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Abstract
A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core (p < 0.05). Importantly, topotecan penetration correlated with its cytotoxic activity. Therefore, the studied tridimensional cell model recapitulated several characteristics of vitreous seeds observed in patients with retinoblastoma and were successfully used to assess live-cell imaging of chemotherapy penetration for drug distribution studies.
Highlights
Retinoblastoma is the most common intraocular tumor of childhood affecting 1 in 15,000 to 1 in 18,000 live births [1,2,3]
There was no significant overlap between both primary cell lines and no cell line corresponded to the DNA profile of the present retinoblastoma cell lines in the short tandem profile (STR) database of the American Type Culture Collection
We established patient-derived retinoblastoma tridimensional culture resembling the architecture of spheres, a class of vitreous seeds, and for the first time used live tumorsphere imaging to gain insight into the penetration process of a chemotherapeutic agent in such tumor models
Summary
Retinoblastoma is the most common intraocular tumor of childhood affecting 1 in 15,000 to 1 in 18,000 live births [1,2,3]. Vitreous seeds remain a challenge in the management of intraocular retinoblastoma and removal of the affected eye may be the only treatment option [5,6]. Each class of seeds required a different cumulative dose and number of intravitreal injections of melphalan to achieve complete response to treatment [7,8,9,10]. Dusts might be more sensitive to treatment because they are more accessible to drugs, as they are composed of clusters of loose cells, while spheres or clouds grow as tight clusters with different layers of viable cells and may hamper homogeneous distribution of the drug after intravitreal injections [8,9]. Assessment of the capacity of chemotherapy to penetrate into the tumor seeds, and thereby to become available to exert its cytotoxic effect would certainly add to the knowledge on and improvement of chemotherapy use and patient management
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