Improving targeting drug delivery for clinical nanomedicine
The great benefit of drug delivery with ligand-targeted nanoparticles and the elucidation of their behaviour in vivo, is the significant increase of drug concentrations in the disease tissue and the reduction of unwanted side effects. Current project aims to elucidate in vivo targeting of ligand-targeted nanoparticles at a cellular level.The great benefit of drug delivery with ligand-targeted nanoparticles (NPs) and the elucidation of their behaviour in vivo is the significant increase of drug concentrations in the disease tissue (e.g. tumours), and at the same time the reduction of unwanted side effects. However, the present strategies for targeted drug delivery and real-time monitoring have important limitations. The present project will try to overcome these limitations in two ways: 1. Establish and implement in vivo real-time imaging modalities (e.g. Intravital microscopy, positron emission topography) in order to quantify NP targeting, localization, and biodistribution from in vivo imaging data, assisted by quantitative state-of-the art ex vivo analysis 2. Bring NPs' design from trial and error approaches to a situation where the design is based on scientific knowledge and quantitative observations about NP behaviour in vivo. These two approaches will contribute significantly to successful implementation of targeted drug delivery in a wide variety of diseases, and also include the concept of personalized medicine as the therapy may be based directly on in vivo imaging data originated from an individual patient. To achieve the aim stated above, we have defined three specific research questions, which their answers will compose our main aims: 1. Elucidate in vivo NPs targeting kinetics using real-time intravital microscopy. 2. Understanding with a quantitative approach the interaction of NPs with immune cells, endothelial cells, and tumour cells using a detailed flow cytometry approach. 3. Quantify targeting and organ biodistribution of NPs at tissue level using positron emission topography (PET). So far, a platform of ligand-targeted self-assembled lipid NPs (liposomes, nanoemulsions, micelles) has been designed for the purpose of this experiment. A higher targeting efficiency has been demonstrated when the ligand was covalently conjugated at the NPs' surface both in vitro in cell culture and in vivo using intravital microscopy at several mouse models (ear imaging, dorsal window chamber imaging, tumour imaging). The intravital microscopy models has been demonstrated to be very suitable for the purpose of the study assuming the high temporal and spatial resolution that can be achieved. It is notable that the higher surface density of the ligand contributed to a higher targeting and cellular uptake of the NPs. In addition to the elucidation of the targeting kinetics, a thorough study of the NPs at a cellular level has revealed a lot of completely novel information with respect to NP interactions with immune cells, endothelium, and tumour cells. The experiments conducted during 2017 have brought us very close to submit 2 reserach articles in high impact (impact factor 10-20) peer reviewed journals and the opportunity to participate in 3 international conferences.
For successful application of targeted NPs in future diagnostic and therapeutic settings, it is crucial to understand NP targeting efficiency and dynamics and relate these to NP design on one side and target availability on the other.Although the project has only just started, I have 1. Established synthesis of targeted liposomes and emulsions at NTNU. 2. Been fully trained to do animal experiments. 3. Admitted to the PhD program Medical Technology. 4. Initiated the first in vivo work Although the first clinical trials with targeted nanomedicine are underway, their interaction with biology is highly dynamic and remains poorly understood. In this project we aim to imporve our understanding of this complex in vivo nanoparticle behavior. In vivo targeting efficiency and kinetics will be characterized and quantified at the cellular level using dynamic intravital microscopy and at the whole organ level using dynamic magnetic resonance imaging (MRI). We have performed the first in vivo microscopy experiments with highly interesting results. The combination with MRI is anticipated to provide us with novel and quantitative understanding of in vivo NP targeting, which will be valuable for targeted image guided drug delivery and molecular imaging in general. By incorporating MRI in our effort, we will obtain insights in how NP targeting dynamics affect image contrast in this clinical modality. The main objectives of the project are: • Develop nanoparticles which efficiently target tumor vasculature • Quantify nanoparticle targeting and target levels with clinically relevant imaging modalities To achieve these objectives we have defined three specific aims: 1. Develop targeted lipid-based nanoparticles. 2. Characterize and quantify NP targeting kinetics at the cellular level in vivo using dynamic intravital microscopy. 3. Characterize and quantify NP targeting kinetics at the whole organ level in vivo using dynamic MRI.