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Hybrid Drug Delivery Systems upon Mesoporous Materials, Self Assembled Therapeutics and Virosomes

Periodic Reporting for period 2 - HYMADE (Hybrid Drug Delivery Systems upon Mesoporous Materials, Self Assembled Therapeutics and Virosomes)

Reporting period: 2017-02-01 to 2019-01-31

HYMADE focused on the development of capsules and engineered colloidal particles for drug delivery, combining mesoporous colloids, the layer-by-layer (LbL) assembly technique and virosomes. The capsules and particles developed during the project were investigated with a view toward their use in the treatment of cancer and inflammatory diseases such as rheumatoid arthritis and uveitis. The overarching aim of HYMADE was to employ a combination of hybrid materials to fabricate advanced drug delivery systems with controlled release and effective targeting to relevant biological entities, such as tumors. Our investigations also aimed to gain understanding of the self-assembly process of hybrid materials and insight into the transport properties of the drug delivery systems developed during the project. The biological fate of the drug delivery systems, along with their drug release, degradation and therapeutic efficiency were studied in vitro and in vivo with state of the art imaging techniques including confocal laser scanning microscopy and positron emission tomography. To achieve these goals, we relied on an international multidisciplinary team of scientists at the forefront of materials science, nanoparticle self-assembly, physics, chemistry, biophysics and molecular imaging. HYMADE was based on the exchange of Early Stage and Experienced Researchers between European and non-European academic institutions, and our team comprised investigators from Germany, Austria, France, Spain, the USA, Argentina and Armenia. HYMADE provided seconded researchers with unique and dynamic opportunities for professional, scientific, and personal development to enhance their career perspectives and generate highly skilled personnel at the interface of the materials and biomedical sciences.
HYMADE was successful in integrating multiple nanoscale components including polyelectrolytes, mesoporous particles, therapeutics, and virosomes into hybrid drug delivery systems. The layer-by-layer technique of assembly, which is based on the sequential assembly of oppositely charged objects by electrostatic interactions, was used to integrate the different components into hybrid delivery systems. Mesoporous colloidal particles have a porous structure that can be filled with therapeutic drugs. Polyelectrolytes were used to coat the porous particles for controlling drug release or for further engineering for targeted drug delivery. Therapeutics, such as silencing RNA and antibodies, were encapsulated in the drug delivery vehicle systems or used as components in the fabrication of the systems forming complexes with polyelectrolytes. In analogy to living cells, lipid membranes were assembled on the colloidal particles to optimize the release of encapsulated drugs. Virosomes, liposomes reconstructed from virus membranes, were fused to the lipid layers supported on colloidal particles to transfer the fusogenic properties of the viruses to the particles.

Our comprehensive studies on self-assembly mechanisms yielded a deep understanding of how the different components of the delivery systems impacted the properties of the hybrid materials. Transport studies through polyelectrolyte multilayers, fundamental for understanding release of encapsulated drugs, were performed and modeled.

The biological fate of the hybrid drug delivery systems was studied in vitro and in vivo. For in vitro studies, the translocation of fluorescently labelled drug delivery vehicles was followed in cells using confocal laser scanning microscopy, and detailed cell uptake studies were performed with flow cytometry. A thorough evaluation of toxicological endpoints of the drug delivery vehicles was also conducted in vitro.

The biodistribution and biokinetics of radiolabelled vehicles were studied in rats in both healthy and triple negative breast cancer models using positron emission tomography (PET). These in vivo studies allowed us to assess the ability of drug delivery vehicles to target triple negative breast cancer tumors for potential diagnosis and treatment. Importantly, we showed that vehicles functionalized with a targeting peptide accumulated in early tumor lesions more than twice as efficiently as untargeted vehicles. Overall, in vitro and in vivo fate studies provided valuable insight into how hybrid materials are processed in biological matrixes, which is fundamental to evaluate their potential application in drug delivery for the diagnosis and treatment of diseases.

Finally, drug delivery systems for siRNA were tested in cell culture. We showed that the systems could successfully deliver siRNA to cells to effectively silence expression of green fluorescent protein. These studies demonstrate the potential utility of our systems for delivering genetic material for a range of biomedical applications.
Through fulfilment of the project’s scientific objectives, HYMADE has advanced on the fabrication of drug delivery systems with heterogeneous components through self-assembly that provide unique features for drug delivery and targeting. The knowledge generated through the project has the potential to be translated into novel drug delivery devices for the treatment of cancer and several other diseases.
Through achievement of the project’s communication, dissemination and training goals, HYMADE produced several open access publications in top journals including Advanced Functional Materials, Soft Matter, Biointerphases, Materials Science and Engineering C, and Oncotarget. HYMADE partners participated in several outreach activities and training events, and organized thematic workshops and a final project conference, where the main results of the project were presented.

HYMADE achieved 98% of the proposed secondments, fostering the exchange of nearly 60 researchers between European countries and partner countries outside of Europe. These exchanges have had a notable positive impact on the career paths of the researchers involved, and have strengthened international collaboration between all countries that participated in the project.