Periodic Reporting for period 2 - NANOMED (Nanomedicine: an integrative approach)
Reporting period: 2018-01-01 to 2019-12-31
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.
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
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.