Periodic Reporting for period 2 - MAGNETO (Nanoengineered magnetoresponsive diagnosis and personalized treatment of pediatric inflammatory bowel disease)
Reporting period: 2022-09-01 to 2024-02-29
Inflammatory bowel disease (IBD) is an incurable, inflammatory condition of the gastrointestinal tract (GIT) that affects millions of patients worldwide and places an enormous economic burden on society. Most alarmingly, children account for one quarter of all IBD cases with steadily increasing incidence. Current clinical practices for IBD diagnosis and therapy are demanding and ineffective in terms of treatment outcome, patient compliance and cost and by far not optimized for children. Our aim is to establish a theranostic platform for diagnosis and personalized treatment of pediatric IBD by an interdisciplinary approach bridging discovery of disease biomarkers, nanomaterial and drug delivery system engineering to manufacture of personalized dosage forms.
We will capitalize on scalable and reproducible flame engineering to tailor the properties of superparamagnetic iron oxide nanoparticles (SPION) and achieve functionalities beyond their current use in the clinic. This multifunctional material will serve as contrast agent in magnetic resonance imaging, tracer particle in magnetic particle imaging and for hyperthermia-triggered drug release. Ligands for disease biomarkers identified by global protein quantification will ensure targeted delivery of the theranostic SPION. We will push the frontiers of magnetic bioimaging for non-invasive and accurate diagnosis of IBD to guide stimuli-responsive drug delivery. To optimize the treatment of sick children, we will design personalized oral dosage forms incorporating our targeted drug carriers by additive manufacturing. The nanoengineering approach along with industrially relevant microencapsulation and 3D printing technologies will provide fundamental insight into physicochemical properties that govern the targeted use of nanomaterials in the challenging GIT environment. The outcome of this research will support personalized therapy of pediatric IBD, improving patient quality of life and reduce the healthcare burden.
We will capitalize on scalable and reproducible flame engineering to tailor the properties of superparamagnetic iron oxide nanoparticles (SPION) and achieve functionalities beyond their current use in the clinic. This multifunctional material will serve as contrast agent in magnetic resonance imaging, tracer particle in magnetic particle imaging and for hyperthermia-triggered drug release. Ligands for disease biomarkers identified by global protein quantification will ensure targeted delivery of the theranostic SPION. We will push the frontiers of magnetic bioimaging for non-invasive and accurate diagnosis of IBD to guide stimuli-responsive drug delivery. To optimize the treatment of sick children, we will design personalized oral dosage forms incorporating our targeted drug carriers by additive manufacturing. The nanoengineering approach along with industrially relevant microencapsulation and 3D printing technologies will provide fundamental insight into physicochemical properties that govern the targeted use of nanomaterials in the challenging GIT environment. The outcome of this research will support personalized therapy of pediatric IBD, improving patient quality of life and reduce the healthcare burden.
Inflammatory bowel disease (IBD) is a chronic condition resulting in impaired intestinal homeostasis. Current practices for diagnosis of IBD are challenged by invasive, demanding procedures. We hypothesized that proteomics analysis could provide a powerful tool for identifying clinical biomarkers for non-invasive IBD diagnosis. Here, the global intestinal proteomes from commonly used in vitro and in vivo models of IBD were analyzed to identify apical and luminal proteins that can be targeted by orally delivered diagnostic agents. Common for the identified proteins is that they can be targeted from the luminal side of the gastrointestinal tract. Thus, compared to serum biomarkers, they are specific for intestinal inflammation. To validate the clinical relevance of the biomarkers identified in our preclinical models, we are currently in the process of collecting intestinal biopsies from pediatric and adolescent IBD patients. Samples are collected from six regions (stomach, proximal and distal small intestine, ascending, transverse and descending large intestine) in the gastrointestinal tract during routine endoscopic procedures. The future bioanalysis of these samples will give us unique information about biomarker expression in different regions of the gastrointestinal tract during inflammation and we will also be able to compare the impact of patient age on the disease state.
The identified preclinical and clinical biomarkers, will be used as anchor points for imaging nanoparticles. With this approach, we aim to provide non-invasive, local and quantitative IBD diagnosis. Towards this end, we are working on manufacturing approaches for nanoparticles suitable for imaging by e.g. magnetic resonance imaging (MRI). Key experts in the field of nanomedicine have consistently emphasized the necessity for controllable, reproducible and scalable nanoparticle synthesis methods to accelerate broad clinical translation of nanomedicines. Thus, we produce our nanoparticles by flame spray pyrolysis (FSP), a scalable technique with excellent reproducibility. Furthermore, to ensure optimal and reproducible performance of the final product, we employ quality-by-design (Qbd) pharmaceutical manufacturing principles during nanoparticle development. We have produced an array of superparamagnetic iron oxide nanoparticle (SPION) compositions and sizes and systematically studied their impact on magnetic hyperthermia performance. The, to the best of our knowledge, unprecedented large dataset generated here combined with its modelling using design of experiments (DoE) enables us to i) systematically correlate physicochemical properties of nanoparticles with their hyperthermia performance and ii) identify an optimal operating space for high-performance SPIONs. We stipulate that the rigorous application of QbD principles and statistical DoE for engineering our nanoparticles can accelerate regulatory approval and support industrial translation of novel nanomedicines. This approach mitigates the risk of discontinued clinical trials arising from unreliable production processes.
