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Author
Corvo Alguacil, Laura
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Abstract
The use of nanostructures as drug delivery systems has gained interest in recent years, which has led to the search for strategies that can prevent nanoparticles from being abducted by the host's immune system before reaching their target. One of the most important factors involved in the immune system's recognition of nanoparticles is the adhesion of proteins around them, creating what is known as a protein crown. So far the most widely used strategy to avoid it is coating with polyethylene glycol, however, its recurrent use in commercial drugs has caused some patients to show autoimmune reactions. For this reason, other strategies are being investigated, among which the use of zwitterionic polymers stands out, materials capable of forming around them a strong hydration layer that can avoid direct contact with the biomolecules around them, such as the proteins involved. in the formation of the protein crown.
In this master's thesis, a combination of computational simulations and experimental techniques is used to characterize the nanometric encapsulation systems for drugs generated from zwitterionic amphipathic block copolymers of sulfobethaine and carboxylicbetaine and their interaction with bovine serum albumin (BSA). and, in this way, confirm the inherent property of avoiding the formation of the protein crown by the zwitterionic materials. Likewise, to corroborate that this property is solely due to its composition, the same study is also carried out using a control nanoparticle composed of a cationic diblock copolymer. The in silico characterization has been carried out by building a coarse-grained structural model that has been able to describe the physicochemical characteristics of the micellar structure of these nanoparticles, as well as representing the interaction between micelles and BSA.
The results obtained from the simulations have been complemented by an experimental study. To do this, the copolymers have been synthesized in proportions equivalent to those simulated to prepare the corresponding nanostructures that have then been characterized through cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) techniques. and nanoparticle tracking analysis (NTA), showing that their structure, size and stability correspond to what was observed in the simulations. Finally, the nanoparticle-BSA interaction has also been evaluated using the differential scanning calorimetry (DSC) technique, confirming the ability of zwitterionic nanoparticles to avoid the interaction with BSA that had been observed in the molecular dynamics simulations carried out.
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