OncoNanoBBB · Development and evaluation of a quantitative imaging technique for assessment of nanoparticle drug delivery across the blood-brain barrier: Applications for brain cancer therapeutics

Development and evaluation of a quantitative imaging technique for assessment of nanoparticle drug delivery across the blood-brain barrier: Applications for brain cancer therapeutics

Final summary Scope: The partners of OnconnanoBBB wish to build a long term European, Industry-Academia consortium, to work on the problem of delivering therapeutic agents, for brain cancer, across the blood-brain barrier (BBB) at the efficacious dose. The project was designed in a way that it could offer a training environment for the participating scientists in different and complementary technologies, ranging from liposome nanoparticles synthesis and characterization, pharmacokinetic studies, radiolabelling, ex vivo biodistributions and in vivo imaging, as well as engineering and imaging systems physics and principle of operation. The main scientific objectives of OncoNanoBBB were: - The design and synthesis of a range of NPs for in vitro and in vivo assessment, suitable for drug delivery across BBB, as well as with efficient radiolabelling yield for in vivo imaging - The physicochemical characterisation (shape and size) of NPs in different mediums (aqueous, organic and biological matrixes) and assessment of their radiochemical stability - The optimization of NPs formulation using a variety of pharmaceutical excipients - The investigation of mechanism of action (MOA), by carrying out high resolution imaging studies, using endothelial cells both in vitro and in vivo - The application of a methodology for labeling NPs with radionuclides, without altering their biological properties and by taking into account factors such as ease of preparation and in vitro and in vivo stability - The assessment of the ability of NPs to enhance transport of a diverse set of existing cancer drugs in in vitro models of BBB - The establishment of the in vivo pharmacokinetics Structural Distribution Relationship (SDR) for these NPs via different administration routes - The establishment of the in vivo neuropharmacokinetics (brain pharmacokinetics) Structural Distribution Relationship (SDR) for these NPs utilised via optimised route identified from above - The establishment and validation of imaging protocols for screening of Cerense™-formulated chemotherapeutics in models of brain cancer - The assessment of CNS and non-CNS penetrating chemotherapeutics with and without the Cerense™ technology in in vivo model of brain cancer Additional project objectives are: - The exploration of a range of future applications for this technology in critical care medicine - The transfer of knowledge among the participating academic institutions and industry - The dissemination of project outcomes to targeted audience and general public - The efficient overall project management and results exploitation Initially, imaging studies usind the conventional brain imaging radiopharmaceutical Tc99m-HMPAO were carried out to have a reference for in vivo brain imaging. TEIA worked on the optimization of the existing scintigraphic imaging system to allow optimized imaging studies. During the project, a pinhole collimator was tested to imporove spatial resolution. In addition an X-ray system was added in order to allow the fusion of both anatomical and functional images. As a result by the end of the project it was possible to provide hybrid images of fused functional and anatomical information. A series of liposomes were synthesized with the collaboration of UoB and TEIA. The technology to develop liposome nanoparticles was made available to TEIA by the end of the project. These liposomes were further modified to allow radiolabelling, as well as brain targeting using glucose. Radiochemical tests were carried out to all products, to assess radiolabelling stability and efficiency. A variety of functionalized liposomes were tested in vitro, ex vivo and in vivo in normal and tumor bearing mice. Pharmakokinetic studies were carried out in drug loaded liposomes and the results were compared against the Cerense system of PPS, which showed superior results. The animal models were tumor bearing (U87MG) scid mice, with tumors grown on the upper shoulders. Different imaging protocols were assessed to assess the optimal setup of imaging parameters, as well as injected doses. The bioluminescence system of PPS, was setup by the end of the project and is under full functionality. The in vivo scintigraphic imaging and biodistribution studies showed a good circulation time in blood and noticeable concentration in brain for some of the designed functionalized liposomes. PPS performed in vitro pharmacokinetic studies using the methatroxane loaded liposomes offered by UoB and Cerense platform to test different drug levels in brain, plasma and major organs, which demonstrated the benefits of using Cerense. The project demonstrated the feasibility of in vivo imaging as a tool to study non invassively the in vivo fate of liposomes in small mice and their ability to cross BBB. This methodology can be used in the study of different types of nanoparticles and biomolecules for a variety of applications. The partners have already used this approaches in other projects in which they participate of submit. In addition, a new company was established, as an outcome of the interaction between ESRs that were seconded in the industrial partner. The company is already self funded, has installed its product (imaging system) in UK and already participates in Horizon2020 projects. Furthermore, exchange of technologies among partners allowed them to increase their available expertise. Finally, the partners wish to continue their cooperation and they submit jointly proposals, as well as try to continue coperation on industrial level. Contact Details: Assistant Professor George Loudos, Department of Biomedical Engineering, Technological Educational Institute of Athens, Ag. Spyridonos 28, Egaleo, 12210, Athens, Greece Tel: 00302105385376, 00306947233203, Fax: 00302105385302 e-mail: gloudos@teiath.gr webpage: http://www.bme.teiath.gr/ni

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