Final Report Summary - NANOTRAC (Tracing the Intracellular Fate of Anticancer Nanomedicines)
Background
There is enormous enthusiasm for a rapid transfer of novel nanomedicines from the bench to the clinic. However, the cellular and subcellular targeting of these medicines has not yet been adequately characterised. This poor understanding of nanomedicine interactions at the cellular level then results in major setbacks when promising nanomedicine lead compounds fail in actual clinical testing. Nanotechnology, in general, is fraught with unfounded fears, but the lack of rigorous testing with respect to cellular uptake and intracellular trafficking is a justified concern.
Project Objectives
Therefore the goal of this proposal was to develop two complementary approaches that showcased the manufacturing of functionalised biopolymer-based nanoparticles and their subsequent biological evaluation in relation to cellular and subcellular trafficking as well as overall biological performance.
Scientific progress
We successfully generated silk nanoparticles of uniform size and charge that were readily loaded with anticancer agents. Furthermore, these silk-based nanomedicines were subjected to surface grafting with polyethylene glycol (PEG); PEGylation is important to design “stealth” nanoparticles to allow their further evolution. We have now tested the potential of these PEGylated silk nanoparticles to serve as an anticancer drug delivery system. We confirmed the pH-dependent drug release using model buffer systems and single cell microscopy studies, which proofed the ability of drug-loaded silk nanoparticles to serve as a lysosomotropic anticancer nanomedicines. We also examined the impact of these silk nanoparticles on cellular metabolomics and (human) haematocompatibility. In parallel studies we assessed the impact of hypoxia, a key factor of the tumour microenvironment, as well as tumour heterogeneity on nanomedicine uptake. Lastly, we have isolated lysosomes by gradient centrifugation and assessed the biodegradation of silk nanoparticles. Overall, NanoTrac has successfully completed all project aims and milestones.
Career Development and Integration
I have taken up a permanent position as a lecturer in Cellular Pharmaceutics at the University of Strathclyde. The award of the CIG has been critical in underpinning my development as a recognized expert in cellular pharmaceutics. Specifically, this seed funding has allowed me to build an independent research group and to support my MRes and PhD candidates. The first cohort of postgraduate candidates has successfully completed their studies. Furthermore, the CIG enabled me to consolidate and expand my collaborative circle through participation at specialized meetings and workshops aligned to the mission of my laboratory. Furthermore, the CIG award has acted as a springboard that has attracted additional funding to further consolidate my research group. Together, these developments have helped the integration of my research program at the University of Strathclyde and in the United Kingdom and Europe as a whole. Please see links for an overview:
http://www.seiblab.com
https://issuu.com/euresearcher/docs/eur10_digital_mag/38
There is enormous enthusiasm for a rapid transfer of novel nanomedicines from the bench to the clinic. However, the cellular and subcellular targeting of these medicines has not yet been adequately characterised. This poor understanding of nanomedicine interactions at the cellular level then results in major setbacks when promising nanomedicine lead compounds fail in actual clinical testing. Nanotechnology, in general, is fraught with unfounded fears, but the lack of rigorous testing with respect to cellular uptake and intracellular trafficking is a justified concern.
Project Objectives
Therefore the goal of this proposal was to develop two complementary approaches that showcased the manufacturing of functionalised biopolymer-based nanoparticles and their subsequent biological evaluation in relation to cellular and subcellular trafficking as well as overall biological performance.
Scientific progress
We successfully generated silk nanoparticles of uniform size and charge that were readily loaded with anticancer agents. Furthermore, these silk-based nanomedicines were subjected to surface grafting with polyethylene glycol (PEG); PEGylation is important to design “stealth” nanoparticles to allow their further evolution. We have now tested the potential of these PEGylated silk nanoparticles to serve as an anticancer drug delivery system. We confirmed the pH-dependent drug release using model buffer systems and single cell microscopy studies, which proofed the ability of drug-loaded silk nanoparticles to serve as a lysosomotropic anticancer nanomedicines. We also examined the impact of these silk nanoparticles on cellular metabolomics and (human) haematocompatibility. In parallel studies we assessed the impact of hypoxia, a key factor of the tumour microenvironment, as well as tumour heterogeneity on nanomedicine uptake. Lastly, we have isolated lysosomes by gradient centrifugation and assessed the biodegradation of silk nanoparticles. Overall, NanoTrac has successfully completed all project aims and milestones.
Career Development and Integration
I have taken up a permanent position as a lecturer in Cellular Pharmaceutics at the University of Strathclyde. The award of the CIG has been critical in underpinning my development as a recognized expert in cellular pharmaceutics. Specifically, this seed funding has allowed me to build an independent research group and to support my MRes and PhD candidates. The first cohort of postgraduate candidates has successfully completed their studies. Furthermore, the CIG enabled me to consolidate and expand my collaborative circle through participation at specialized meetings and workshops aligned to the mission of my laboratory. Furthermore, the CIG award has acted as a springboard that has attracted additional funding to further consolidate my research group. Together, these developments have helped the integration of my research program at the University of Strathclyde and in the United Kingdom and Europe as a whole. Please see links for an overview:
http://www.seiblab.com
https://issuu.com/euresearcher/docs/eur10_digital_mag/38