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Abstract
Even though in vitro co-culture tumor spheroid model plays an important role in screening drug candidates, its wide applications are currently limited due to the lack of reliable and high throughput methods for generating well-defined and 3D complex co-culture structures. Herein, we report the development of a hydrogel microwell array to generate uniform-sized multicellular tumor spheroids. Our developed multicellular tumor spheroids are structurally well-defined, robust and can be easily transferred into the widely used 2D culture substrates while maintaining our designed multicellular 3D-sphere structures. Moreover, to develop effective anti-cancer therapeutics we integrated our recently developed gold-graphene hybrid nanomaterial (Au@GO)-based photothermal cancer therapy into a series of multicellular tumor spheroid co-culture system. The multicellular tumor spheroids were harvested onto a two-dimensional (2D) substrate, under preservation of their three-dimensional (3D) structure, to evaluate the photothermal therapy effectiveness of graphene oxide (GO)-wrapped gold nanoparticles (Au@GO). From the model of co-culture spheroids of HeLa/Ovarian cancer and HeLa/human umbilical vein endothelial cell (HUVEC), we observed that Au@GO nanoparticles displayed selectivity towards the fast-dividing HeLa cells, which could not be observed to this extent in 2D cultures. Overall, our developed uniform-sized 3D multicellular tumor spheroid could be a powerful tool for anticancer drug screening applications.
Highlights
The American Cancer Society predicts 1.6 million new cancer cases and 600,000 Americans to die of cancer in 2017
To demonstrate an application of the spheroids as a model system for tumor screening applications, we further investigate the potential of a novel hybrid gold nanoparticle-functionalized graphene oxide (Au@GO) for photothermal therapy (PTT)-based anti-cancer applications
We developed PEG hydrogel microwells to generate uniform-sized multicellular tumor spheroids (Fig. 1)
Summary
The American Cancer Society predicts 1.6 million new cancer cases and 600,000 Americans to die of cancer in 2017. Concave poly(dimethylsiloxane) (PDMS)-based microwells have been used to generate cancer spheroids which were used for screening anticancer drug-loaded nanoparticles[18] Due to their biocompatibility, tunable physical and biodegradable properties, hydrogels have widely been used for microwell fabrication[19]. Despite being a highly potent cancer theragnostic reagent, its therapeutic effects have not yet been evaluated in well-defined 3D culture systems This is further compounded by the dramatically increased sizes and more heterogeneous surface chemistries from nanomedicinal reagents, which could lead to a higher complexity during drug screening as compared to conventional small molecules. Addressing the aforementioned challenges, we developed a high-throughput hydrogel microwell-based method to generate uniform-sized multicellular tumor spheroids. To demonstrate an application of the spheroids as a model system for tumor screening applications, we further investigate the potential of a novel hybrid gold nanoparticle-functionalized graphene oxide (Au@GO) for photothermal therapy (PTT)-based anti-cancer applications
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