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Multifunctional, chitosan-based nano therapeutics: design and application for two- and three-dimensional cell culture systems

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dc.contributor.advisor Meng, Yizhi en_US
dc.contributor.author Suarato, Giulia en_US
dc.contributor.other Department of Materials Science and Engineering en_US
dc.date.accessioned 2017-09-20T16:49:51Z
dc.date.available 2017-09-20T16:49:51Z
dc.date.issued 2016-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76258 en_US
dc.description 270 pg. en_US
dc.description.abstract There is a constant demand for sensitive and effective anti-cancer drug delivery systems, capable of detecting early-stage pathological conditions and increasing patient survival. Recently, chitosan-based drug delivery nanocomplexes have shown to smartly respond to the distinctive features of the tumor microenvironment, a complex network of extracellular molecules, stromal and endothelial cells, which supports the tumor formation and its metastatic invasion. Due to biocompatibility, easy chemical tailorability, and pH-responsiveness, chitosan has emerged as a promising candidate for the formulation of supramolecular multifunctional materials. The present study focuses on the design, fabrication and characterization of fluorescently labelled, hydrophobically modified glycol chitosan nano-micelles (HGC NPs), suitably tailored for the delivery of anti-neoplastic compounds to various tumor models. Doxorubicin-loaded HGC NPs have been delivered to a bone cancer model, both in monolayer and in 3D spheroid configuration, to assess for differences in the delivery profiles and in the therapeutic efficacy. Compared to the free drug, nanocomplexes showed rapid uptake and a more homogeneous distribution in 3D spheroids, a powerful cellular tool which recapitulates some of the in vivo tumor microenvironment features. In a second part of this thesis work, with the purpose of designing an active targeting tumor-homing nano-therapeutic system, HGC NPs have been linked, via avidin-biotin interaction, with a IVS4 peptide, a small molecule with inhibitory activity on MMP-14–mediated functions. An extensive study conducted on triple negative breast cancer cells in monolayer revealed the MMP-14–IVS4-HGC association at the cancer cell membrane, the preferential uptake, and the consequent impairment of protease-associated migratory ability. As an additional application of our engineered construct, HGC micelles have been decorated with a liver kinase B1 (LKB1), a critical kinase involved in neuronal cell polarization, with the aim of regulating axon development. Our preliminary data indicated that, when treated with HGC-LKB1 NPs, primary ray embryo hippocampal neurons in vitro presented a multiple axon phenotype, validating the potential use of our multifunctional system as local protein delivery agent. In addition, we successfully performed for the first time in utero electroporation delivery of the chitosan nano-micelles, demonstrating the in vivo uptake potential of our system. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Materials Science -- Biomedical engineering -- Nanotechnology en_US
dc.subject.other 3D cultures, Cancer microenvironment, Nanoparticles en_US
dc.title Multifunctional, chitosan-based nano therapeutics: design and application for two- and three-dimensional cell culture systems en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Meng, Yizhi en_US
dc.contributor.committeemember Gersappe, Dilip en_US
dc.contributor.committeemember Cotlet, Mircea en_US
dc.contributor.committeemember Yin, Wei en_US
dc.contributor.committeemember Shelly, Maya . en_US

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