469193 A 3D Air-Grown Lung Cancer Tumor Spheroid Assay As a Preclinical Model for the Evaluation for Anticancer Therapeutics

Monday, November 14, 2016: 9:12 AM
Continental 7 (Hilton San Francisco Union Square)
Sweta K. Gupta, Chemical Engineering, University of Rhode Island, Kingston, RI and Samantha A. Meenach, Chemical Engineering and Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI

Cancer is the second most common cause of death in United States, with lung cancer resulting in the highest mortality rate and being ranked as the top malignant cancer killer in the world [12]. Despite significant advancements in the cancer therapeutics, lung cancer remains one of the most challenging malignancies to treat. In 2016, 224,390 cases of lung cancer are anticipated, with 158,080 cases likely resulting in death [3]. The relative survival rate for lung cancer is lower (18%) than other cancers partly because most of the cases are diagnosed at advanced stage [34]. Therefore, there is a need for improvement in early diagnosis and development of more effective anticancer therapeutics.

The development of lung cancer therapeutics currently relies on two-dimensional (2D) cell culture assays, which does not recapitulate in vivo conditions. Due to this unnatural microenvironment, 2D cell assays often provide unpredictable and contrasting results in comparison to animal studies and clinical trials, which contributes to the low success rates and high costs associated with drug development. Three-dimensional (3D) spheroids provide improved representation of cancer tissues that tend to form solid tumors in vivo. By exhibiting intrinsic physiological and morphological characteristics similar to tumor tissue, 3D spheroids have been reported to closely mimic in vivo biology [5] and are characterized for having hypoxic cells and a necrotic core, which often gives them high resistance to the treatments [6].

The objective of the present study was to develop air-grown in vitro 3D multicellular spheroids and evaluate their potential to act as preclinical models for the evaluation of anticancer therapeutics. Growing the spheroids at an air-liquid interface (air-grown) aids in mimicking the environment where lung tumors typically present themselves, e.g. in the airways. Alginate gels were used as scaffold matrix and 3D Petri Dishes® were used to imprint uniform-sized micro-wells in the alginate scaffolds. A549 (lung adenocarcinoma) cells were seeded in the alginate micro-wells after they were transferred to Transwells in a multi-well plate, which allowed for the cells to grow in air on the apical side of the platform and have nutrient access through media on the basolateral side. The air-grown spheroids were assessed for their growth and viability to ensure that they are optimal in the evaluation of aerosol anticancer therapeutics. A chemotherapeutic drug, paclitaxel (PTX) was used against A549 spheroids to study drug penetration behavior and cell apoptosis in the spheroids.

Keywords: lung cancer; spheroids; alginate; paclitaxel, A549

Reference:

[1] A. Jemal, F. Bray, et al., Global cancer statistics, CA Cancer J Clin, 2011. 61 69-90.

[2] J. Wang, Z.H. Li, et al., Lung cancer stem cells and implications for future therapeutics, Cell Biochem Biophys, 2014. 69 389-398.

[3] R.L. Siegel, K.D. Miller, et al., Cancer statistics, 2016, CA Cancer J Clin, 2016. 66 7-30.

[4] M. Reck, D.F. Heigener, et al., Management of non-small-cell lung cancer: recent developments, Lancet, 2013. 382 709-719.

[5] D. Loessner, K.S. Stok, et al., Bioengineered 3D platform to explore cell-ECM interactions and drug resistance of epithelial ovarian cancer cells, Biomaterials, 2010. 31 8494-8506.

[6] A.I. Minchinton, I.F. Tannock, Drug penetration in solid tumours, Nature Reviews Cancer, 2006. 6  583-592.


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See more of this Session: Engineering in Cancer Biology and Therapy I
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