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Development of lipid-polymer nanoparticles for administration of oligonucleotides for gene expression inhibition.

Alice Giuffrida

Development of lipid-polymer nanoparticles for administration of oligonucleotides for gene expression inhibition.

Rel. Gianluca Ciardelli, Clara Mattu. Politecnico di Torino, Corso di laurea magistrale in Ingegneria Biomedica, 2023

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Uterine leiomyoma (UL), also called myoma, is a benign tumor that develops in the smooth muscle of the uterus. It is one of the most common pathologies in women and has been estimated to affect approximately 70% of the premenopausal population. The 30% of women affected by this neoplasm show obvious symptoms and resort to invasive gynecological treatments. The most common symptoms are dysmenorrhea, abnormal bleeding, infertility, recurrent miscarriages, and pelvic pain. Leiomyomas are monoclonal and the synchronous appearance of multiple tumors is common. There are hormonal medical treatments, but to date the most adopted solutions remain surgical ones such as hysterectomy, myomectomy and endometrial ablation which involve irreversible consequences for the patients, including the risk of preterm birth, cesarean section, or infertility(1). The formation of dysfunctional extracellular matrix and the transformation of the myometrium into myoma have been identified as mechanisms underlying this pathology. Myoma is characterized by specific mutations. One of these is that of mediator complex subunit 12 (MED12), with a reported frequency in the range of 50-85%, it is the most frequently mutated gene in uterine leiomyomas. Furthermore, leiomyoma size is inversely correlated with the presence of MED12 mutations(2). The aim of this work is the development of lipid-polymer hybrid nanoparticles (LPNP), with a polymer core and a lipid shell, to be injected locally in patients’ UL. The nanoparticles are apt to internalize a nucleotide sequence, specifically a GapmeR. The nanoparticles in question are developed using two distinct methods, in comparison, a modified single-step nanoprecipitation and microfluidics. Since nanoprecipitation has limitations, such as reproducibility batch to batch, microfluidics has been used to overcome these disadvantages. Different formulations have been investigated with the aim of making a LPNP as biomimetic and simple as possible, trying to limit the use of PEGylated components because there is mounting evidence that PEG causes immunogenic responses (3). The prediction is that, once in situ, the nanoparticles will implement the silencing of the MED12 gene and induce the apoptosis of UL tumor cells. For nanoparticles to be assimilated by cells, it is important that they have specific physicochemical characteristics like average size, zetapotential and surface components. When a stable formulation was obtained, by nanoprecipitation, and with acceptable characteristics according to the design guidelines, such as average size<200 nm, PdI<0.3, and distinctly positive zetapotential; then the parameters to implement the same formulation by microfluidics were sought. Nanoparticles produced by microfluidics, in comparison with those produced by nanoprecipitation, showed in some batches a decrease in average size, but higher polydispersity and positive zetapotential.

Relators: Gianluca Ciardelli, Clara Mattu
Academic year: 2022/23
Publication type: Electronic
Number of Pages: 53
Corso di laurea: Corso di laurea magistrale in Ingegneria Biomedica
Classe di laurea: New organization > Master science > LM-21 - BIOMEDICAL ENGINEERING
Aziende collaboratrici: UNIVERSIDAD DE LA LAGUNA
URI: http://webthesis.biblio.polito.it/id/eprint/27887
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