scholarly journals A Cancer Spheroid Array Chip for Selecting Effective Drug

Micromachines ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 688 ◽  
Author(s):  
Jae Won Choi ◽  
Sang-Yun Lee ◽  
Dong Woo Lee

A cancer spheroid array chip was developed by modifying a micropillar and microwell structure to improve the evaluation of drugs targeting specific mutations such as phosphor-epidermal growth factor receptor (p-EGFR). The chip encapsulated cells in alginate and allowed cancer cells to grow for over seven days to form cancer spheroids. However, reagents or media used to screen drugs in a high-density spheroid array had to be replaced very carefully, and this was a tedious task. Particularly, the immunostaining of cancer spheroids required numerous steps to replace many of the reagents used for drug evaluation. To solve this problem, we adapted a micropillar and microwell structure to a spheroid array. Thus, culturing cancer spheroids in alginate spots attached to the micropillar allowed us to replace the reagents in the microwell chip with a single fill of fresh medium, without damaging the cancer spheroids. In this study, a cancer spheroid array was made from a p-EGFR-overexpressing cell line (A549 lung cancer cell line). In a 12 by 36 column array chip (25 mm by 75 mm), the spheroid over 100 µm in diameter started to form at day seven and p-EGFR was also considerably overexpressed. The array was used for p-EGFR inhibition and cell viability measurement against seventy drugs, including ten EGFR-targeting drugs. By comparing drug response in the spheroid array (spheroid model) with that in the single-cell model, we demonstrated that the two models showed different responses and that the spheroid model might be more resistant to some drugs, thus narrowing the choice of drug candidates.

2020 ◽  
Vol 14 (1) ◽  
pp. 9
Author(s):  
Ranza Elrayess ◽  
Yasmine M. Abdel Aziz ◽  
Mohamed Saleh Elgawish ◽  
Marwa Elewa ◽  
Asmaa S. A. Yassen ◽  
...  

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC50 values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC50 value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC50 of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.


2011 ◽  
Vol 31 (10) ◽  
pp. 1091-1095
Author(s):  
Xiao-lin LI ◽  
Yan-fang ZHANG ◽  
Kai TANG ◽  
Ying TANG ◽  
Ruo-bing JIN ◽  
...  

2013 ◽  
Vol 13 (3) ◽  
pp. 414-421 ◽  
Author(s):  
Raquel T. Lima ◽  
Gemma A. Barron ◽  
Joanna A. Grabowska ◽  
Giovanna Bermano ◽  
Simranjeet Kaur ◽  
...  

2021 ◽  
Vol 27 ◽  
pp. 101089
Author(s):  
Kazuo Ohara ◽  
Shintaro Kinoshita ◽  
Jun Ando ◽  
Yoko Azusawa ◽  
Midori Ishii ◽  
...  

2004 ◽  
Vol 95 (2) ◽  
pp. 142-148 ◽  
Author(s):  
Tatsuya Yoshimasu ◽  
Teruhisa Sakurai ◽  
Shoji Oura ◽  
Issei Hirai ◽  
Hirokazu Tanino ◽  
...  

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