Prof. Dr. Jörg Huwyler Department of Pharmaceutical Sciences Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 15 foundShow per page10 10 20 50 Multifunctional lipid nanoparticles as carriers for DNA-therapeutics: Treatment of a genetic liver disease Research Project | 1 Project MembersImported from Grants Tool 4700451 Design of lipid based nanoparticles for gene delivery Research Project | 1 Project MembersNo Description available High Performance Transmission Electron Microscope for Present and Future Nanomaterials Research Project | 9 Project MembersThe rise of nanoscience and nanotechnology would not have been happened without the impressive development of instruments that allow to resolve structure on the nanometer scale with atomic resolution. Examples are scanning-probe and electron microscopy techniques. In recent years, several major breakthroughs gave rise to an exceptional boost in the performance of today's electron microscopy (EM), both for solid-state and soft (e.g. biological) materials: 1) high-resolution through image corrections, 2) fast and highly efficient electron detectors, 3) efficient artifact-free sample fabrication (cryo-EM and FIBEM), and 4) 3D tomography and image reconstruction. This has given a leap to what can be imaged today, allowing for example to reconstruct the atomic structure of single proteins and image complex interfaces in solid-state materials with atomic scale. The University of Basel (UBAS) is nationally and internationally recognized as a leader in nanoscience and nanotechnology. It was the leading house of the National Center in Competence and Research (NCCR) on Nanoscience, which later became the Swiss Nanoscience Institute (SNI), the institution that submits the current proposal. UBAS is also co-leading the NCCR Molecular Systems Engineering and the NCCR QSIT on Quantum Science (both together with ETHZ). Nanoscience is a focus area in the research portfolio of UBAS and instrumental for the recent development of quantum science. The present proposal to the SNF R'Equip scheme has been put together by key researchers at UBAS who work on current topics in nanoscience and nanotechnology in various disciplines from quantum science, material science, polymer chemistry to molecular biology, and, who make use of EM available within the SNI. The principle investigators, who submit this proposal together, do research that relies on the availability of state-of-the-art nanoimaging tools, such as a transmission electron microscope (TEM). The proposal outlines a convincing case for the purchase of special, unique TEM that combines state-of-the-art (and fast) atomic resolution imaging with material analysis using EDX and scanning TEM (STEM). This combination is unique and crucial for the University of Basel to stay at the forefront of science. Development of novel synthetic gene transfer vectors for metabolic liver therapy Research Project | 2 Project MembersTherapeutic vectors for gene delivery remain the currently most challenging factor for human gene therapy. The translation from in vitro to in vivo applications remains a major hurdle for most nucleic acid delivery systems since there is an inherent lack of both efficient and safe carrier systems. For liver targeting of postmitotic hepatocytes, adeno-associated virus (AAV) derived vectors are thought to have the greatest potential despite concerns about a future routine clinical use. The major hurdles of AAV vectors for long-term treatment of pediatric patients are the risk of chromosomal integration and development of hepatocellular carcinoma, immune responses to viral vectors, limited loading capacity, and the difficulty to treat neonates which likely would require subsequent further injections. Consequently, the development of non-viral gene delivery systems has gained much attention due to their versatility, safety, and ease of manufacturing. During the last decades, a wide range of nanoparticle based gene delivery systems were developed and remarkable results in the field of RNA therapeutics were achieved. However, the induced pharmacological effects obtained by these siRNA or mRNA delivery strategies are short-lived and thus weekly administrations of therapeutic formulations are necessary. The use of DNA-based therapeutics would offer a favorable option for the induction of long-term therapeutic effects without need for insertion into the genome. Here, we propose an alternative approach to overcome the challenges of viral vectors or RNA-based therapeutics by developing novel nanoparticles for delivery of non-integrating, so-called minicircle (MC) vectors lacking any viral or bacterial components for liver-directed gene therapy. The successful use of MC vectors to treat genetic (metabolic) liver defects is based on the experience of one application partner with naked DNA-vectors delivered in an experimental setting by hydrodynamic pressure to either target pericentral or periportal hepatocytes to treat two classical defects in mouse models for human diseases, phenylketonuria (PKU) and ornithine transcarbamylase (OTC) deficiency, respectively. Such MC vectors exhibited persistent expression combined with basically no DNA size limitation, which made it possible to use natural promoters/enhancers in combination with introns to mimic "physiological" expression. While MC vectors bear almost ideal properties with great potential for liver gene therapy, delivery of naked DNA