Browsing by Author "Raj, Emmanuel Naveen"

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Co-delivery of paclitaxel and cetuximab by nanodiamond enhances mitotic catastrophe and tumor inhibition
(2017-08-29)
Lin, Yu-Wei
;
Raj, Emmanuel Naveen
;
Liao, Wei-Siang
;
Lin, Johnson
;
Liu, Kuang-Kai
The poor intracellular uptake and non-specific binding of anticancer drugs into cancer cells are the bottlenecks in cancer therapy. Nanocarrier platforms provide the opportunities to improve the drug efficacy. Here we show a carbon-based nanomaterial nanodiamond (ND) that carried paclitaxel (PTX), a microtubule inhibitor, and cetuximab (Cet), a specific monoclonal antibody against epidermal growth factor receptor (EGFR), inducing mitotic catastrophe and tumor inhibition in human colorectal cancer (CRC). ND-PTX blocked the mitotic progression, chromosomal separation, and induced apoptosis in the CRC cells; however, NDs did not induce these effects. Conjugation of ND-PTX with Cet (ND-PTX-Cet) was specifically binding to the EGFR-positive CRC cells and enhanced the mitotic catastrophe and apoptosis induction. Besides, ND-PTX-Cet markedly decreased tumor size in the xenograft EGFR-expressed human CRC tumors of nude mice. Moreover, ND-PTX-Cet induced the mitotic marker protein phospho-histone 3 (Ser10) and apoptotic protein active-caspase 3 for mitotic catastrophe and apoptosis. Taken together, this study demonstrated that the co-delivery of PTX and Cet by ND enhanced the effects of mitotic catastrophe and apoptosis in vitro and in vivo, which may be applied in the human CRC therapy.
Targeting EGFR of triple-negative breast cancer enhances the therapeutic efficacy of paclitaxel- and cetuximab-conjugated nanodiamond nanocomposite
(2019-03-01)
Liao, Wei-Siang
;
Ho, Yu
;
Lin, Yu-Wei
;
Raj, Emmanuel Naveen
;
Liu, Kuang-Kai
Breast cancer is the most common malignancy and a leading cause of cancer-related mortality among women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). However, epidermal growth factor receptor (EGFR) is highly expressed in most of the TNBCs, which may provide a potential target for EGFR targeting therapy. Nanodiamond (ND) is a carbon-based nanomaterial with several advantages, including fluorescence emission, biocompatibility, and drug delivery applications. In this study, we designed a nanocomposite by using ND conjugated with paclitaxel (PTX) and cetuximab (Cet) for targeting therapy on the EGFR-positive TNBC cells. ND-PTX inhibited cell viability and induced mitotic catastrophe in various human breast cancer cell lines (MDA-MB-231, MCF-7, and BT474); in contrast, ND alone did not induce cell death. ND-PTX inhibited the xenografted human breast tumors in nude mice. We further investigated ND-PTX-Cet drug efficacy on the TNBC of MDA-MB-231 breast cancer cells. ND-PTX-Cet could specifically bind to EGFR and enhanced the anticancer effects including drug uptake levels, mitotic catastrophe, and apoptosis in the EGFR-expressed MDA-MB-231 cells but not in the EGFR-negative MCF-7 cells. In addition, ND-PTX-Cet increased the protein levels of active caspase-3 and phospho-histone H3 (Ser10). Furthermore, ND-PTX-Cet showed more effective on the reduction of TNBC tumor volume by comparison with ND-PTX. Taken together, these results demonstrated that ND-PTX-Cet nanocomposite enhanced mitotic catastrophe and apoptosis by targeting EGFR of TNBC cells, which can provide a feasible strategy for TNBC therapy. Statement of significance Current TNBC treatment is ineffective against the survival rate of TNBC patients. Therefore, the development of new treatment strategies for TNBC patients is urgently needed. Here, we have designed a nanocomposite by targeting on the EGFR of TNBC to enhance therapeutic efficacy by ND-conjugated PTX and Cet (ND-PTX-Cet). Interestingly, we found that the co-delivery of Cet and PTX by ND enhanced the apoptosis, mitotic catastrophe and tumor inhibition in the EGFR-expressed TNBC in vitro and in vivo. Consequently, this nanocomposite ND-PTX-Cet can be applied for targeting EGFR of human TNBC therapy. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Ubiquitin-coated nanodiamonds bind to autophagy receptors for entry into the selective autophagy pathway
(2017-01-01)
Liu, Kuang-Kai
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Qiu, Wei-Ru
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Raj, Emmanuel Naveen
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Liu, Huei-Fang
;
Huang, Hou-Syun
Selective macroautophagy/autophagy plays a pivotal role in the processing of foreign pathogens and cellular components to maintain homeostasis in human cells. To date, numerous studies have demonstrated the uptake of nanoparticles by cells, but their intracellular processing through selective autophagy remains unclear. Here we show that carbon-based nanodiamonds (NDs) coated with ubiquitin (Ub) bind to autophagy receptors (SQSTM1 [sequestosome 1], OPTN [optineurin], and CALCOCO2/NDP52 [calcium binding and coiled-coil domain 2]) and are then linked to MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) for entry into the selective autophagy pathway. NDs are ultimately delivered to lysosomes. Ectopically expressed SQSTM1-green fluorescence protein (GFP) could bind to the Ub-coated NDs. By contrast, the Ub-associated domain mutant of SQSTM1 (UBA)-GFP did not bind to the Ub-coated NDs. Chloroquine, an autophagy inhibitor, prevented the ND-containing autophagosomes from fusing with lysosomes. Furthermore, autophagy receptors OPTN and CALCOCO2/NDP52, involved in the processing of bacteria, were found to be involved in the selective autophagy of NDs. However, ND particles located in the lysosomes of cells did not induce mitotic blockage, senescence, or cell death. Single ND clusters in the lysosomes of cells were observed in the xenografted human lung tumors of nude mice. This study demonstrated for the first time that Ub-coated nanoparticles bind to autophagy receptors for entry into the selective autophagy pathway, facilitating their delivery to lysosomes.
