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 models 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. By addressing these challenges with possible solutions, multicellular spheroids are becoming an increasingly useful in vitro tool for drug screening and delivery to pathological tissues and organs.
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- "Often, promising results obtained from 2D cannot be translated similarly into in vivo settings (Goodman et al., 2008). Whereas cells on 2D are exposed to a uniform environment with sufficient oxygen and nutrients, cells in solid tumors are exposed to gradients of critical chemical and biological signals (Mehta et al., 2012), which can exert both stimulatory and inhibitory effects on tumor progression (Mehta et al., 2012). Intriguingly, certain tumor cells from cancer patients are intrinsically resistant to a broad spectrum of chemotherapeutic drugs without any previous exposure to those cytotoxic agents (Sanchez et al., 2009; Zhu et al., 2005, 2012). "
ABSTRACT: Cancer occurs when cells acquire genomic instability and inflammation, produce abnormal levels of epigenetic factors/proteins and tumor suppressors, reprogram the energy metabolism and evade immune destruction, leading to the disruption of cell cycle/normal growth. An early event in carcinogenesis is loss of polarity and detachment from the natural basement membrane, allowing cells to form distinct three-dimensional (3D) structures that interact with each other and with the surrounding microenvironment. Although valuable information has been accumulated from traditional in vitro studies in which cells are grown on flat and hard plastic surfaces (2D culture), this culture condition does not reflect the essential features of tumor tissues. Further, fundamental understanding of cancer metastasis cannot be obtained readily from 2D studies because they lack the complex and dynamic cell-cell communications and cell-matrix interactions that occur during cancer metastasis. These shortcomings, along with lack of spatial depth and cell connectivity, limit the applicability of 2D cultures to accurate testing of pharmacologically active compounds, free or sequestered in nanoparticles. To recapitulate features of native tumor microenvironments, various biomimetic 3D tumor models have been developed to incorporate cancer and stromal cells, relevant matrix components, and biochemical and biophysical cues, into one spatially and temporally integrated system. In this article, we review recent advances in creating 3D tumor models employing tissue engineering principles. We then evaluate the utilities of these novel models for the testing of anticancer drugs and their delivery systems. We highlight the profound differences in responses from 3D in vitro tumors and conventional monolayer cultures. Overall, strategic integration of biological principles and engineering approaches will both improve understanding of tumor progression and invasion and support discovery of more personalized first line treatments for cancer patients.Biotechnology Advances 11/2014; 32(7). DOI:10.1016/j.biotechadv.2014.07.009 · 8.91 Impact Factor
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- "The main advantages of the MTS are their simple spherical symmetry and the fact that they can be produced in large quantities. These characteristics make them popular both in mathematical modeling and in biological research: MTS provide an experimental biological model that has allowed researchers to determine protein expression McMahon et al. (2012); Gupta and Johansson (2012), check mathematical models Radszuweit et al. (2009); Bertuzzi et al. (2010); Kazmi et al. (2012), and study drug delivery to treat cancer disease Mehta et al. (2012); Gibot et al. (2013), to mention a few applications. The understanding of how MTS grow is indeed crucial to further comprehend some aspects of in vivo tumor progression. "
ABSTRACT: Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Their interaction between them characterizes the system evolution. To obtain information about these interactions we apply the recently developed vector universality (VUN) formalism to various instances of competition between tumor populations. The formalism allows us: (a) to quantify the growth mechanisms of a HeLa cell colony, describing the phenotype switching responsible for its fast expansion, (b) to reliably reconstruct the evolution of the necrotic and viable fractions in both in vitro and in vivo tumors using data for the time dependences of the total masses, and (c) to show how the shedding of cells leading to subspheroid formation is beneficial to both the spheroid and subspheroid populations, suggesting that shedding is a strong positive influence on cancer dissemination.Journal of Theoretical Biology 03/2014; 365. DOI:10.1016/j.jtbi.2014.10.038 · 2.30 Impact Factor
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- "In vitro three-dimensional tumor models, which restore physiologically-relevant 3D tumor architecture and signaling that are absent in traditional monolayer cell culture, have emerged as valuable tools in cancer research        . While the utility of optical microscopy for probing structural and functional changes in these systems has been well established          , there are noteworthy inherent limitations in standard commercially available optical microscopy techniques in these complex 3D systems. "
ABSTRACT: While three-dimensional tumor models have emerged as valuable tools in cancer research, the ability to longitudinally visualize the 3D tumor architecture restored by these systems is limited with microscopy techniques that provide only qualitative insight into sample depth, or which require terminal fixation for depth-resolved 3D imaging. Here we report the use of digital holographic microscopy (DHM) as a viable microscopy approach for quantitative, non-destructive longitudinal imaging of in vitro 3D tumor models. Following established methods we prepared 3D cultures of pancreatic cancer cells in overlay geometry on extracellular matrix beds and obtained digital holograms at multiple timepoints throughout the duration of growth. The holograms were digitally processed and the unwrapped phase images were obtained to quantify nodule thickness over time under normal growth, and in cultures subject to chemotherapy treatment. In this manner total nodule volumes are rapidly estimated and demonstrated here to show contrasting time dependent changes during growth and in response to treatment. This work suggests the utility of DHM to quantify changes in 3D structure over time and suggests the further development of this approach for time-lapse monitoring of 3D morphological changes during growth and in response to treatment that would otherwise be impractical to visualize.Proceedings of SPIE - The International Society for Optical Engineering 02/2014; DOI:10.1117/12.2040515 · 0.20 Impact Factor