solely by hydrodynamic pressure is not applicable in a clinical setting. In an interdisciplinary approach, we want to develop multifunctional polymeric nanoparticles encapsulating MC vectors for non-viral gene delivery specifically to the key pathogenic cell type, i.e. hepatocytes. In order to optimize gene delivery efficiency, a novel library of polymer-peptide hybrids will be created, formulations strategies will be optimized and resulting nanoparticles will be validated in vivo using various animal models, i.e. transgenic mice, xenotransplanted mice with human liver or pig models. The combination of this novel class of polymer-peptide hybrids with a reproducible and scalable nanoparticle formulation technique (i.e. microfluidics) is expected to greatly impact further optimization of the synthetic gene delivery system for clinical applications. The overall aim of this translational project is the development of an alternative approach to AAV vectors with the potential of a breakthrough for liver gene therapy and thus a paradigm shift from potentially harmful viral vectors to safe, efficient and completely synthetic non-viral vectors. Drug Targeting to Hepatocytes: Gene Delivery using Myrcludex B Coupled Lipid Nanoparticles Research Project | 3 Project MembersHepatic disorders affect millions of people around the globe and incidence rates are further increasing. Current therapies for diseases of hepatocytes are limited and in most cases only treat symptoms. Therefore, improved therapeutic technologies are needed. Nanomedicines for the delivery of therapeutic genes have the potential to overcome the lack of satisfactory and alternative treatment options. This grant application focuses on the design of functional nanomedicines for targeted nucleic acid delivery (i.e. plasmid DNA) to liver parenchymal cells. The proposed project consists of three work-packages, which can be summarized as follows:First, specific and highly selective targeting of hepatocytes will be achieved using a targeting ligand derived from hepatitis B virus (HBV). This HBV entry inhibitor "Myrcludex B" consists of a lipid-conjugated polypeptide (i.e. the PreS1 domain of the large surface glycoprotein of HBV) and is characterized by a strong tropism for hepatocytes. Optimized Myrcludex B-derived lipopeptides will be conjugated to the surface of pegylated liposomes to mediate hepatocyte specific drug delivery. Second, in order to optimize loading and retention of DNA expression plasmids within lipid nanoparticles, a novel library of double tailed, ionizable amino-lipids will be created and screened for efficient and safe transfection activity. The combination of this new class of amino-lipids with a novel nanoparticle formulation technique (i.e. microfluidics) offers the possibility to optimize the transfection efficiency of the lipid-based delivery system. Third, in the final part of the project, both technologies will be combined to achieve targeted gene delivery to human hepatocytes; both in vitro in human liver derived cell lines as well as in vivo in different mouse models expressing the mouse or human NTCP, i.e. the entry point for HBV and at the same time our highly selective target structure on hepatocytes. With our novel targeting strategy, we have the possibility to address an unmet medical need. Non-viral gene delivery may offer well tolerated therapeutic options for diseases of the liver such as Crigler-Najjar syndrome, where a single gene defect leads to severe clinical manifestations. The proposed project will be the first step towards a future therapeutic intervention for this and other orphan liver diseases. A Phospholipid-Functionalized Calcium Carbonate Based Drug Delivery System to Improve the Bioavailability of Poorly Water-Soluble Drugs Research Project | 1 Project MembersNo Description available NanoREG II - Development and Implementation of Grouping and Safe-by-Design approaches within regulatory frameworks Research Project | 2 Project MembersOne of the greatest challenges facing regulators in the ever changing landscape of novel nano-materials is how to design and implement a regulatory process which is robust enough to deal with a rapidly diversifying system of manufactured nanomaterials (MNM) over time. The challenge is to build a regulatory system which is flexible enough to be able to deal with new targets and requirements in the future, and this can be helped by the development and introduction of Safe by Design (SbD) principles. The NANoREG II project, built around the challenge of coupling SbD to the regulatory process, will demonstrate and establish new principles and ideas based on data from value chain implementation studies to establish SbD as a fundamental pillar in the validation of a novel MNM. Grouping concepts that will be developed by NanoREG II can be regarded as a major innovation, and in the form of guidance documents will support industries and regulatory agencies as well as supporting commercial launch of new NM. Small volume parenterals: filling, in process control, particulate testing Research Project | 1 Project MembersProject Outline & Milestones: 1) Optimization of the piezo-based dosing system in terms of size, weight and filling parameters 2) Identification of suitable measurement techniques for in process control (IPC) of low fill-volume (Target: 100 ml - 10 µl) 3) Identification of a method to visually inspect (conical) vials with fill-volumes < 500 µl for foreign particulate matter 4) Identification and development of strategies around sampling & measuring subvisible particles in dosage forms with low fill-volumes Designing a physiologically relevant in vitro model to predict the stability of ocular antibody drug delivery formulations in the vitreous Research Project | 1 Project MembersThe project aims to develop a dynamic in vitro release model to evaluate physical stability of protein and formulation components in the presence of VH. Also, it aims to study and compare the performance of different proteins formats, and physicochemical parameters which are complex to measure in in vivo study setup. Interaction of drug solutions with surfaces of pharmaceutical primary packaging containers and their components Research Project | 1 Project MembersMany of the actual challenges in the pharmaceutical industry are related to the interaction of the drug solution with surfaces of pharmaceutical primary packaging containers and their components. Prominent examples are phenomena like fogging, delamination or leaching of components of the containers into the drug solution ("metal impurities", tungsten). Therefore, the health authorities also focus on the determination of the underlying root causes of these phenomena. Additionally, the interest is high from a scientific point of view because most questions on this field are still unanswered. 12 12 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 15 foundShow per page10 10 20 50 Multifunctional lipid nanoparticles as carriers for DNA-therapeutics: Treatment of a genetic liver disease Research Project | 1 Project MembersImported from Grants Tool 4700451 Design of lipid based nanoparticles for gene delivery Research Project | 1 Project MembersNo Description available High Performance Transmission Electron Microscope for Present and Future Nanomaterials Research Project | 9 Project MembersThe rise of nanoscience and nanotechnology would not have been happened without the impressive development of instruments that allow to resolve structure on the nanometer scale with atomic resolution. Examples are scanning-probe and electron microscopy techniques. In recent years, several major breakthroughs gave rise to an exceptional boost in the performance of today's electron microscopy (EM), both for solid-state and soft (e.g. biological) materials: 1) high-resolution through image corrections, 2) fast and highly efficient electron detectors, 3) efficient artifact-free sample fabrication (cryo-EM and FIBEM), and 4) 3D tomography and image reconstruction. This has given a leap to what can be imaged today, allowing for example to reconstruct the atomic structure of single proteins and image complex interfaces in solid-state materials with atomic scale. The University of Basel (UBAS) is nationally and internationally recognized as a leader in nanoscience and nanotechnology. It was the leading house of the National Center in Competence and Research (NCCR) on Nanoscience, which later became the Swiss Nanoscience Institute (SNI), the institution that submits the current proposal. UBAS is also co-leading the NCCR Molecular Systems Engineering and the NCCR QSIT on Quantum Science (both together with ETHZ). Nanoscience is a focus area in the research portfolio of UBAS and instrumental for the recent development of quantum science. The present proposal to the SNF R'Equip scheme has been put together by key researchers at UBAS who work on current topics in nanoscience and nanotechnology in various disciplines from quantum science, material science, polymer chemistry to molecular biology, and, who make use of EM available within the SNI. The principle investigators, who submit this proposal together, do research that relies on the availability of state-of-the-art nanoimaging tools, such as a transmission electron microscope (TEM). The proposal outlines a convincing case for the purchase of special, unique TEM that combines state-of-the-art (and fast) atomic resolution imaging with material analysis using EDX and scanning TEM (STEM). This combination is unique and crucial for the University of Basel to stay at the forefront of science. Development of novel synthetic gene transfer vectors for metabolic liver therapy Research Project | 2 Project MembersTherapeutic vectors for gene delivery remain the currently most challenging factor for human gene therapy. The translation from in vitro to in vivo applications remains a major hurdle for most nucleic acid delivery systems since there is an inherent lack of both efficient and safe carrier systems. For liver targeting of postmitotic hepatocytes, adeno-associated virus (AAV) derived vectors are thought to have the greatest potential despite concerns about a future routine clinical use. The major hurdles of AAV vectors for long-term treatment of pediatric patients are the risk of chromosomal integration and development of hepatocellular carcinoma, immune responses to viral vectors, limited loading capacity, and the difficulty to treat neonates which likely would require subsequent further injections. Consequently, the development of non-viral gene delivery systems has gained much attention due to their versatility, safety, and ease of manufacturing. During the last decades, a wide range of nanoparticle based gene delivery systems were developed and remarkable results in the field of RNA therapeutics were achieved. However, the induced