Magneto-Chemotherapy: Modeling of Radiofrequency Magnetic Field-Induced Delivery of an Anticancer Drug by Polymer Nano-Vesicles and Monitoring by MRI of a Glioblastoma Model – MagnetoChemoBlast

Among the different classes of polymeric nanomedicines, block copolymer vesicle i.e. polymersome is an attractive morphology for drug delivery applications due to its high colloidal stability and loading capacity of both hydrophilic and hydrophobic species. After drug loading, a vesicle disruption inducing drug release can be triggered either in response to a biologically internal (pH, enzyme, redox potential…) or external stimulus (temperature, light, magnetic field…). Even if a great variety of polymeric drug delivery nanocarriers showed efficient entrapment and controlled release of drugs in vitro, evaluating the carrier biodistribution after injection is more complex. To address this issue, labeling probes are incorporated in the polymer nanovectors together with drugs. Such dual-loaded polymeric nanocarriers for tumor imaging and treatment open the field of “theranostics” combining diagnostic and therapy functions in a “all-in-one” nanoparticle.[1]
Among the different probes developed for bioimaging, Ultra-small Superparamagnetic Iron Oxide (USPIO) particles are magnetic mono-domains of iron oxide around 10 nm in size[2] commonly used as contrast agents in MRI,[3] a routinely used diagnostic method for three-dimensional non-invasive scans of the human body. In addition to MRI contrast enhancement, USPIOs can also destroy cancer cells by localized heating with radio-frequency magnetic fields, due to thermal dissipation by the relaxation processes of the magnetic moments. Hyperthermia (i.e. heat treating) has been recognized promising for cancer therapy, particularly in synergy with chemo- or radio-therapy.[4] But unlike conventional hyperthermia treatments aimed at destroying tumor cells by heat shock,[5] our strategy is built on drug delivery triggered by the application of a RF magnetic field through the local increase of temperature in the vicinity of the polymer membrane impacting strongly its permeability. This strategy named “magneto-chemotherapy” arisen just one decade ago for lipid vectors has attracted an enormous attention for polymeric drug carriers since two years. The primary aim of this project is to fill the lack of fundamental understanding of magneto-chemotherapy, especially the mechanism of drug-delivery into the cells without need of global warming of the tumor. It will utilize two levels of modeling: one physical based on microfluidics, high resolution IR thermography and numerical simulations; one biological with both in vitro (cytotoxicity and uptake pathways ito cells) and in vivo (subcutaneous tumor treatment), both levels being addressed with the same physicochemical systems, to get full insight of the mechanism. The biological model will consist in rat brain glioma C6 cells injected subcutaneously into mice. Of course this choice is a simplification compared to an orthotopic brain tumor model. But it is more realistic than a deeper tumor if we keep in mind that deciphering the mechanisms of drug delivery from magnetic field sensitive carriers in a biological tissue is already a challenge. In clinical cases, the access of nano-carriers to brain tumors is greatly facilitated by disruption of the blood-brain barrier characteristic of high grade glioblastoma. In our model experiments, tumor homing will be insured thank to magnetic guiding by a magnetic field gradient applied near the tumor, in order to reach the minimum needed concentration of drug carriers that will be determined beforehand. All along the project, the physical modeling and the biological studies will be conducted in parallel. For instance the tracking magnetic of magnetic carriers by MRI will be compared to concentration profiles in micro-channels of appropriate characteristics to model the leaky blood capillary in the tumor vasculature. A special attention will be paid on quantitative analysis of the temperature and drug concentration profiles in the vicinity of the thermo-sensitive vesicles under an applied RF magnetic field.