Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy

Abstract

Multicellular spheroids are three dimensional in vitro microscale tissue analogs. The current article examines the suitability of spheroids as an in vitro platform for testing drug delivery systems. Spheroids model critical physiologic parameters present in vivo, including complex multicellular architecture, barriers to mass transport, and extracellular matrix deposition. Relative to two-dimensional cultures, spheroids also provide better target cells for drug testing and are appropriate in vitro model for studies of drug penetration. Key challenges associated with creation of uniformly sized spheroids, spheroids with small number of cells and co-culture spheroids are emphasized in the article. Moreover, the assay techniques required for the characterization of drug delivery and efficacy in spheroids and the challenges associated with such studies are discussed. Examples for the use of spheroids in drug delivery and testing are also emphasized. With these challenges and the possible solutions, multicellular spheroids are becoming an increasingly useful in vitro tool for drug screening and delivery to pathological tissues and organs.

Spheroids Formation on Non‐Adhesive Surfaces by Liquid Overlay Technique: Considerations and Practical Approaches

“…[12] Notwithstanding, spheroids are also a valuable 3D cellular model to replicate the features of human solid tumors, as discussed in different reviews. [13][14][15] Such is owed to the fact that spheroids display inherent metabolic (oxygen, carbon dioxide, nutrients, and wastes) gradients similarly to poorly vascularized tumors. These gradients lead to the establishment of three main cellular layers in the spheroids, namely an external layer composed of proliferative cells, an intermediate layer constituted by quiescence cells, and an inner acidic and hypoxic layer comprised of necrotic cells.…”

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

“…With this combinatory approach, it will be possible to gain a more complete picture of the cancer microenvironment and ascertain potential avenues of treatment. Additionally, non-cell factors such as chemotaxis, 130 3D culture 94,[131][132][133][134][135][136] , and hypoxia 137 should be considered for future investigations, in conjunction with mechanical cues to create a microenvironment that can more fully recapitulate in vivo conditions. The study of ovarian cancer mechanotransduction promises to improve patient treatment through future investigations that utilize designs pertinent to the specific microenvironment.…”

Three-dimensional neuronal cell culture: in pursuit of novel treatments for neurodegenerative disease

“…oxygen and nutrients) and cell-cell and cell-extra cellular matrix (ECM) interactions. [36,38,39] With time, a variety of methods have been developed to produce spheroids, one well-known example being the hanging drop method. [36,38] In this approach, aliquots of cell suspensions are seeded on an adherent surface, which is subsequently reverted, yet allowing the droplets to stay attached due to surface tension, resulting in gravity-enforced cell aggregation at the bottom of the droplets.…”

“…[38] All these different methods are associated with their own advantages and disadvantages, resulting in spheroids of different sizes and shapes, and should be chosen depending on the experimental needs and final application. [36,39] To date, spheroids have been successfully generated from a variety of cell types, including neuronal cells. [40] For example, Dingle et al generated neural spheroids from primary rat cortical tissues by means of micromolding, which were reproducible in size and cellular composition.…”