Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice

Thymoquinone (TQ), the bioactive compound extracted from seeds of Nigella sativa, has exhibited anti-cancer properties against several cancer cell lines including breast cancer cells. Despite the promising anti-cancer activities, the clinical translation of TQ was hindered by its hydrophobic propert...

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Main Author: Ong, Yong Sze
Format: Thesis
Language:English
Published: 2019
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Online Access:http://psasir.upm.edu.my/id/eprint/78490/1/IB%202019%203%20ir.pdf
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spelling my-upm-ir.784902022-01-17T04:44:20Z Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice 2019-04 Ong, Yong Sze Thymoquinone (TQ), the bioactive compound extracted from seeds of Nigella sativa, has exhibited anti-cancer properties against several cancer cell lines including breast cancer cells. Despite the promising anti-cancer activities, the clinical translation of TQ was hindered by its hydrophobic property. In order to overcome its low water solubility and poor bioavailability, TQ has been encapsulated into a lipid based nanocarrier known as nanostructured lipid carrier (NLC) in the previous study. TQ that was loaded into NLC (TQNLC) has shown in vitro anti-proliferative activity towards breast cancer cell lines (MDA-MB-231 and MCF-7) and cervical cancer cell lines (HeLa and SiHa). Towards realising the clinical translation of TQNLC, the toxicity and anti-breast cancer properties of TQNLC in 4T1-tumour bearing BALB/c mice were evaluated in the present study. After the production of TQNLC by hot highpressure homogenisation, its physicochemical characteristics and cytotoxicity were determined. The oral acute and sub-acute toxicity studies were conducted in healthy BALB/c mice in accordance with Organisation for Economic Cooperation and Development (OECD) 420 and 407 Guidelines, respectively. The toxicological parameters including mortality, body weight change, haematological profile, biochemical profile and histological change were assessed. The anti-breast cancer properties of oral administration of TQNLC and TQ for 28 days in 4T1-tumour bearing female BALB/c mice were determined based on the tumour volume, tumour weight, survival time and survival rate. India ink staining was performed to assess the inhibition of lung metastases. Apoptosis in the tumour was evaluated by TUNEL assay. Effects of TQNLC on the expression of apoptotic-, metastatic- and angiogenic-related proteins were analysed by Western blot. TQNLC has excellent physicochemical characteristics such as particle size less than 50 nm, polydispersity index less than 0.2, high zeta potential, high encapsulation efficiency (98.96%), high drug loading (7.45%) and good stability. In the acute toxicity study, the encapsulation in NLC minimised the toxic effect of TQ based on the LD50 value. TQNLC is regarded safe at the dose of 10 mg/kg in mice with human equivalent dose of 0.813 mg/kg/d for long term oral consumption. Both treatments at 50 mg/kg and 100 mg/kg of TQNLC and TQ reduced the tumour volume and weight via induction of intrinsic apoptotic pathway with downregulation in the expression of Bcl-2 protein and up-regulation of Bax and caspase-8. Treatment with 25 mg/kg of TQ and 50 mg/kg of TQNLC significantly inhibited lung metastasis (p<0.05) by suppressing the expression of MMP-2. NLC enhanced the therapeutic effect of TQ by improving the survival rate of the tumour-bearing mice. In conclusion, TQNLC is a potential anti-breast cancer agent as compared to free TQ and doxorubicin (the standard chemotherapeutic drug) with reduced side effect and improved survival rate. Breast - Cancer - Prevention Plant Extracts - Therapeutic use 2019-04 Thesis http://psasir.upm.edu.my/id/eprint/78490/ http://psasir.upm.edu.my/id/eprint/78490/1/IB%202019%203%20ir.pdf text en public doctoral Universiti Putra Malaysia Breast - Cancer - Prevention Plant Extracts - Therapeutic use Saiful Yazan, Latifah
institution Universiti Putra Malaysia
collection PSAS Institutional Repository
language English
advisor Saiful Yazan, Latifah
topic Breast - Cancer - Prevention
Plant Extracts - Therapeutic use

spellingShingle Breast - Cancer - Prevention
Plant Extracts - Therapeutic use

Ong, Yong Sze
Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice
description Thymoquinone (TQ), the bioactive compound extracted from seeds of Nigella sativa, has exhibited anti-cancer properties against several cancer cell lines including breast cancer cells. Despite the promising anti-cancer activities, the clinical translation of TQ was hindered by its hydrophobic property. In order to overcome its low water solubility and poor bioavailability, TQ has been encapsulated into a lipid based nanocarrier known as nanostructured lipid carrier (NLC) in the previous study. TQ that was loaded into NLC (TQNLC) has shown in vitro anti-proliferative activity towards breast cancer cell lines (MDA-MB-231 and MCF-7) and cervical cancer cell lines (HeLa and SiHa). Towards realising the clinical translation of TQNLC, the toxicity and anti-breast cancer properties of TQNLC in 4T1-tumour bearing BALB/c mice were evaluated in the present study. After the production of TQNLC by hot highpressure homogenisation, its physicochemical characteristics and cytotoxicity were determined. The oral acute and sub-acute toxicity studies were conducted in healthy BALB/c mice in accordance with Organisation for Economic Cooperation and Development (OECD) 420 and 407 Guidelines, respectively. The toxicological parameters including mortality, body weight change, haematological profile, biochemical profile and histological change were assessed. The anti-breast cancer properties of oral administration of TQNLC and TQ for 28 days in 4T1-tumour bearing female BALB/c mice were determined based on the tumour volume, tumour weight, survival time and survival rate. India ink staining was performed to assess the inhibition of lung metastases. Apoptosis in the tumour was evaluated by TUNEL assay. Effects of TQNLC on the expression of apoptotic-, metastatic- and angiogenic-related proteins were analysed by Western blot. TQNLC has excellent physicochemical characteristics such as particle size less than 50 nm, polydispersity index less than 0.2, high zeta potential, high encapsulation efficiency (98.96%), high drug loading (7.45%) and good stability. In the acute toxicity study, the encapsulation in NLC minimised the toxic effect of TQ based on the LD50 value. TQNLC is regarded safe at the dose of 10 mg/kg in mice with human equivalent dose of 0.813 mg/kg/d for long term oral consumption. Both treatments at 50 mg/kg and 100 mg/kg of TQNLC and TQ reduced the tumour volume and weight via induction of intrinsic apoptotic pathway with downregulation in the expression of Bcl-2 protein and up-regulation of Bax and caspase-8. Treatment with 25 mg/kg of TQ and 50 mg/kg of TQNLC significantly inhibited lung metastasis (p<0.05) by suppressing the expression of MMP-2. NLC enhanced the therapeutic effect of TQ by improving the survival rate of the tumour-bearing mice. In conclusion, TQNLC is a potential anti-breast cancer agent as compared to free TQ and doxorubicin (the standard chemotherapeutic drug) with reduced side effect and improved survival rate.
format Thesis
qualification_level Doctorate
author Ong, Yong Sze
author_facet Ong, Yong Sze
author_sort Ong, Yong Sze
title Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice
title_short Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice
title_full Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice
title_fullStr Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice
title_full_unstemmed Toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice
title_sort toxicity and anti-breast cancer properties of thymoquinone-loaded nanostructured lipid carrier in mice
granting_institution Universiti Putra Malaysia
publishDate 2019
url http://psasir.upm.edu.my/id/eprint/78490/1/IB%202019%203%20ir.pdf
_version_ 1747813300021755904