YY Ubiquitin-coated nanodiamonds bind to autophagy receptors for entry into the selective autophagy pathway
(2017)
Liu, Kuang-Kai
;
Qiu, Wei-Ru
;
Raj, Emmanuel Naveen
;
Liu, Huei-Fang
;
Huang, Hou-Syun
Selective macroautophagy/autophagy plays a pivotal role in the processing of foreign pathogens and cellular components to maintain homeostasis in human cells. To date, numerous studies have demonstrated the uptake of nanoparticles by cells, but their intracellular processing through selective autophagy remains unclear. Here we show that carbon-based nanodiamonds (NDs) coated with ubiquitin (Ub) bind to autophagy receptors (SQSTM1 [sequestosome 1], OPTN [optineurin], and CALCOCO2/NDP52 [calcium binding and coiled-coil domain 2]) and are then linked to MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) for entry into the selective autophagy pathway. NDs are ultimately delivered to lysosomes. Ectopically expressed SQSTM1-green fluorescence protein (GFP) could bind to the Ub-coated NDs. By contrast, the Ub-associated domain mutant of SQSTM1 (UBA)-GFP did not bind to the Ub-coated NDs. Chloroquine, an autophagy inhibitor, prevented the ND-containing autophagosomes from fusing with lysosomes. Furthermore, autophagy receptors OPTN and CALCOCO2/NDP52, involved in the processing of bacteria, were found to be involved in the selective autophagy of NDs. However, ND particles located in the lysosomes of cells did not induce mitotic blockage, senescence, or cell death. Single ND clusters in the lysosomes of cells were observed in the xenografted human lung tumors of nude mice. This study demonstrated for the first time that Ub-coated nanoparticles bind to autophagy receptors for entry into the selective autophagy pathway, facilitating their delivery to lysosomes.
YY Ubiquitin-coated nanodiamonds bind to autophagy receptors for entry into the selective autophagy pathway
(2017)
Liu, Kuang-Kai
;
Qiu, Wei-Ru
;
Raj, Emmanuel Naveen
;
Liu, Huei-Fang
;
Huang, Hou-Syun
Selective macroautophagy/autophagy plays a pivotal role in the processing of foreign pathogens and cellular components to maintain homeostasis in human cells. To date, numerous studies have demonstrated the uptake of nanoparticles by cells, but their intracellular processing through selective autophagy remains unclear. Here we show that carbon-based nanodiamonds (NDs) coated with ubiquitin (Ub) bind to autophagy receptors (SQSTM1 [sequestosome 1], OPTN [optineurin], and CALCOCO2/NDP52 [calcium binding and coiled-coil domain 2]) and are then linked to MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) for entry into the selective autophagy pathway. NDs are ultimately delivered to lysosomes. Ectopically expressed SQSTM1-green fluorescence protein (GFP) could bind to the Ub-coated NDs. By contrast, the Ub-associated domain mutant of SQSTM1 (UBA)-GFP did not bind to the Ub-coated NDs. Chloroquine, an autophagy inhibitor, prevented the ND-containing autophagosomes from fusing with lysosomes. Furthermore, autophagy receptors OPTN and CALCOCO2/NDP52, involved in the processing of bacteria, were found to be involved in the selective autophagy of NDs. However, ND particles located in the lysosomes of cells did not induce mitotic blockage, senescence, or cell death. Single ND clusters in the lysosomes of cells were observed in the xenografted human lung tumors of nude mice. This study demonstrated for the first time that Ub-coated nanoparticles bind to autophagy receptors for entry into the selective autophagy pathway, facilitating their delivery to lysosomes.