진학프로석·박사 채용 접수 플랫폼

This 3-years PhD project aims at developing a family of modular nanogels able to cross the blood brain barrier and deliver a taxi cargo to cancer cells to fight medulloblastoma.

The project relies on the collaboration between institute of Biomolecule Max Mousseron (university of Montpellier; France) and Bovenschen lab (University medical center, university of Utrecht)

Medulloblastoma is the most common paediatric brain cancer, typically diagnosed around age 5. Current treatments include surgery, radiation, and chemotherapy, but these methods often prove ineffective, with high mortality rates or causing severe long-term side effects in survivors. Unfortunately, classical immunotherapies that block tumour immune checkpoints – proteins like PDL1 and B7-H3, are not efficient on such tumours with limited immune infiltrate and a multitude mechanism of resistance. Among the possible ways to trigger cell death, granzymes are an interesting choice to bypass the tumour’s immune evasion tactics. Granzymes are a family of five serine proteases released by immune cells along with cell penetrating peptides to cleave intracellular targets triggering apoptosis. Unfortunately, immune cells cannot reach efficiently this type of ‘cold immune’ tumors.

Adding to the complexity, a major challenge arises in effectively transporting therapeutics through the blood-brain barrier. Thus, there is a need for innovative therapies able to tackle all these challenges.

Nanogels are nanosized hydrogels networks which may encapsulate therapeutics to be delivered to specific tissues or cells thanks to surface modifications. Moreover, they could cross the blood-brain barrier through several mechanisms including transcytosis.

Herein, we propose to develop a novel class of personalised nanomedicines to target medulloblastoma relying on a modular approach using silylated building blocks assembled though biorthogonal sol-gel chemistry. Nanogels with a size of about 100 nm will be prepared by water-in-oil emulsion from various biopolymers compositions (e.g. hyaluronic acid, gelatine and dextrin). (i) Their degradability and swelling will be tuned by introducing reduction or enzyme-sensitive linkers and by controlling the degree of silylation within biopolymers. (ii) Silylated charged amino acids (e.g. Arg, Ne-trimethyl lysine) will be introduced to control the isoelectric point of the network, favouring noncovalent interaction with their cargo. (iii) Silylated His residues or His-rich peptides could be used to trigger endosomal escape of the nanogels by proton sponge effect. (iv) Toxic payload will be encapsulated after or during nanogel sol-gel synthesis. As a first instance, a modulable cocktail of different granzymes will be loaded in the nanogels. Noteworthy and depending on the release profile, granzymes will interact in a non-covalent way with the hydrogel network or will be covalent linked to it through reduction-sensitive linkers. (v) The surface of the nanogels will be conjugated by two types of molecules: (i) vectorisation elements like apopolipoprotein E (ApoE) and peptides derived from ApoE for active BBB crossing, and (ii) targeting elements such as peptides ligands of cancer overexpressed receptors or anti B7H3 nanobody for a synergistic effect of targeting and immune checkpoint inhibition.

The PhD student will carry out the design and the synthesis of all the building blocks and the preparation of nanogels. Silylated biomolecules will be characterized by LC/MS, NMR (1H 13C). He or she will perform the synthesis of hydrogel by sol-gel process and study the rheology, the mechanical properties and the three dimensional network structure at different scales. He/She will set up bioconjugation strategies to immobilize molecules inside or at the surface of the nanogel eventually through a sensitive linker to ensure controlled release. He/She will study the biocompatibility, degradability of the materials as well as the kinetics of release of the different cargoes. She/he will optimize the nanogel preparation in close collaboration with Niels Boveschen’s lab in Utrecht university and will participate in the bioassays for in vitro BBB crossing and cancer cell targeting.