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Molecular and coarse grained modelling to characterize and optimize dendrimer-based nanocarriers for siRNA delivery

Filip Stojceski

Molecular and coarse grained modelling to characterize and optimize dendrimer-based nanocarriers for siRNA delivery.

Rel. Marco Agostino Deriu, Umberto Morbiducci. Politecnico di Torino, Corso di laurea magistrale in Ingegneria Biomedica, 2019

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Abstract:

Rheumatoid arthritis (RA) is a chronic autoimmune inflammation disorder, which mainly affects the articulations, leading them to progressive destruction. RA bear upon 0.5-1% of people in the developed world according to statistics drafted in 2015. The onset of symptoms often takes several weeks, leading to the appearance of warmness, redness, swelling and pain in affected juncture. Nowadays, the therapy to treat RA consists mainly in relieving the symptoms and slowing the evolution of the disease using analgesic, anti-inflammatory and disease-modifying anti-rheumatic drugs (DMARDs) drugs. Nevertheless, there is still no therapy that completely blocks the progression of the disease. A new treatment currently in phase of in vivo testing, achieve the goal of halting the development of RA, blocking the destruction of articulations. This is the case of gene silencing therapy mediated by short interfering RNA (siRNA), which hinter the normal production of cytokines in leukocytes. The concept is to obstacle the production of cytokines that cause the inflammatory state which will suppress the auto-immune response. Once the inflammation is arrested, the cartilage reabsorption is also interrupted. One of the mainly issues is carry siRNAs inside the cells keeping their structure intact, avoiding the extra-cellular environment degradation. Therefor is necessary to develop a biocompatible, reliable and efficient drug delivery system. Dendrimers are polymeric hyperbranched nano-carriers that has demonstrate a greater capability to transport numerous different type of cargos inside cells, even siRNAs. In several in vitro and in vivo experiments, it has been shown that dendrimers can bind siRNAs and release them in the target areas. The purpose of this master thesis work is to explore the supramolecular characteristic of dendrimers-siRNA complexation. Through the use of coarse grained (CG) molecular dynamics (MD) we elucidate some aggregation mechanisms between multiple dendrimers and siRNAs, still unclear. Two types of engineered dendrimers were considered: Pyrrolidinium dendrimers (DP) and Morpholinium dendrimers (DM). Firstly was investigated the self-assembly behavior of DM and DP dendrimers, highlighting that DP has a greater capability to interact with each other, forming precipitate in solution. Afterwards, DM and DP stoichiometry values in binding siRNA were evaluated, shed light on the more efficient ability of DP to bind 2 siRNAs, while DM can mostly bind 1 siRNA. Lastly, dendrimers-siRNAs binding competition behavior was assessed, verifying if the stoichiometric values are influenced by this mechanism. Analyzing supramolecular aggregation proprieties by MD, makes possible establish the guidelines for developing or modifying the actual dendrimers chemical structure, with aim to realize even more efficient and reliable dendrimers nano-carriers. Moreover, MD simulations can try to determinate molecular phenomena in aggregation of dendrimers-siRNA that may be otherwise unexplained.

Relators: Marco Agostino Deriu, Umberto Morbiducci
Academic year: 2018/19
Publication type: Electronic
Number of Pages: 90
Subjects:
Corso di laurea: Corso di laurea magistrale in Ingegneria Biomedica
Classe di laurea: New organization > Master science > LM-21 - BIOMEDICAL ENGINEERING
Aziende collaboratrici: IDSIA
URI: http://webthesis.biblio.polito.it/id/eprint/10691
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