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Sinteza, karakterizacija i biološka ispitivanja fulerenol/doksorubicin nanokompozita

Synthesis, characterisation and biological activity investigation of fullerenol/doxorubicin nanocomposite

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Author
Jović, Danica
Mentor
Đorđević, Aleksandar
Committee members
Vaštag, Đenđi
Đorđević, Aleksandar
Vraneš, Milan
Srdić, Vladimir
Knežević, Nikola
Mrđanović, Jasminka
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Abstract
U radu je predstavljena sinteza i karakterizacija  novog fulerenol/doksorubicin nanokompozita, sintetisanog sa ciljem dobijanja potencijalne nove nanoformulacije postojećeg antineoplastika doksorubicina, koja bi pokazala veću biološku aktivnost uz smanjenje neželjenih sporednih efekata koje sam lek izaziva, na prvom mestu kardiotoksičnosti. Nanokompozit fulerenol/doksorbicin je okarakterisan brojnim  metodama prateći dva osnovna eksperimentalna pristupa: molekulsko-spektroskopske metode (XPS, denzitometrija i transportne osobine, NMR, UPLC, Ramanska i UV-spektroskopija, SFM) i metode  nanokarakterizacije (DLS, AFM, TEM), kao i računske simulacije(RDF). Osnovni cilj ispitivanja je bila detekcija postojanja nekovalentnog nanokompozita koji ostvaruju doksorubicin i fulerenolske nanočestice u vodenom rastvoru. Rezultati karakterizacije jasno i nedvosmisleno ukazuju na postojanje nekovalentnih interakcija unutar nanokompozita, što dalje utiče na organizaciju i udruživanje čestica, a što usl...ovljava i drugačiju biološku aktivnost takvog sistema u odnosu na pojedinačne komponente.  Rezultati bioloških ispitivanja na in vitro modelu različitih tumorskih ćelijskih linija pokazuju  značajan antiproliferativni efekat nanokompozita, kao i selektivnost prema tumorskim u odnosu na zdravu ćelijsku liniju. Eksperimenti na in vivo modelu zebrica potvrđuju smanjenje toksičnosti nanokompozita u poređenju sa lekom, primarno kardiotoksičnosti. Računske simulacije, mikroskopski i spektroskopski podaci, kao i rezultati  in vitro i in vivo studija ukazuju na to da nekovalentne interakcije između fulerenola i doksorubicina mogu biti ključni korak u stvaranju sinergističkog sistema za dostavu leka u biološki sistem. Multipotentnost fulerenola kao nanonosača lekova i nespecifičnost strukture doksorubicina kao leka, ukazuje na to da bi fulerenol mogao biti efikasan nanonosač i drugih antineoplastika, što daje prostora za unapređenje antitumorskih osobina lekova posredstvom istovremene administracije leka.

The focus of this thesis was the synthesis and characterization of a novel fullerenol/doxorubicin nanocomposite, with the aim to obtain a potential nanoformulation of antineoplastic drug doxorubicin, which would  express greater biological activity and lower level of adverse effects than the drug itself, in the first place cardiotoxicity. Nanocomposite fullerenol/doxorubicin was characterized by means of numerous methods  following two main experimental approaches: molecular-spectroscopic methods (XPS, densitometry and transport properties, NMR, UPLC, Raman and UVspectroscopy, SFM) and mehods of  anocharacterisation  (DLS, AFM,  TEM), as well as computer simulations (RDF). The goal of characterization was detection of  non-covalent interactions within nanocomposite that are established between fullerenol nanoparticles and doxorubicin in aqueous solution. The results clearly indicate the existence of non- covalent interactions within nanocomposite that affect the organization and assemb...ling of the particles, which further exhibit different biological activity of such a system in comparison to components themselves. Results of biological activity on in vitro model of different tumor cell lines show significant antiproliferative effect of  nanocomposite, as well as selectivity towards tumor cell lines. Experiments conducted on in vivo zebrafish model confirm the lowering ofthe adverse effects of the drug, especially cardiotoxicity, in case when nanocomposite was applied. Computer simulations, microscopic and  spectroscopic results combined with encouraging in vitro and in vivo results point out  that non-covalent interactions between fullerenol nanoparticles and doxorubicin may present the keyrole in formation of a synergistic system for nanodrug delivery into biological system. Multipotential of fullerenol nanoparticles as a nanocarrier and non-specific structure of doxorubicin as a drug imply that fullerenol may serve as a efficient nanocarrier of numerous other antineoplastics, which further allows the improvement of antitumor properties of drugs withsimultaneous drug administration.

Faculty:
Универзитет у Новом Саду, Природно-математички факултет
Date:
19-04-2018
Projects:
  • Functional, Functionalized and Advanced Nanomaterials (RS-45005)
Keywords:
Fulerenol / Fullerenol / nanokompozit / antineoplastici / doksorubicin / biološki efekti / nanocomposite / antineoplastics / doxorubicin / biological effects
[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_nardus_9427
URI
https://www.cris.uns.ac.rs/DownloadFileServlet/Disertacija151420320451431.pdf?controlNumber=(BISIS)106903&fileName=151420320451431.pdf&id=10832&source=NaRDuS&language=sr
https://nardus.mpn.gov.rs/handle/123456789/9427
https://www.cris.uns.ac.rs/record.jsf?recordId=106903&source=NaRDuS&language=sr
https://www.cris.uns.ac.rs/DownloadFileServlet/IzvestajKomisije151420323155241.pdf?controlNumber=(BISIS)106903&fileName=151420323155241.pdf&id=10833&source=NaRDuS&language=sr

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