pharmacological effects obtained by these siRNA or mRNA delivery strategies are short-lived and thus weekly administrations of therapeutic formulations are necessary. The use of DNA-based therapeutics would offer a favorable option for the induction of long-term therapeutic effects without need for insertion into the genome. Here, we propose an alternative approach to overcome the challenges of viral vectors or RNA-based therapeutics by developing novel nanoparticles for delivery of non-integrating, so-called minicircle (MC) vectors lacking any viral or bacterial components for liver-directed gene therapy. The successful use of MC vectors to treat genetic (metabolic) liver defects is based on the experience of one application partner with naked DNA-vectors delivered in an experimental setting by hydrodynamic pressure to either target pericentral or periportal hepatocytes to treat two classical defects in mouse models for human diseases, phenylketonuria (PKU) and ornithine transcarbamylase (OTC) deficiency, respectively. Such MC vectors exhibited persistent expression combined with basically no DNA size limitation, which made it possible to use natural promoters/enhancers in combination with introns to mimic "physiological" expression. While MC vectors bear almost ideal properties with great potential for liver gene therapy, delivery of naked DNA solely by hydrodynamic pressure is not applicable in a clinical setting. In an interdisciplinary approach, we want to develop multifunctional polymeric nanoparticles encapsulating MC vectors for non-viral gene delivery specifically to the key pathogenic cell type, i.e. hepatocytes. In order to optimize gene delivery efficiency, a novel library of polymer-peptide hybrids will be created, formulations strategies will be optimized and resulting nanoparticles will be validated in vivo using various animal models, i.e. transgenic mice, xenotransplanted mice with human liver or pig models. The combination of this novel class of polymer-peptide hybrids with a reproducible and scalable nanoparticle formulation technique (i.e. microfluidics) is expected to greatly impact further optimization of the synthetic gene delivery system for clinical applications. The overall aim of this translational project is the development of an alternative approach to AAV vectors with the potential of a breakthrough for liver gene therapy and thus a paradigm shift from potentially harmful viral vectors to safe, efficient and completely synthetic non-viral vectors. Drug Targeting to Hepatocytes: Gene Delivery using Myrcludex B Coupled Lipid Nanoparticles Research Project | 3 Project MembersHepatic disorders affect millions of people around the globe and incidence rates are further increasing. Current therapies for diseases of hepatocytes are limited and in most cases only treat symptoms. Therefore, improved therapeutic technologies are needed. Nanomedicines for the delivery of therapeutic genes have the potential to overcome the lack of satisfactory and alternative treatment options. This grant application focuses on the design of functional nanomedicines for targeted nucleic acid delivery (i.e. plasmid DNA) to liver parenchymal cells. The proposed project consists of three work-packages, which can be summarized as follows:First, specific and highly selective targeting of hepatocytes will be achieved using a targeting ligand derived from hepatitis B virus (HBV). This HBV entry inhibitor "Myrcludex B" consists of a lipid-conjugated polypeptide (i.e. the PreS1 domain of the large surface glycoprotein of HBV) and is characterized by a strong tropism for hepatocytes. Optimized Myrcludex B-derived lipopeptides will be conjugated to the surface of pegylated liposomes to mediate hepatocyte specific drug delivery. Second, in order to optimize loading and retention of DNA expression plasmids within lipid nanoparticles, a novel library of double tailed, ionizable amino-lipids will be created and screened for efficient and safe transfection activity. The combination of this new class of amino-lipids with a novel nanoparticle formulation technique (i.e. microfluidics) offers the possibility to optimize the transfection efficiency of the lipid-based delivery system. Third, in the final part of the project, both technologies will be combined to achieve targeted gene delivery to human hepatocytes; both in vitro in human liver derived cell lines as well as in vivo in different mouse models expressing the mouse or human NTCP, i.e. the entry point for HBV and at the same time our highly selective target structure on hepatocytes. With our novel targeting strategy, we have the possibility to address an unmet medical need. Non-viral gene delivery may offer well tolerated therapeutic options for diseases of the liver such as Crigler-Najjar syndrome, where a single gene defect leads to severe clinical manifestations. The proposed project will be the first step towards a future therapeutic intervention for this and other orphan liver diseases. A Phospholipid-Functionalized Calcium Carbonate Based Drug Delivery System to Improve the Bioavailability of Poorly Water-Soluble Drugs Research Project | 1 Project MembersNo Description available NanoREG II - Development and Implementation of Grouping and Safe-by-Design approaches within regulatory frameworks Research Project | 2 Project MembersOne of the greatest challenges facing regulators in the ever changing landscape of novel nano-materials