Giant Unilamellar Vesicles (GUVs)
Treatment with of one or more cytotoxic small molecules (cisplatin, paclitaxel, vincristine, doxorubicin) is widely used to kill highly proliferative cancer cells. However these drugs also kill other proliferative cells in bone marrow, the gastrointestinal tract and hair follicles, leading to the common side effects such as compromised immune system. Nanomaterials such as liposomes encapsulate toxic drugs during transport and harness their cytotoxic power at the target tumor site. The few FDA-approved nanomaterial-based drug therapy platforms in existence rely on liposome-encapsulated or alubumin-bound drug conjugates. An example is Doxil®, a pegylated phospholipid based liposome that entraps doxorubicin. Liposome entrapment of doxorubicin reduces the observed cardiotoxicity. and results in enhanced tumour accumulations in brain and breast cancers. The ability of liposomes to extravasate through leaky blood vessels in tumours (enhanced permeability and retention (EPR) effect) coupled with their long circulation time are key factors promoting the accumulation of liposome-encapsulated drug into the tumor vasculature. Surprisingly, even in commercial FDA approved platform, the mechanism of drug release is poorly understood. Consequently, there is a clear need for improving our understanding of the physiological imposed design constraint (vasculature porosity, pressure gradients, tumor redox and pH state, enzyme availability) and the structure-property relations of the engineered liposomes.
We propose to design smart drug delivery liposomes based on the use of redox active phospholipids. Our goal is to develop redox triggered liposomes, suitable for applications in tumours with altered redox states i.e. multidrug resistant. Having obtained proof of principle in giant unilamellar vesicles (1-50 µm diameter) of the ability of redox liposomes to disaggregate and release their contents upon oxidation of surface-exposed ferrocenyl units, our primary areas of interest concerning redox liposomes are (i) translating the GUV system into a more clinically relevant SUV/LUV-based analog for the evaluation of its properties in vivo (in collaboration with researchers at the McGill-Montreal Jewish General Hospital) and (ii) evaluating alternative redox-active substrates for incorporation into liposomes with the aim of improving sustainability and scalability in the process.
We propose to design smart drug delivery liposomes based on the use of redox active phospholipids. Our goal is to develop redox triggered liposomes, suitable for applications in tumours with altered redox states i.e. multidrug resistant. Having obtained proof of principle in giant unilamellar vesicles (1-50 µm diameter) of the ability of redox liposomes to disaggregate and release their contents upon oxidation of surface-exposed ferrocenyl units, our primary areas of interest concerning redox liposomes are (i) translating the GUV system into a more clinically relevant SUV/LUV-based analog for the evaluation of its properties in vivo (in collaboration with researchers at the McGill-Montreal Jewish General Hospital) and (ii) evaluating alternative redox-active substrates for incorporation into liposomes with the aim of improving sustainability and scalability in the process.
Recent group publications
1. Noyhouzer, T.; L'Homme, C.; Beaulieu, I.; Mazurkiewicz, S.; Kuss, S.; Kraatz, H.; Canesi, S.; Mauzeroll, J. Ferrocene-modified Phospholipid: an Innovative Precursor for Redox- Triggered Drug Delivery Vesicles Selective to Cancer Cells. Langmuir 2016, 32(17), 4169-4178.
1. Noyhouzer, T.; L'Homme, C.; Beaulieu, I.; Mazurkiewicz, S.; Kuss, S.; Kraatz, H.; Canesi, S.; Mauzeroll, J. Ferrocene-modified Phospholipid: an Innovative Precursor for Redox- Triggered Drug Delivery Vesicles Selective to Cancer Cells. Langmuir 2016, 32(17), 4169-4178.