Three-dimensional spheroid culture targeting versatile tissue bioassays using a PDMS-based hanging drop array

Kuo, Ching Te; Wang, Jong Yueh; Lin, Yu Fen; Wo, Andrew M.; Chen, Benjamin P.C.; Lee, Hsinyu

doi:10.1038/s41598-017-04718-1

Cited by 95 publications

(66 citation statements)

References 42 publications

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“…As suggested by Kuo et al (22), 3D sphere cultures may reflect the in vivo-like microenvironments more effectively than the conventional 2D adherent ones. This sphere culture system takes into account the critical interaction of cells with their neighbors and their environments.…”

Section: Discussionmentioning

confidence: 94%

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

et al. 2018

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Recently, it has been well‑recognized that the response toward anticancer drugs differs between two‑ and three‑dimensional (2D and 3D) in vitro cancer cell growth models. In the present study, we have demonstrated that, similar to the conventional 2D monolayer culture systems which often lack in vivo physiological insights, RUNX2 gene silencing increases the gemcitabine (GEM) sensitivity of the 3D spheres generated from p53‑mutated pancreatic cancer MiaPaCa‑2 cells. According to our results, MiaPaCa‑2 cells, but not p53‑wild‑type pancreatic cancer SW1990 cells efficiently formed sphere structures in serum‑free sphere‑forming medium. Although GEM treatment caused a marked induction of TAp73/TAp63 in MiaPaCa‑2 spheres accompanied by the transcriptional activation of p53 family‑target genes such as p21WAF1 and NOXA, only 20% of cells underwent cell death. Under these experimental conditions, mutant p53 expression level was increased in response to GEM and RUNX2 remained unchanged at the protein level regardless of GEM exposure, which may suppress the pro‑apoptotic activity of TAp73/TAp63. Notably, RUNX2 gene silencing markedly augmented GEM‑mediated cell death of MiaPaCa‑2 spheres compared to that of non‑depleted ones. Expression analyses revealed that forced depletion of RUNX2 further stimulated GEM‑induced upregulation of TAp63 as well as its downstream target genes such as p21WAF1 and NOXA. In summary, our observations strongly indicated that, similarly to 2D monolayer culture, RUNX2 gene silencing increased GEM sensitivity of MiaPaCa‑2 spheres and highlighted the therapeutic potential of RUNX2 in pancreatic cancer with p53 mutation.

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Section: Discussionmentioning

confidence: 94%

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

et al. 2018

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“…To verify the proposed enhanced tumor penetration of DOX loaded nanobots, multicellular cancer cell 3D spheroids were used to simulate in vivo tumors (Fig. 7) 49 . HCT116 spheroids were cultured for 3 days by hanging drop method which promoted 3D tumor formation.…”

Section: Antitumor Efficacy Of Drug Loaded Nanobots On 3d Spheroidal mentioning

confidence: 99%

“…Culture of HCT116 cell 3D spheroidal tumor. 3D tumor spheroids were formed by a modified method of the hanging drop technique 49 . In brief, the lid of sterile 12 well plates were coated with poly(dimethoxysiloxane) (PDMS) and Sylgard 184 in a 10:1 ratio and cured at 80 °C for around 45 min.…”

Section: Synthesis Of Cnt-dox-fementioning

confidence: 99%

Self-Propelling Targeted Magneto-Nanobots for Deep Tumor Penetration and pH-Responsive Intracellular Drug Delivery