is how to design and implement a regulatory process which is robust enough to deal with a rapidly diversifying system of manufactured nanomaterials (MNM) over time. The challenge is to build a regulatory system which is flexible enough to be able to deal with new targets and requirements in the future, and this can be helped by the development and introduction of Safe by Design (SbD) principles. The NANoREG II project, built around the challenge of coupling SbD to the regulatory process, will demonstrate and establish new principles and ideas based on data from value chain implementation studies to establish SbD as a fundamental pillar in the validation of a novel MNM. Grouping concepts that will be developed by NanoREG II can be regarded as a major innovation, and in the form of guidance documents will support industries and regulatory agencies as well as supporting commercial launch of new NM. Small volume parenterals: filling, in process control, particulate testing Research Project | 1 Project MembersProject Outline & Milestones: 1) Optimization of the piezo-based dosing system in terms of size, weight and filling parameters 2) Identification of suitable measurement techniques for in process control (IPC) of low fill-volume (Target: 100 ml - 10 µl) 3) Identification of a method to visually inspect (conical) vials with fill-volumes < 500 µl for foreign particulate matter 4) Identification and development of strategies around sampling & measuring subvisible particles in dosage forms with low fill-volumes Designing a physiologically relevant in vitro model to predict the stability of ocular antibody drug delivery formulations in the vitreous Research Project | 1 Project MembersThe project aims to develop a dynamic in vitro release model to evaluate physical stability of protein and formulation components in the presence of VH. Also, it aims to study and compare the performance of different proteins formats, and physicochemical parameters which are complex to measure in in vivo study setup. Interaction of drug solutions with surfaces of pharmaceutical primary packaging containers and their components Research Project | 1 Project MembersMany of the actual challenges in the pharmaceutical industry are related to the interaction of the drug solution with surfaces of pharmaceutical primary packaging containers and their components. Prominent examples are phenomena like fogging, delamination or leaching of components of the containers into the drug solution ("metal impurities", tungsten). Therefore, the health authorities also focus on the determination of the underlying root causes of these phenomena. Additionally, the interest is high from a scientific point of view because most questions on this field are still unanswered. 12 12
Multifunctional lipid nanoparticles as carriers for DNA-therapeutics: Treatment of a genetic liver disease Research Project | 1 Project MembersImported from Grants Tool 4700451
Design of lipid based nanoparticles for gene delivery Research Project | 1 Project MembersNo Description available
High Performance Transmission Electron Microscope for Present and Future Nanomaterials Research Project | 9 Project MembersThe rise of nanoscience and nanotechnology would not have been happened without the impressive development of instruments that allow to resolve structure on the nanometer scale with atomic resolution. Examples are scanning-probe and electron microscopy techniques. In recent years, several major breakthroughs gave rise to an exceptional boost in the performance of today's electron microscopy (EM), both for solid-state and soft (e.g. biological) materials: 1) high-resolution through image corrections, 2) fast and highly efficient electron detectors, 3) efficient artifact-free sample fabrication (cryo-EM and FIBEM), and 4) 3D tomography and image reconstruction. This has given a leap to what can be imaged today, allowing for example to reconstruct the atomic structure of single proteins and image complex interfaces in solid-state materials with atomic scale. The University of Basel (UBAS) is nationally and internationally recognized as a leader in nanoscience and nanotechnology. It was the leading house of the National Center in Competence and Research (NCCR) on Nanoscience, which later became the Swiss Nanoscience Institute (SNI), the institution that submits the current proposal. UBAS is also co-leading the NCCR Molecular Systems Engineering and the NCCR QSIT on Quantum Science (both together with ETHZ). Nanoscience is a focus area in the research portfolio of UBAS and instrumental for the recent development of quantum science. The present proposal to the SNF R'Equip scheme has been put together by key researchers at UBAS who work on current topics in nanoscience and nanotechnology in various disciplines from quantum science, material science, polymer chemistry to molecular biology, and, who make use of EM available within the SNI. The principle investigators, who submit this proposal together, do research that relies on the availability of state-of-the-art nanoimaging tools, such as a transmission electron microscope (TEM). The proposal outlines a convincing case for the purchase of special, unique TEM that combines state-of-the-art (and fast) atomic resolution imaging with material analysis using EDX and scanning TEM (STEM). This combination is unique and crucial for the University of Basel to stay at the forefront of science.
