Abstract
Nanomaterials are increasingly valued tools in drug delivery research as they offer enhanced stability, controlled release and more effective drug encapsulation. Though yet to be introduced in clinical trial, mesoporous silica nanoparticles are promising delivery systems, due to their high chemical and mechanical stability while remaining biodegradable. This work provides proof of concept for particle based vaccines as cost-effective alternatives for dendritic cell immunotherapy. Synthesis and surface chemistry of the nanoparticles are optimized for protein conjugation and nanoparticles are characterized for their physicochemical properties and biodegradation. Ovalbumin is used as a model protein to load nanoparticles to produce a nanovaccine. The vaccine is tested in vitro on dendritic cultures to verify particle and vaccine uptake, toxicity, maturation effects and explicitly ovalbumin cross-presentation on MHC class I molecules. The optimized synthesis protocol renders reproducible mesoporous silica nanoparticles, resistant against agglomeration, within the required size range and have carboxylic surface functionalization necessary for protein conjugation. They are biodegradable over a time span of 1 week. This period is adjustable by changing synthesis parameters. UV sterilization of the particles does not induce quality loss, nor does it have toxic effects on cells. Treatment with mesoporous silica nanoparticles increases expression of MHC and costimulatory molecules of dendritic cells, indicating an adjuvant effect of nanoparticles on the adaptive immune system. Nanovaccine uptake and cross-presentation of ovalbumin are observed and the latter is increased when delivered by nanoparticles as compared to control conditions. This confirms the large potential of mesoporous silica nanoparticle based vaccines to replace dendritic-based active specific immunotherapy, offering a more standardized production process and higher efficacy.
Highlights
Cancer is a leading cause of morbidity and mortality with ∼18 million new cases and 9.6 million cancer-related deaths worldwide in 2018
The latter band is slightly visible in the FTIR spectrum of tert-butyl alcohol (TBA) washed particles (MSNP-COOH, red curve in Figure 1), but not present for ethanol washed particles (MSNP-COOH**, orange)
mesoporous silica nanoparticles (MSNPs) caused moderate maturation, which is further increased by LPS. These results indicated the adjuvant effect of MSNPs on dendritic cells (DCs). which was a first suggestion of DCs being able to communicate the protein information delivered by NPs to the T-cells of the immune system
Summary
Cancer is a leading cause of morbidity and mortality with ∼18 million new cases and 9.6 million cancer-related deaths worldwide in 2018. The role of the immune system in the development and maintenance of tumors was unraveled (Van Gool, 2015) On this basis, cancer immunotherapy emerged as an innovative treatment for immunogenic tumors. Silica is already an additive in medical formulations These particles offer biocompatibility and biodegradability, relatively high chemical and mechanical stability, a variety of surface functionalization due to abundant silanol groups and a simple synthesis procedure which can be upscaled to industrial applications (Seré et al, 2018). The effect of the washing alcohol on the functional groups, the optimal amount of carboxylation and the optimal silica precursor were studied by complete characterization and biodegradation From these studies, the optimal synthesis procedure was determined significantly lowering the cost of the vaccine production. Besides being a good cost-effective alternative, another strong feature of this NP-based vaccine is the ability to load the particles with immunomodulatory agents to amplify the immune stimulating effects and increase the efficacy of the vaccine
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