Andhari¹,

Wavhale

Dhobale

et al. 2020

Sci Rep

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Self-propelling magnetic nanorobots capable of intrinsic-navigation in biological fluids with enhanced pharmacokinetics and deeper tissue penetration implicates promising strategy in targeted cancer therapy. Here, multi-component magnetic nanobot designed by chemically conjugating magnetic fe 3 o 4 nanoparticles (NPs), anti-epithelial cell adhesion molecule antibody (anti-EpCAM mAb) to multiwalled carbon nanotubes (CNT) loaded with an anticancer drug, doxorubicin hydrochloride (DOX) is reported. Autonomous propulsion of the nanobots and their external magnetic guidance is enabled by enriching fe 3 o 4 nps with dual catalytic-magnetic functionality. the nanobots propel at high velocities even in complex biological fluids. In addition, the nanobots preferably release DOX in the intracellular lysosomal compartment of human colorectal carcinoma (HCT116) cells by the opening of Fe 3 o 4 np gate. Further, nanobot reduce ex vivo HCT116 tumor spheroids more efficiently than free DOX. The multicomponent nanobot's design represents a more pronounced method in targeting tumors with selfassisted anticancer drug delivery for 'far-reaching' sites in treating cancers. Designing miniaturized and versatile robots in the dimensional-range of a few micrometers or less offer potential for unprecedented biomedical applications, such as refinements in targeted drug delivery platforms 1-7. Miniature robotic systems provide considerable benefits over conventional and micro/nanoparticle-based therapies 8,9. Existing anticancer drug delivery systems demonstrate pharmacokinetic (PK) limitations as they are passive systems driven by the blood fluidics and lack intrinsic navigation for long circulation time, targeting, localized delivery, and tissue penetration 10,11. Furthermore, despite surface functionalization with a specific ligand that allows nanocarriers to increase the active targeting ability; the nanocarriers are unable to guide themselves to a target. Hence, for targeted anticancer delivery of therapeutic payloads to disease sites, drug carriers are desired to possess some distinctive traits, including self-propelling force and velocity, navigational functions, precise cell targeting, drug cargo-towing and finally tissue penetration with the release of drug payload 12-16. Micro/nanomotors with efficient cargo towing and effective penetrating abilities make them excellent delivery vehicles that can meet the necessary features for targeted delivery of therapeutics 6. Chemically propelled micro-/ nanorobots have been widely explored for active drug delivery, and tremendous progresses has been made in the past few years 17. However, designing nanobots for biological functionality is still a challenge as they have some inherent limitations, such as complex preparation technology, difficulty of surface modification, difficulty of motion in biological fluids and depending on the material, poor biocompatibility or biodegradability 6,18,19. Furthermore, none of the reported micro/nanobot system has demonstrated practically useful speed hig...

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“…This method generates spheroids with rather similar sizes regardless of the cell line. However, this technique is time consuming, in spite of recent works speeding up the fabrication process [86]. In contrast, rotative systems allow the production of massive amounts of spheroids but are expensive and create heterogeneous populations of spheroids [82].…”

Section: D Cell Culture and Spheroids As Cancer Modelsmentioning

confidence: 99%

Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors

Roy

Magne

Vaillancourt-Audet

et al. 2020

BioMed Research International

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Cancer research has considerably progressed with the improvement of in vitro study models, helping to understand the key role of the tumor microenvironment in cancer development and progression. Over the last few years, complex 3D human cell culture systems have gained much popularity over in vivo models, as they accurately mimic the tumor microenvironment and allow high-throughput drug screening. Of particular interest, in vitrohuman 3D tissue constructs, produced by the self-assembly method of tissue engineering, have been successfully used to model the tumor microenvironment and now represent a very promising approach to further develop diverse cancer models. In this review, we describe the importance of the tumor microenvironment and present the existing in vitro cancer models generated through the self-assembly method of tissue engineering. Lastly, we highlight the relevance of this approach to mimic various and complex tumors, including basal cell carcinoma, cutaneous neurofibroma, skin melanoma, bladder cancer, and uveal melanoma.

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Three-dimensional spheroid culture targeting versatile tissue bioassays using a PDMS-based hanging drop array

Cited by 95 publications

References 42 publications

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

Self-Propelling Targeted Magneto-Nanobots for Deep Tumor Penetration and pH-Responsive Intracellular Drug Delivery

Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors

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