Nowadays, cancer remains one of the major public health problem. Although chemotherapeutic drugs efficiently kill cancer cells, these cells can defend themselves from such toxic compounds with a process called cancer multidrug resistance (MDR). Because of unsatisfactory treatment scenario there has been growing interest in the health advantages of using plant-derived compounds for cancer prevention or in the treatment of chemo-resistant cells. Anthocyanidins are a group of pigments belonging to the family of flavonoids present in red-blue fruits and vegetables. Several studies demonstrated that, together with their glycosylated forms, they exert intense biological activity towards normal and cancer cells, including selective cytotoxicity, capability to interact with extrusion pumps, cell cycle perturbation, anti-proliferation and apoptosis. Usually, the concentrations used to prove the biological effects of such compounds are far from those obtained when the assumption passes only through the ingestion of food rich of phytochemicals, and there is a lack of information on the possible long term toxic effects.
 Beyond proven biological effect, anthocyanins have low stability and bioavailability. Moreover, when ingested, their bioavailability is drastically reduced by their poor chemical stability in the weak alkaline conditions of the small intestine, thus challenging the possibility to translate their proven biological effects into therapeutic applications. Nanotechnologies has been widely applied in pharmaceutical field to improve the absorption of bioactive compounds. Delphinidin, one of the major anthocyanidins naturally found in red-blue fruits and vegetable, is a compound that exhibits a wide range of biological activities such as anti-tumor and anti-inflammatory and exert great effect on oxidative stress. In this study, we aimed to: a) Evaluate the effects of a non-toxic long-term treatment with delphinidin on LoVo/Dx cells (metastatic human colorectal adenocarcinoma cell line, doxorubicin resistant). Precisely, we studied the interferences with cell cycle, the expression of specific membrane transporters responsible for drug resistance, the accumulation of the drug in the cells, its cytotoxicity and the cellular ATP levels after treatment. Significant results, like cell cycle arrest and increase of doxorubicin accumulation were reported, but they were not linked to a down regulation of protein and ATP levels. Since these effects were not maintained in time, we hypothesized that the failure in chronic treatment with delphinidin could be attributable to adaptive metabolic response. Moreover, the low stability of the molecule in aqueous solution, such as culture media, suggested a higher suitability of action in acute conditions. b) Produce and assess different chemical and biological properties of Delphinidin-nanoparticles (DNPs) on biological samples. In particular, Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) were used to measure size, dispersity and morphology. The encapsulation of delphinidin within chitosan nanoparticles was investigated through UV Resonant Raman Spectroscopy. The encapsulation efficiency of the nanoparticles was determined to be 73%, and their stability was strongly increased in comparison to the free compound. Results indicated that the DNPs are positively charged and are, therefore, an ideal carrier on targeting the colon mucosa. On different colon cancer cell lines, the DNPs treatment showed a dramatic increase of doxorubicin uptake in doxorubicin-resistant colon cells (LoVo/DX). In addition, preliminary results showed even a combined reduction of the expression of inflammatory biomarkers. In conclusion, these results show the higher performance of DNPs for applications in cancer drug development and might give rise to a new antitumor therapeutic approach avoiding cancer multidrug resistance.

Nanoparticles based delivery System of Flavonoids for Cancer Therapy / Kalaja, Odeta. - (2018 Feb 23).

Nanoparticles based delivery System of Flavonoids for Cancer Therapy

KALAJA, ODETA
2018-02-23

Abstract

Nowadays, cancer remains one of the major public health problem. Although chemotherapeutic drugs efficiently kill cancer cells, these cells can defend themselves from such toxic compounds with a process called cancer multidrug resistance (MDR). Because of unsatisfactory treatment scenario there has been growing interest in the health advantages of using plant-derived compounds for cancer prevention or in the treatment of chemo-resistant cells. Anthocyanidins are a group of pigments belonging to the family of flavonoids present in red-blue fruits and vegetables. Several studies demonstrated that, together with their glycosylated forms, they exert intense biological activity towards normal and cancer cells, including selective cytotoxicity, capability to interact with extrusion pumps, cell cycle perturbation, anti-proliferation and apoptosis. Usually, the concentrations used to prove the biological effects of such compounds are far from those obtained when the assumption passes only through the ingestion of food rich of phytochemicals, and there is a lack of information on the possible long term toxic effects.
 Beyond proven biological effect, anthocyanins have low stability and bioavailability. Moreover, when ingested, their bioavailability is drastically reduced by their poor chemical stability in the weak alkaline conditions of the small intestine, thus challenging the possibility to translate their proven biological effects into therapeutic applications. Nanotechnologies has been widely applied in pharmaceutical field to improve the absorption of bioactive compounds. Delphinidin, one of the major anthocyanidins naturally found in red-blue fruits and vegetable, is a compound that exhibits a wide range of biological activities such as anti-tumor and anti-inflammatory and exert great effect on oxidative stress. In this study, we aimed to: a) Evaluate the effects of a non-toxic long-term treatment with delphinidin on LoVo/Dx cells (metastatic human colorectal adenocarcinoma cell line, doxorubicin resistant). Precisely, we studied the interferences with cell cycle, the expression of specific membrane transporters responsible for drug resistance, the accumulation of the drug in the cells, its cytotoxicity and the cellular ATP levels after treatment. Significant results, like cell cycle arrest and increase of doxorubicin accumulation were reported, but they were not linked to a down regulation of protein and ATP levels. Since these effects were not maintained in time, we hypothesized that the failure in chronic treatment with delphinidin could be attributable to adaptive metabolic response. Moreover, the low stability of the molecule in aqueous solution, such as culture media, suggested a higher suitability of action in acute conditions. b) Produce and assess different chemical and biological properties of Delphinidin-nanoparticles (DNPs) on biological samples. In particular, Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) were used to measure size, dispersity and morphology. The encapsulation of delphinidin within chitosan nanoparticles was investigated through UV Resonant Raman Spectroscopy. The encapsulation efficiency of the nanoparticles was determined to be 73%, and their stability was strongly increased in comparison to the free compound. Results indicated that the DNPs are positively charged and are, therefore, an ideal carrier on targeting the colon mucosa. On different colon cancer cell lines, the DNPs treatment showed a dramatic increase of doxorubicin uptake in doxorubicin-resistant colon cells (LoVo/DX). In addition, preliminary results showed even a combined reduction of the expression of inflammatory biomarkers. In conclusion, these results show the higher performance of DNPs for applications in cancer drug development and might give rise to a new antitumor therapeutic approach avoiding cancer multidrug resistance.
23-feb-2018
DONATI, IVAN
TRAMER, FEDERICA
30
2016/2017
Settore BIO/10 - Biochimica
Università degli Studi di Trieste
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2917683
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