Glyconanoparticle-based Synthetic Carbohydrate Anticancer Vaccines

Many cancers are associated with the over-expression of sugar molecules on the surface of cancer cells, which provides scientists with the possibility of creating vaccines against these cancers. However, the sugars themselves do not lead to the production of the required antibodies - they require assistance from other molecules (peptides) that will stimulate the immune system. In this work, we will prepare very small (10,000 times less than the diameter of a human hair) gold particles that will carry many copies of i) sugar molecules known to be associated with certain cancers and ii) peptides to stimulate the immune system. This will be achieved by first of all making the correct sugar molecules, modifiying them to make them able to be converted into polymers (long chain molecules that have many copies of the sugar attached to the chain), then making the required polymers. The method of making the polymers produces chains with one ?sticky end?, which will allow them to be attached easily to the surface of the gold particles. At the same time, we will attach to the particle surface the correct peptides molecules, producing the particles loaded with the necessary components. We expect that this will result in a simple method of producing materials that act as effective anti-cancer vaccines.

The overexpression of certain carbohydrates on the surface of malignant cells presents an attractive target for the development of anticancer vaccines. However, carbohydrates themselves illicit neither a large immunological response nor one with sufficient B-cell involvement. Molecules possessing both carbohydrates and immunogenic proteins or peptides provide the advantage of a system that might be both T and B-cell active and therefore likely to induce a longer-term immune response ? a response genuinely fitting of the description vaccine. Herein, we suggest a simple strategy towards this end, which employs gold nanoparticles as easily constructed and tuned biocompatible, multicomponent carriers of carbohydrate cancer antigens and immunogenic peptides. The gold nanoparticle is ideal for this purpose as: i) it is easily and flexibly functionalised with thiol-containing molecules; ii) several different types of these molecules can be simultaneously coadsorbed onto the particle surface, providing mixed monolayer-protected particles; iii) simply by tuning adsorption conditions and concentrations, density, composition and activity on the particle may be readily tuned; iv) gold has low toxicity; v) particle sizes are tuneable in the range 2-50 nm; and vi) particle sizes may be exploited to modulate in vivo circulation time. Our target carbohydrate structures will contain a number of antigens that are representative biomarkers present at higher levels on cancerous cells. The protein MUC-1 is displayed at the membrane of epithelial cells. These, so-called core 1, glycans are all found at higher levels in the immunodominant, extracellular domain of MUC-1 on cancerous cells compared to other glycan types. Polymers bearing core 1 glycans will be prepared by a method known as RAFT, which not only gives exquisite control of macromolecular architecture (e.g. molecular weight and molecular weight distribution, composition) but also produces polymers with a terminal thiol that allows easy attachment to gold surfaces. The polymers will be coadsorbed with immunogenic peptides onto gold nanoparticles, producing multifunctional nanoparticles for evaluation as anticancer vaccines. Subsequently, the binding affinities of the glycosylated particles with key target proteins will be evaluated in vitro, and their immunogenic properties will be studied in in vivo trials with animal models (rabbit and goat). The results of the research will initially be protected by patent applications, before being disseminated to the academic and industrial communities, as well as the general public, by means of conference presentations, peer-reviewed publications, press releases and publications in popular science magazines.