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Nanomedicine: an integrative approach

Periodic Reporting for period 2 - NANOMED (Nanomedicine: an integrative approach)

Reporting period: 2018-01-01 to 2019-12-31

Nanomedicine (NM) is regarded as one of the most promising applications of nanotechnology, as it would allow the development of tailored therapies, with a high level of selectivity and efficacy. Although much research has been performed over the past decades, translation from academia to commercial application remains disappointingly low. Reasons that explain the current moderate success of NM are: (1) promising preclinical results are often poorly predictive for clinical safety and effectiveness, (2) the efficient, scalable and reproducible GMP production of nanocarriers has proven to be challenging and (3) regulatory frameworks are not yet fully equipped to efficiently facilitate the introduction of novel nanomedicines. These obstacles are often encountered since the developmental process from carrier design to clinical assessment is performed by a range of scientists from different backgrounds who have difficulty interacting and communicating with each other to clearly understand the necessary design criteria and the scope and limitations of NM. NANOMED brings together all the necessary expertise to oversee the entire development trajectory required for NM. This is achieved by the combined effort of 7 beneficiaries from academia and industry and 5 non-academic partner organisations, which are all thoroughly rooted in nanosciences and pharmaceutical sciences. Our objective is to develop scalable and highly controllable design and synthesis methods for the most promising nanomedicine types in a preclinical setting. NANOMED will train the next generation of NM scientists by offering an extensive joint training programme to 15 incoming ESRs. It focuses on promoting scientific excellence and exploits the specific research and commercial expertise and infrastructure of the NANOMED network as a whole. The exposure to all elements of NM design enables NANOMED to translate expertise from all disciplines to the ESRs, to educate the future leading scientists in the NM field.
The research performed within the NanoMed consortium can be divided into three work packages. First, nanoparticles are produced which meet the criteria for application in nanomedicine. Secondly, these particles are investigated with regard to their interaction with living cells. Third, the scalability and in vivo behavior of the most promising nanocarriers is evaluated. The target diseases are cancer and age-related ocular pathologies, which are treated via administration of the particles in blood, in the peritoneum or via the lungs in case of cancer, and in the vitreous in case of ophthalmic diseases. On all different levels much progress has been made
A range of different particles has been created. Micelles, vesicles and nanogels have been prepared, for the transport of hydrophobic drugs and siRNA, respectively. Scalable nanocarrier preparation methods have been developed, which can be performed in an aqueous medium. Besides spherical particles, also tube-like morphologies have been created. As building blocks degradable synthetic polymers and polypeptides have been successfully employed. Furthermore, the surface properties of the particles have been fine-tuned for their biological application. These properties include pegylation and regulation of surface charge to prevent undesired interactions with the immune system; functionalization with targeting moieties for effective and selective cell uptake; and conjugation of therapeutic moieties to endow the particles with active cargo. As a result of these activities a library of well-defined particles has been created. Loading and release studies of model drugs has successfully been performed.
NanoMed ESRs have developed strategies to prolong circulation lifetime, stable self-assembled drug delivering micelles, the synthesis and characterization of photoactivating liposomes, RNA-delivering nanomaterial studies in serum, and the delivery of liposomes via intravitreal injection in the intact porcine eye. We are applying state of the art characterization techniques to understand and predict the material properties (particle stability, pH responsiveness, drug retention and release, and agglomeration) in in vivo-like environments. We have also investigated how nanocarriers interact with cells and how they have been taken up. Novel characterization tools, such as label-free Raman spectroscopy and high resolution Focussed Ion beam – Scanning Electron Microscopy (FIB-SEM) have been implemented to better understand the fate of particles upon entering living cells.
To evaluate the behavior of particles in an in vivo situation mathematical models and experimental procedures have been developed for nanocarrier distribution in the eye. Distribution of nanocarriers in the ex vivo bovine vitreous has also been monitored using histological approaches. Not only particle motion but also drug release has been evaluated and modeled with state of the art distribution models. A recently developed method for intraperitoneal nanomedicine administration has been applied to nanogels developed in the consortium. A much better distribution and colocalization with tumor cells was observed. Finally, one of the most promising polymer micelle particles was evaluated for its scalability in production. Both the synthesis of the block copolymers as the micelle formation process were optimized and it was demonstrated that this carrier system is a highly interesting candidate for the transport of hydrophobic drugs in cancer treatment.
The following progress beyond the state of the art has been made:

A comprehensive approach to nanoparticle development has been established
Development of versatile routes to nanoparticle production in water
Demonstration of robust and scalable synthesis of a polymer micelle carrier system
Assessment of particle fate in living cells with advanced characterization techniques
Intravitreal diffusion and release of drugs from nanoparticles has been modelled and experimentally validated
Novel intraperitoneal administration methods have been successfully employed

Results expected for the end of the project:
Two particle formulations will be evaluated with regard to in vitro and in vivo behaviour; they will be assessed for their scalability
At least one formulation will be transferred to a company for further development into a clinically applicable product
Nanoparticles with adaptive behaviour and full control over physicochemical features will be constructed
Full chemical and in vitro characterization will be achieved for 5 different particle formulations
Predictable models for particle diffusion and drug release will be set up and validated

Potential impact

First and foremost, a new generation of researchers will be educated who have a comprehensive understanding of the requirements for successful nanomedicine development. These researchers will be of great importance for the pharmaceutical industry in order to boost their innovative character and to develop more effective systems for drug delivery. Secondly, a number of highly interesting nanoparticle formulations will be produced that will be ready for (pre)clinical testing to treat cancer and ophthalmic diseases. The interaction with the industrial partners within the consortium facilitates the transfer of knowledge and prevents that further development is terminated at the end of the NanoMed program.
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