DECENT AID · Novel drug delivery system produced by centrifugal technologies – composed to minimize adverse immune reactions and designed for optimised therapeutic effects

Novel drug delivery system produced by centrifugal technologies – composed to minimize adverse immune reactions and designed for optimised therapeutic effects

OBJECTIVES The following key objectives were defined for the IAPP project Decent AID (project number: 324275): 1. Development of innovative production technologies for nanocapsules as a drug delivery system with highest possible encapsulation efficiencies using centrifugation, colloidal and fluid mechanical techniques. 2. Versatility of the encapsulation technologies for a wide class of hydrophilic, amphiphilic and/or lipophilic active substances. The novel techniques should be especially suited for proteins and other sensitive biomolecules which are vulnerable to degradation by thermal, pH or organic solvent conditions used in existing encapsulation technologies. 3. Tailor-made nanocapsule shells to allow different functionalities for the inside and outside leaflets of the shells. 4. Complete encapsulation of active substances without expensive downstream purification processes. Non-encapsulated active pharmaceutical ingredients (API) can stimulate antibody formation and dramatically reduce the efficiency of the therapy. 5. Development of a polymer system covering the nanocapsules. This polymer cover has to enable long circulation times of the drug delivery system (DDS) without provoking any innate or specific immune reactions by the complement, the coagulation and the phagocytic systems. Other than established polymer protection systems, the novel polymer protection should not be immunogenic to avoid accelerated blood clearance upon repeated administration. 6. Testing of the novel DDS for stability in human blood in vitro. Investigation of encapsulated showcase API with specific endocytosis mechanisms in suitable cancer models to compare drug efficiency, immune reactions and organ distribution of encapsulated and non-encapsulated API. 7. Promotion of multidisciplinary research and innovation in nanotechnology for nanomedicine. Multidisciplinarity was to be achieved by collaboration in a intersectoral research consortium comprising mechanical and process engineering, pharmaceutical technology, immunology and cancer research offering career development for researchers at all levels of experience. MAIN RESULTS Overall, the project even exceeded expectations in several aspects, worked hard on some persistent constraints, achieved breakthrough and produced many results of both scientific and industrial significance with relevant socio-economic impact. 1. An innovative production technology was established to generate liposomes or nanocapsules as a drug delivery system with very high encapsulation efficiencies using centrifugation both as a batch process and a continuous process ready for industrial scale-up. Breakthrough was achieved by elucidating the colloidal properties of membrane lipids at interfaces to prepare the formation of novel asymmetric bilayers. 2. The versatility of the encapsulation technologies could be shown exemplarily for different classes of proteins to model hydrophilic sensitive biomolecules which are vulnerable to degradation by thermal, pH or organic solvent conditions used in existing encapsulation technologies. 3. Tailor-made nanocapsule shells of lipid bilayers were proved to be achievable to allow different functionalities for the inside and outside leaflets of the shells. A proof was shown using a batch process which can now be transferred to a continuous process. 4. Complete encapsulation was approached with high encapsulation efficiencies up to 95%. The system can now be adapted to industrial conditions and scale-up, for which a suitable framework could be established. 5. A novel coating system for liposomes or nanocapsules was developed based on heparin, a polysaccharide, i.e. a glycosaminoglycan, which is naturally produced by many vertebrates and arthropoda. Heparin showed clear advantages compared to the current standard coating by polyethylene glycol (PEG) with respect to much lower activation of the complement system in a human whole blood model. The results achieved will enable in the future to produce liposome or nanocapsule coatings which are small enough in their coating thickness. A reduced size is necessary to enable long circulation without provoking any innate or specific immune reactions by the complement, the coagulation and the phagocytic systems. Such a novel coating system is still a major unsatisfied demand since accelerated blood clearance upon repeated administration occurs with PEG as own in vivo tests show. 6. Testing of the novel drug delivery system was performed for stability in human blood in vitro. The investigation of the encapsulated showcase API, mistletoe lectin, elucidated the so-far unknown specific endocytosis mechanisms in murine and human cancer cells in vitro. The release of API from liposomes was studied and different mechanisms to increase release using thermosensitive liposomal membranes were established. Half maximal inhibitory concentration (IC50) were tested for different cell lines. A variety of immune reactions on liposomes were investigated. 7. Multidisciplinary research was efficiently enabled by the collaboration of 3 renowned universities and a medium sized, internationally-active pharmaceutical company. CONCLUSIONS: The innovations in production processes for nanotechnology allowed to develop a completely new drug delivery system for nanomedicine of any hydrophilic active pharmaceutical ingredient of biological origin. This successful approach will be focused for the next phase of exploitation to enable a fast track to clinical trials within the next research phase. EXPLOITATION PERSPECTIVES Industrial scale-up is planned in compliance with the rules of Good Manufacturing Practice (GMP). The production technology has to be developed to allow the execution of pre-clinical and clinical trials. The consortium partners plan to commercialize own active pharmaceutical ingredients (API) to be encapsulated in the novel drug delivery system which are to be tested clinically to prove the superior properties compared to non-encapsulated API. Simultaneously, the own drug formulation developments will be used as a showcase for the commercialization of the production technology, comprising both technological devices, processes, material compositions and their novel properties. SOCIO-ECONOMIC IMPACT The perspective of clinical trials in cancer therapy is of high societal relevance. Outreach activities and public engagement reached more than 25,000 cancer patients during the lifetime of the project. Young people of different age groups were given support by lab training allowing intriguing experiences with science. The uptake mistletoe lectins, the most widely used anti-cancer drug in Germany, was elucidated by life imaging and presented to the general public in open days and will soon be presented on dedicated websites, such as the project website: www.decentaid.eu and others.

Data: CORDIS, © European Union