a fundamental understanding of BBB transport mechanisms which is key for further improvements of treatments for brain diseases. The cutting-edge science, knowledge and expertise accumulated and developed in their PhD programs will provide the BrainTrain ESRs with a significant advantage over their competitors on the future market place.
Recent research [7] shows that when liposomes are injected into biological fluids, such as the blood, they are interacting with biomolecules present. Biological media comprise thousands of active biomolecules (for example, blood plasma has 3,700 identified proteins) and most of them compete for space on the liposome surface. Protein binding results in formation of a rich protein coating around liposomes, the so called 'protein corona', which depends on the physicochemical properties of lipid surface [8]. At present, active targeting is believed to be the most suitable approach for accelerating drug delivery towards clinical application. Understanding and controlling the bio-nano-interactions of liposomes with biological media is central to future developments in the area of active targeting of nanoparticles. In recent works of our group, we have shown that exploitation of the protein corona offers unique opportunities for targeted delivery of drugs and genes [9-16]. The adsorbed protein layer would include proteins engaged from the blood that could lead the nanoparticle to interact with specific receptors expressed on the plasma membrane of target cells. Evidently, this pioneering targeting strategy needs two main requirements: (i) understanding which plasma proteins effectively deliver particles to which location and (ii) identifying those proteins with the highest affinity for lipid surfaces of different compositions or surface characteristics.
The new challenge of the research project, here proposed, is to develop effective and multidisciplinary approaches to new methods of adjuvant treatment that might improve the results of existing treatments of brain diseases, as expected by the medical community since many years. As a matter of fact, drug delivery to the brain poses a major challenge to the scientific and drug development communities, mostly due to the impact of the BBB. Several different approaches to design drug-loaded brain-targeting nanoparticles for crossing BBB are currently in development. Among nanoparticles, liposomes can be loaded a wide range of compounds, like small molecules, peptides, proteins and RNA to be encapsulated without changing their function and protecting them against degradation and immune responses. Also other interactions, e.g. related to the drug's activity, are prevented and thus the risks of toxicity are minimized. This research is often technical and is rarely followed by mechanistic and quantitative in vivo studies regarding their feasibility for production and future human use. However a lot is still unknown about the liposome journey from the blood to the brain, traversing the BBB. For instance, what happens to the liposome while surrounded by vast amounts of cells and proteins in the blood? A protein corona is formed; could the protein corona be exploited for BBB targeting? All these questions are of major importance to speed up both fundamental research and clinical implementation of liposome technologies for targeting drugs to the brain. Coating of liposomes with PEG will ensure a prolonged circulation time in plasma, whereas the protein corona will target the liposomes towards the active receptors/transporters at the BBB. Importantly, all building blocks (i.e. liposomes, approved drugs, plasma proteins) are already being used in medical settings and considered safe. the Liposome-Protein Corona Technology will be a tremendous impact on the treatment of brain diseases. It cannot be stressed enough, that the proposed research will foster all the aspects of "to-BBB" delivery that must be elucidated for successful development of new nanodelivery devices, i.e. all aspects from production of the formulations, via in vitro studies in cell cultures, to in vivo studies on the impact of the BBB delivery. In conclusion, for the character of translational research that is proposed in the, the results might find a soon and reliable application in the clinical domain beyond the current state-of-the-art.
[7] a) Monopoli, M. et al. J. Am. Chem. Soc. 2011, 133, 2525. b) Tenzer, S. et al. Nature Nanotechnology 2013, 8, 772.
[8] Delyan R. Hristov et al. Scientific RepoRts | 5:17040
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