Design of a novel polymer based nanocarrier for the development of a glioblastoma vaccine

Details

Supervisors

Dupont-Gillain, Christine C. ; Préat, Véronique

Faculty

Faculté des bioingénieurs

Degree label

Master [120] : bioingénieur en chimie et bioindustries, à finalité spécialisée

Abstract

Glioblastoma (GBM) is one of the most aggressive tumors occurring in the central nervous system and is an unmet clinical need. Around 200,000 people are dying from GBM each year. The median survival of glioblastoma patients is below 2 years and only 5% of patients are surviving up to 5 years after the diagnosis. The current standard of care is consisting of surgical resection of the tumor (if feasible), local radiotherapy and systemic chemotherapy (Temozolomide) often combined with corticosteroids. The research of new treatment against GBM is being limited mostly due to intra- and intertumor heterogeneity, highly proliferative nature, the presence of a physical barrier called the Blood-Brain Barrier, the chemotherapy resistance developed by the GBM, the low infiltration of immune cells and the Tumor Immunosuppressive Microenvironment. To tackle those limitations, it is thought that a vaccine could be effective to treat GBM. The first hypothesis about this vaccine consists of a dual-component polymeric platform that should be able to intrinsically activate the innate immune system. Using polymeric NPs as a delivery system of antigens has various advantages. Parameters such as molecular weight, components ratio and antigen loading can be optimized to achieve better efficacy of the treatment. The vaccine will be in a form of NPs constituted by HA and PLL conjugates due to their specific inherent properties that could be useful. The second hypothesis is to use antigens linked to those NPs to trigger adaptive immunity. Those two assumptions are needed for the vaccine to target several arms of global GBM immunity. Microfluidic technology will be used for the formulation to meet some important criteria such as size and reproducibility. In this project, some HA and PLL conjugates were synthesized to form a linking chemistry between both polymers and achieve better size stability in physiological conditions and after freeze-drying. Some antigen was also linked to nanoparticles. Different types of nanoparticles made of HA and PLL conjugates were formed and characterized. Two different interesting mass ratios of HA : PLL were investigated. The characterization by XPS, NTA, DLS and Cryo-TEM was performed and the stability in different mediums and over time was also assessed. Moreover, the reproducibility and the ability to scale up the formulation of the nanoparticles by microfluidic were investigated. An in-vitro cell viability assay was also performed to check the cytotoxicity properties of the formulations. Finally, in-vivo experiments have been made. The goals for those experiments were to highlight the innate immunity activation in the injection site, characterize the uptake of nanoparticles and the activation of immune cells in the spleen and the lymph nodes.