We have applied click chemistry-based bioconjugation approaches to functionalize our nanoparticles with ligands targeting biomarkers in our preclinical IBD models. Click chemistry enables control of the antibody orientation on the particle surface, ensuring exposure of the active site. Our findings suggest that click chemistry allows simple and controlled bioconjugation of ligands onto SiO2-coated SPION surfaces, which enables the development of efficient and targeted MRI-contrast agents for IBD. First results indicate increased cellular uptake in vitro and enhanced binding in inflamed tissue compared to the healthy control in vivo for the functionalized nanoparticles. We are now also developing magnetic biosensors incorporating the functionalized nanoparticles. The biosensors will be used to quantify IBD disease activity in situ in the gastrointestinal tract by MRI. In order to achieve this goal, we have to improve our understanding of how gastrointestinal pathologies may affect nanoparticle stability and physicochemical properties after oral administration. For example, it has been reported that normal pH values, osmolality, and lecithin concentration in the gastrointestinal tract can dramatically change when patients suffer from IBD. To study the dynamic phenomena occurring during nanoparticle transport through the gastrointestinal tract, we have developed a microfluidic device, that can in a miniaturized format generate information about how the stability, aggregation, and protein corona formation around inorganic nanoparticles evolve during their passage through the gastrointestinal tract.
Our final goal is also to develop oral drug delivery systems that enable the local treatment of IBD. Here, we are exploring various indigenous and exogenous triggers that can be used to locally release drugs in the gastrointestinal tract. We specifically focus on biological drugs that are used in the treatment of moderate to severe cases of IBD and where today there is a lack of patient compliant treatments specifically tailored for pediatric patients. For this, we have developed drug formulations that can be 3D printed into solid oral dosage forms. Here, 3D printing enables the personalization of the dose for pediatric patients.
The identified preclinical and clinical biomarkers, will be used as anchor points for imaging nanoparticles. With this approach, we aim to provide non-invasive, local and quantitative IBD diagnosis. Towards this end, we are working on manufacturing approaches for nanoparticles suitable for imaging by e.g. magnetic resonance imaging (MRI). Key experts in the field of nanomedicine have consistently emphasized the necessity for controllable, reproducible and scalable nanoparticle synthesis methods to accelerate broad clinical translation of nanomedicines. Thus, we produce our nanoparticles by flame spray pyrolysis (FSP), a scalable technique with excellent reproducibility. Furthermore, to ensure optimal and reproducible performance of the final product, we employ quality-by-design (Qbd) pharmaceutical manufacturing principles during nanoparticle development. We have produced an array of superparamagnetic iron oxide nanoparticle (SPION) compositions and sizes and systematically studied their impact on magnetic hyperthermia performance. The, to the best of our knowledge, unprecedented large dataset generated here combined with its modelling using design of experiments (DoE) enables us to i) systematically correlate physicochemical properties of nanoparticles with their hyperthermia performance and ii) identify an optimal operating space for high-performance SPIONs. We stipulate that the rigorous application of QbD principles and statistical DoE for engineering our nanoparticles can accelerate regulatory approval and support industrial translation of novel nanomedicines. This approach mitigates the risk of discontinued clinical trials arising from unreliable production processes.
We have applied click chemistry-based bioconjugation approaches to functionalize our nanoparticles with ligands targeting biomarkers in our preclinical IBD models. Click chemistry enables control of the antibody orientation on the particle surface, ensuring exposure of the active site. Our findings suggest that click chemistry allows simple and controlled bioconjugation of ligands onto SiO2-coated SPION surfaces, which enables the development of efficient and targeted MRI-contrast agents for IBD. First results indicate increased cellular uptake in vitro and enhanced binding in inflamed tissue compared to the healthy control in vivo for the functionalized nanoparticles. We are now also developing magnetic biosensors incorporating the functionalized nanoparticles. The biosensors will be used to quantify IBD disease activity in situ in the gastrointestinal tract by MRI. In order to achieve this goal, we have to improve our understanding of how gastrointestinal pathologies may affect nanoparticle stability and physicochemical properties after oral administration. For example, it has been reported that normal pH values, osmolality, and lecithin concentration in the gastrointestinal tract can dramatically change when patients suffer from IBD. To study the dynamic phenomena occurring during nanoparticle transport through the gastrointestinal tract, we have developed a microfluidic device, that can in a miniaturized format generate information about how the stability, aggregation, and protein corona formation around inorganic nanoparticles evolve during their passage through the gastrointestinal tract.