Development of novel synthetic gene transfer vectors for metabolic liver therapy Research Project | 2 Project MembersTherapeutic vectors for gene delivery remain the currently most challenging factor for human gene therapy. The translation from in vitro to in vivo applications remains a major hurdle for most nucleic acid delivery systems since there is an inherent lack of both efficient and safe carrier systems. For liver targeting of postmitotic hepatocytes, adeno-associated virus (AAV) derived vectors are thought to have the greatest potential despite concerns about a future routine clinical use. The major hurdles of AAV vectors for long-term treatment of pediatric patients are the risk of chromosomal integration and development of hepatocellular carcinoma, immune responses to viral vectors, limited loading capacity, and the difficulty to treat neonates which likely would require subsequent further injections. Consequently, the development of non-viral gene delivery systems has gained much attention due to their versatility, safety, and ease of manufacturing. During the last decades, a wide range of nanoparticle based gene delivery systems were developed and remarkable results in the field of RNA therapeutics were achieved. However, the induced pharmacological effects obtained by these siRNA or mRNA delivery strategies are short-lived and thus weekly administrations of therapeutic formulations are necessary. The use of DNA-based therapeutics would offer a favorable option for the induction of long-term therapeutic effects without need for insertion into the genome. Here, we propose an alternative approach to overcome the challenges of viral vectors or RNA-based therapeutics by developing novel nanoparticles for delivery of non-integrating, so-called minicircle (MC) vectors lacking any viral or bacterial components for liver-directed gene therapy. The successful use of MC vectors to treat genetic (metabolic) liver defects is based on the experience of one application partner with naked DNA-vectors delivered in an experimental setting by hydrodynamic pressure to either target pericentral or periportal hepatocytes to treat two classical defects in mouse models for human diseases, phenylketonuria (PKU) and ornithine transcarbamylase (OTC) deficiency, respectively. Such MC vectors exhibited persistent expression combined with basically no DNA size limitation, which made it possible to use natural promoters/enhancers in combination with introns to mimic "physiological" expression. While MC vectors bear almost ideal properties with great potential for liver gene therapy, delivery of naked DNA solely by hydrodynamic pressure is not applicable in a clinical setting. In an interdisciplinary approach, we want to develop multifunctional polymeric nanoparticles encapsulating MC vectors for non-viral gene delivery specifically to the key pathogenic cell type, i.e. hepatocytes. In order to optimize gene delivery efficiency, a novel library of polymer-peptide hybrids will be created, formulations strategies will be optimized and resulting nanoparticles will be validated in vivo using various animal models, i.e. transgenic mice, xenotransplanted mice with human liver or pig models. The combination of this novel class of polymer-peptide hybrids with a reproducible and scalable nanoparticle formulation technique (i.e. microfluidics) is expected to greatly impact further optimization of the synthetic gene delivery system for clinical applications. The overall aim of this translational project is the development of an alternative approach to AAV vectors with the potential of a breakthrough for liver gene therapy and thus a paradigm shift from potentially harmful viral vectors to safe, efficient and completely synthetic non-viral vectors.
