Učinak nanokristala resveratrola na angiogenezu i rast Ehrlichova ascitesnoga i solidnoga tumora u miša

doctoral thesis

• Title (english): Effects of resveratrol nanocrystals on angiogenesis and proliferation of Ehrlich ascites and solid tumour in mice
• Author: Daniela Ančić
• Mentor: Nada Oršolić (mentor)
• Mentor: Ivan Pepić (komentor)
• Committee member: Jozsef Petrik (predsjednik povjerenstva)
• Committee member: Anita Hafner (član povjerenstva)
• Committee member: Ranko Stojković (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of pharmaceutical technology); Zagreb
• Defense date and country: 2023-12-19, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Resveratrol (3,5,4′-trihidroksi-stilben) jest potencijalan protutumorski spoj zbog svoje antioksidativne,
protuupalne, proapoptotičke, antiangiogene i antiproliferativne aktivnosti. Terapijska primjena
resveratrola ograničena je njegovim fizikalno-kemijskim i farmakokinetičkim svojstvima. Temeljem
navedenog, cilj rada bio je primijeniti resveratrol u obliku nanokristala te istražiti njegov učinak na rast
angiogenetski ovisnog, brzo rastućeg Ehrlichovog ascitesnog i solidnog tumora (EAT) te interakciju
nanokristala s biološkim tkivom kroz biokemijske i histološke promjene stanica bubrega, jetre i EAT.
Rezultati pokazuju da primjena otopine resveratrola (RSV) i suspenzije nanokristala resveratrola
(NANO-RSV) dovodi do značajnog smanjenja proliferacije tumorskih stanica u trbušnoj šupljini, te
smanjenja broja krvnih žila u potrbušnici, uz nisku sistemsku toksičnost. Prooksidativni učinak
resveratrola primijenjenog ip vodi kroničnoj upali, polarizaciji makrofaga od M1 prema M2 fenotipu te
skraćenom životnom vijeku nositelja tumora. U histopatološkim ispitivanjima, vidljiva je veća
hepatocelularna nekroza i apoptoza, jetrena fibroza oko središnje vene i degeneracija s manjim masnim
promjenama u miševa nakon obrade s RSV nego u miševa nakon obrade s NANO-RSV. Primjena RSV
i NANO-RSV vodi upali s proksimalnom tubularnom nekrozom i oticanjem bubrežnog glomerula,
zajedno s blagim povećanjem biokemijskih parametara kao pokazatelja narušenog funkcionalnog
kapaciteta bubrega. Intratumoralna primjena otopine resveratrola i nanokristala resveratrola u solidni
EAT pokazala je da dulja nazočnost nanokristala unutar tumorskog tkiva rezultira učinkovitijim
antiangiogenim i imunomodulatornim doza-ovisnim učinkom nanokristala u odnosu na otopinu
resveratrola te značajno većim preživljenjem nositelja tumora. Sažimajući navedeno, te uzimajući u
obzir dobrobit ljudi i ekološku sigurnost, mehanizam toksičnosti resveratrola i njegovih nanokristala
potrebno je detaljnije proučiti u cilju boljeg iskorištavanja pozitivnih učinaka nanokristala resveratrola
te smanjenja potencijalnih nuspojava njihove terapijske primjene.

Abstract (english)

Resveratrol (3,5,4′ -trihydroxystilbene) is a potential antitumor agent due to its proven anti-oxidative,
anti-inflammatory, pro-apoptotic, anti-angiogenic and anti-proliferative properties. Nevertheless, his
therapeutic use is limited by its physico-chemical (poor solubility, photo instability) and
pharmacokinetic (rapid metabolism and elimination, low bioavailability) properties. The aim of this
study was to investigate the potential use of resveratrol (RSV) and its nanocrystals (NANO-RSV) as
antitumor agents in Ehrlich ascites tumour (EAT)-bearing mice in ascites and solid form and the
interaction of nanocrystals with biological tissue through biochemical and histological changes of
kidney, liver and EAT cells. The results show that the administration of resveratrol and its nanocrystals
lead to significant reductions in the proliferation of tumour cells in the abdominal cavity, and a reduction
of the number of blood vessels in the peritoneum, with low systemic toxicity. Due to pro-oxidative
effects of resveratrol after ip administration, chronic inflammation, macrophage polarisation from M1
to M2 phenotype as well as shorter lifespan of resveratrol-treated mice was observed. In
histopathological examinations, greater hepatocellular necrosis and apoptosis, hepatic fibrosis around
the central vein and degeneration with minor fatty change were observed with RSV than with NANORSV.
Inflammation with proximal tubular necrosis and renal glomerulus swelling were also observed,
together with slight elevation of several biochemical parameters in both the RSV and NANO-RSV
groups. Intra-tumoral administration of RSV and NANO-RSV showed that longer presence of
nanocrystals in the tumor tissue improves anti-angiogenic and immunomodulatory dose- depending
effects of resveratrol, including overall survival of the mice. With respect for human health and
environmental safety, the mechanisms of toxicity require further clarification in order to increase the
beneficial effects and reduce the possible risks of therapeutic application of RSV nanocrystals.

• Keywords: resveratrol; nanokristali; Ehrlichov ascitesni tumor u miša; angiogeneza; protutumorski učinak; toksičnost nanokristala
• Keywords (english): resveratrol; nanocrystals; Ehrlich ascites tumor in mice; angiogenesis; anti-tumor effect; toxicity of nanocrystals
• Language: croatian
• URN:NBN: urn:nbn:hr:163:008050
• Promotion: 2023
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-12-19
• Created on: 2024-01-26 11:45:10