Our final goal is also to develop oral drug delivery systems that enable the local treatment of IBD. Here, we are exploring various indigenous and exogenous triggers that can be used to locally release drugs in the gastrointestinal tract. We specifically focus on biological drugs that are used in the treatment of moderate to severe cases of IBD and where today there is a lack of patient compliant treatments specifically tailored for pediatric patients. For this, we have developed drug formulations that can be 3D printed into solid oral dosage forms. Here, 3D printing enables the personalization of the dose for pediatric patients.
The overall objective of this project is to develop a novel diagnostic and therapeutic platform to treat inflammatory bowel disease (IBD) in children. We are producing magnetic nanomaterials by flame manufacturing, a highly scalable and reproducible process. A key achievement so far, has been the employment of pharmaceutical quality-by-design principles during nanomanufacturing, to ensure rapid translation of the nanomaterials to the clinical settings and minimizing the risk of discontinued clinical trials due to poor batch reproducibility. The systematic approach has also allowed us to identify nanoparticles with optimal performance for e.g. magnetic hyperthermia. We are also tailoring nanoparticles with maximum performance as T1 and T2 contrast agents in magnetic resonance imaging (MRI), a well-established clinical imaging technique.
The main hypothesis of our project, is that it is possible to achieve non-invasive imaging, diagnosis and treatment of IBD by using functional, magnetic nanomaterials targeting biomarkers present in the inflamed intestine. We analyze proteomics data with a unique focus on pediatric IBD to support the development of a targeted, nanoengineered theranostic platform. We are in the unique position to compare biomarkers found in experimental disease models with human patient biopsies. This will further support a systematic scaling of our nanoengineered platform going from relevant in vitro to in vivo systems. Another key achievement of our project so far, has been the development of a microfluidic device that allows us to study the fate of orally administered nanomedicines in terms of their potential non-specific interactions with proteins and enzymes in the gastrointestinal tract. This is key to guide the design of nanoparticles that can be orally administered to IBD patients in order to diagnose the disease and also guide drug delivery systems to the inflamed site in the intestine. Nanoparticle-based contrast agents for MRI have so far mainly been explored for intravenously administered formulations, despite the oral route being the most patient convenient way of administration. The use of orally administered, biocompatible SPION contrast agents will enable patients to evade the current invasive diagnostic methods and allow physicians to detect, diagnose and determine the extent of diseases through MRI.
Finally, we have also initiated our work to develop personalized treatment options for pediatric IBD with a special focus on oral delivery of biological drugs. In future, our platform will enable highly localized oral drug delivery that can increase efficacy of biological drugs for local treatment in the gastrointestinal tract, thereby reducing costs and adverse side effects associated with systemic administration. Additive manufacturing will enable dose level adjustments for children and optimized treatment based on the diagnostic outcome. We are now in the position to 3D print solid oral dosage forms that contain complex lipid-based drug formulations. We plan to incorporate biological drugs into these lipid-based formulations, and are currently enhancing our mechanistic understanding of the digestibility of such formulations. At the end of this project, our approach will result in an integrated platform for simplified diagnosis and monitoring of IBD and enable an efficient oral administration of biological drugs.
The main hypothesis of our project, is that it is possible to achieve non-invasive imaging, diagnosis and treatment of IBD by using functional, magnetic nanomaterials targeting biomarkers present in the inflamed intestine. We analyze proteomics data with a unique focus on pediatric IBD to support the development of a targeted, nanoengineered theranostic platform. We are in the unique position to compare biomarkers found in experimental disease models with human patient biopsies. This will further support a systematic scaling of our nanoengineered platform going from relevant in vitro to in vivo systems. Another key achievement of our project so far, has been the development of a microfluidic device that allows us to study the fate of orally administered nanomedicines in terms of their potential non-specific interactions with proteins and enzymes in the gastrointestinal tract. This is key to guide the design of nanoparticles that can be orally administered to IBD patients in order to diagnose the disease and also guide drug delivery systems to the inflamed site in the intestine. Nanoparticle-based contrast agents for MRI have so far mainly been explored for intravenously administered formulations, despite the oral route being the most patient convenient way of administration. The use of orally administered, biocompatible SPION contrast agents will enable patients to evade the current invasive diagnostic methods and allow physicians to detect, diagnose and determine the extent of diseases through MRI.
Finally, we have also initiated our work to develop personalized treatment options for pediatric IBD with a special focus on oral delivery of biological drugs. In future, our platform will enable highly localized oral drug delivery that can increase efficacy of biological drugs for local treatment in the gastrointestinal tract, thereby reducing costs and adverse side effects associated with systemic administration. Additive manufacturing will enable dose level adjustments for children and optimized treatment based on the diagnostic outcome. We are now in the position to 3D print solid oral dosage forms that contain complex lipid-based drug formulations. We plan to incorporate biological drugs into these lipid-based formulations, and are currently enhancing our mechanistic understanding of the digestibility of such formulations. At the end of this project, our approach will result in an integrated platform for simplified diagnosis and monitoring of IBD and enable an efficient oral administration of biological drugs.