Embedded multicellular spheroids as a biomimetic 3D cancer model for evaluating drug and drug-device combinations (original) (raw)
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International Journal of Nanomedicine, 2017
The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS) model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM) components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs) play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a better comprehension of the interactions between NPs and tumor components that affect tumor drug delivery. MCTS is particularly suitable for the high-throughput screening of new nanodrugs.
Impact of multicellular tumor spheroids as an in�vivo‑like tumor model on anticancer drug response
International Journal of Oncology, 2016
The incidence of colorectal cancer is higher in men than in women, amounting to 15% of cancer-related diseases as a whole. As such, undesirable effects, arising from the administration of current chemotherapeutic agents (the FOLFIRI/FOLFOX combinations), which are exerted on the remaining non-cancerous tissues and/or cells, have contributed to the occurrence of resistance to multiple drugs, thus markedly reducing their efficacy. However, the delivery of chemotherapeutic agents may be improved and their action may be more selectively targeted to diseased tissues/cells by means of developing biotechnologies and nano-techniques. Thus, the current focus is on creating biological tissue and related tumor models, by means of three-dimensional (3D) spheres, in an attempt to bridge the gap between results obtained in the pre-clinical phase and promising outcomes obtained in clinical trials. For this purpose, the characterization and use of so-called 'multicellular tumor spheroids', may prove to be invaluable. In this study, we focus on describing the efficacy of a model 3D system as compared to the traditional 2D tumor spheres in determining drug response, highlighting a potentially greater effect of the drugs following the encapsulation of respective liposomes. The results obtained demonstrate the successful preparation of a suspension of liposomes loaded with folinic acid, oxaliplatin and 5-fluorouracil (5-FU), and loaded with meso-tetra (4-sulfonatophenyl) porphyrin. Following its use on HT-29 colorectal cancer cells, an important comparative reduction was noted in the viability of the HT-29 cells, demonstrating the efficacy of multicellular tumor spheroids carrying liposomes loaded with therapeutic drugs. These findings indicate that the method of drug encapsulation in liposomes may improve the treatment efficacy of chemotherapeutic agents.
Emerging tumor spheroids technologies for 3D in vitro cancer modeling
Pharmacology & therapeutics, 2018
Cancer is a leading cause of mortality and morbidity worldwide. Around 90% of deaths are caused by metastasis and just 10% by primary tumor. The advancement of treatment approaches is not at the same rhythm of the disease; making cancer a focal target of biomedical research. To enhance the understanding and prompts the therapeutic delivery; concepts of tissue engineering are applied in the development of in vitro models that can bridge between 2D cell culture and animal models, mimicking tissue microenvironment. Tumor spheroid represents highly suitable 3D organoid-like framework elucidating the intra and inter cellular signaling of cancer, like that formed in physiological niche. However, spheroids are of limited value in studying critical biological phenomenon such as tumor-stroma interactions involving extra cellular matrix or immune system. Therefore, a compelling need of tailoring spheroid technologies with physiologically relevant biomaterials or in silico models, is ever emer...
2021
The poor clinical translation of oncological nanomedicine products is one of the greatest challenges faced by research today. The use of reductionist in vitro models of human cancer and non-predictive animal models is generally considered as one of the main causes of such very low translation rate. The integration of three-dimensional (3D) tumour spheroids in the early stages of the preclinical screening pipeline could significantly facilitate the translation of nanomedicine candidates into clinical practice, by allowing for a more reliable prediction of their efficacy and safety in humans. To lead a successful integration of 3D spheroids, protocols that satisfy issues of ease-of-use, reproducibility and compatibility with conventional and high-throughput assays, without losing the advantages offered by two-dimensional (2D) cell systems, are still needed. To address such need, protocols for the formation and characterisation of scaffold-free 3D tumour spheroids of human adenocarcino...
Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research
Pharmaceutics, 2020
Most cancer biologists still rely on conventional two-dimensional (2D) monolayer culture techniques to test in vitro anti-tumor drugs prior to in vivo testing. However, the vast majority of promising preclinical drugs have no or weak efficacy in real patients with tumors, thereby delaying the discovery of successful therapeutics. This is because 2D culture lacks cell–cell contacts and natural tumor microenvironment, important in tumor signaling and drug response, thereby resulting in a reduced malignant phenotype compared to the real tumor. In this sense, three-dimensional (3D) cultures of cancer cells that better recapitulate in vivo cell environments emerged as scientifically accurate and low cost cancer models for preclinical screening and testing of new drug candidates before moving to expensive and time-consuming animal models. Here, we provide a comprehensive overview of 3D tumor systems and highlight the strategies for spheroid construction and evaluation tools of targeted th...
Tumor stroma-containing 3D spheroid arrays: A tool to study nanoparticle penetration
Journal of controlled release : official journal of the Controlled Release Society, 2016
Nanoparticle penetration through tumor tissue after extravasation is considered as a key issue for tumor distribution and therapeutic effects. Most tumors possess abundant stroma, a fibrotic tissue composed of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), which acts as a barrier for nanoparticle penetration. There is however a lack of suitable in vitro systems to study the tumor stroma penetration of nanoparticles. In the present study, we developed and thoroughly characterized a 3D co-culture spheroidal array to mimic tumor stroma and investigated the penetration of silica and PLGA nanoparticles in these spheroids. First, we examined human breast tumor patient biopsies to characterize the content and organization of stroma and found a high expression of alpha-smooth muscle actin (α-SMA; 40% positive area) and collagen-1 (50% positive area). Next, we prepared homospheroids of 4T1 mouse breast cancer cells or 3T3 mouse fibroblasts alone as well as heterospheroi...
Unraveling the Safety Profile of Nanoscale Particles and Materials - From Biomedical to Environmental Applications, 2018
The poor clinical translation of oncological nanomedicine products is one of the greatest challenges faced by research today. The use of reductionist in vitro models of human cancer and non-predictive animal models is generally considered as one of the main causes of such very low translation rate. The integration of three-dimensional (3D) tumour spheroids in the early stages of the preclinical screening pipeline could significantly facilitate the translation of nanomedicine candidates into clinical practice, by allowing for a more reliable prediction of their efficacy and safety in humans. To lead a successful integration of 3D spheroids, protocols that satisfy issues of ease-of-use, reproducibility and compatibility with conventional and high-throughput assays, without losing the advantages offered by two-dimensional (2D) cell systems, are still needed. To address such need, protocols for the formation and characterisation of scaffold-free 3D tumour spheroids of human adenocarcinoma cells were developed and optimised in this study for their application in nanomedicine safety testing. The protocols reported in this chapter provide the ground on how 3D tumour spheroids could be implemented to design nanomedicine products and speed up experimental cancer research, eliminating those candidates that are likely to be ineffective or unsafe in human at early development stages.
Engineering a scaffold-free 3D tumor model for in vitro drug penetration studies
Biomaterials, 2010
a b s t r a c t in vitro cultures are recognized for recapitulating the physiological microenvironment and exhibiting high concordance with in vivo conditions. In cancer research, the multi-cellular tumor spheroid (MCTS) model is an established 3D cancer model that exhibits microenvironmental heterogeneity close to that of tumors in vivo. However, the established process of MCTS formation is time-consuming and often uncontrolled. Here, we report a method for engineering MCTS using a transient inter-cellular linker which facilitates cell-cell interaction. Using C3A cells (a hepatocellular carcinoma cell line) as a model, we formed linker-engineered spheroids which grew to a diameter of 250 mm in 7 days, as compared to 16 days using conventional non-adherent culture. Seven-day old linkerengineered spheroids exhibited characteristics of mature MCTS, including spheroid morphology, gene expression profile, cell-cell interaction, extracellular matrix secretion, proliferation and oxygen concentration gradients, and cellular functions. Linker-engineered spheroids also displayed a resistance to drug penetration similar to mature MCTS, with dose-dependent extracellular accumulation of the drug. The linker-engineered spheroids thus provide a reliable accelerated 3D in vitro tumor model for drug penetration studies.