Drug Targeting to Hepatocytes: Gene Delivery using Myrcludex B Coupled Lipid Nanoparticles Research Project | 3 Project MembersHepatic disorders affect millions of people around the globe and incidence rates are further increasing. Current therapies for diseases of hepatocytes are limited and in most cases only treat symptoms. Therefore, improved therapeutic technologies are needed. Nanomedicines for the delivery of therapeutic genes have the potential to overcome the lack of satisfactory and alternative treatment options. This grant application focuses on the design of functional nanomedicines for targeted nucleic acid delivery (i.e. plasmid DNA) to liver parenchymal cells. The proposed project consists of three work-packages, which can be summarized as follows:First, specific and highly selective targeting of hepatocytes will be achieved using a targeting ligand derived from hepatitis B virus (HBV). This HBV entry inhibitor "Myrcludex B" consists of a lipid-conjugated polypeptide (i.e. the PreS1 domain of the large surface glycoprotein of HBV) and is characterized by a strong tropism for hepatocytes. Optimized Myrcludex B-derived lipopeptides will be conjugated to the surface of pegylated liposomes to mediate hepatocyte specific drug delivery. Second, in order to optimize loading and retention of DNA expression plasmids within lipid nanoparticles, a novel library of double tailed, ionizable amino-lipids will be created and screened for efficient and safe transfection activity. The combination of this new class of amino-lipids with a novel nanoparticle formulation technique (i.e. microfluidics) offers the possibility to optimize the transfection efficiency of the lipid-based delivery system. Third, in the final part of the project, both technologies will be combined to achieve targeted gene delivery to human hepatocytes; both in vitro in human liver derived cell lines as well as in vivo in different mouse models expressing the mouse or human NTCP, i.e. the entry point for HBV and at the same time our highly selective target structure on hepatocytes. With our novel targeting strategy, we have the possibility to address an unmet medical need. Non-viral gene delivery may offer well tolerated therapeutic options for diseases of the liver such as Crigler-Najjar syndrome, where a single gene defect leads to severe clinical manifestations. The proposed project will be the first step towards a future therapeutic intervention for this and other orphan liver diseases.
A Phospholipid-Functionalized Calcium Carbonate Based Drug Delivery System to Improve the Bioavailability of Poorly Water-Soluble Drugs Research Project | 1 Project MembersNo Description available
NanoREG II - Development and Implementation of Grouping and Safe-by-Design approaches within regulatory frameworks Research Project | 2 Project MembersOne of the greatest challenges facing regulators in the ever changing landscape of novel nano-materials is how to design and implement a regulatory process which is robust enough to deal with a rapidly diversifying system of manufactured nanomaterials (MNM) over time. The challenge is to build a regulatory system which is flexible enough to be able to deal with new targets and requirements in the future, and this can be helped by the development and introduction of Safe by Design (SbD) principles. The NANoREG II project, built around the challenge of coupling SbD to the regulatory process, will demonstrate and establish new principles and ideas based on data from value chain implementation studies to establish SbD as a fundamental pillar in the validation of a novel MNM. Grouping concepts that will be developed by NanoREG II can be regarded as a major innovation, and in the form of guidance documents will support industries and regulatory agencies as well as supporting commercial launch of new NM.
Small volume parenterals: filling, in process control, particulate testing Research Project | 1 Project MembersProject Outline & Milestones: 1) Optimization of the piezo-based dosing system in terms of size, weight and filling parameters 2) Identification of suitable measurement techniques for in process control (IPC) of low fill-volume (Target: 100 ml - 10 µl) 3) Identification of a method to visually inspect (conical) vials with fill-volumes < 500 µl for foreign particulate matter 4) Identification and development of strategies around sampling & measuring subvisible particles in dosage forms with low fill-volumes
Designing a physiologically relevant in vitro model to predict the stability of ocular antibody drug delivery formulations in the vitreous Research Project | 1 Project MembersThe project aims to develop a dynamic in vitro release model to evaluate physical stability of protein and formulation components in the presence of VH. Also, it aims to study and compare the performance of different proteins formats, and physicochemical parameters which are complex to measure in in vivo study setup.
Interaction of drug solutions with surfaces of pharmaceutical primary packaging containers and their components Research Project | 1 Project MembersMany of the actual challenges in the pharmaceutical industry are related to the interaction of the drug solution with surfaces of pharmaceutical primary packaging containers and their components. Prominent examples are phenomena like fogging, delamination or leaching of components of the containers into the drug solution ("metal impurities", tungsten). Therefore, the health authorities also focus on the determination of the underlying root causes of these phenomena. Additionally, the interest is high from a scientific point of view because most questions on this field are still unanswered.
