A 3D fluid-dynamic cancer model to resemble the in vivo drug administration as a new platform for drug testing

INTRODUCTION:The integration of 3D human tumor organoids with fluidic cell culture chambers allows to mimic the in vivo organ-organ fluidic connections and drug systemic administration, finally offering a reliable and fast approach for novel molecules prescreening tests. In this work, 3D cell-laden hydrogels have been properly realized as ovarian tumor models and cultured within a fluidic Multi In vitro Organ-MIVO®-device for in vitro resembling the cancer environment and carry out drug efficacy assays, alternative to animal preclinical models, by monitoring the cancer regression over time. METHODS:Human ovarian cancer cell line (SKOV-3) has been used to realize alginate-based 3D cell-laden hydrogel-based tumor models, as reported (1). 3D tumor tissues have been cultured within MIVO® chamber under fluid flow resembling the capillary blood flow feeding the tumor. Drug (cisplatin) efficacy have been evaluated in MIVO resembling the in vivo systemic drug transport mechanisms and compared with (i) the in vitro tissue culture under static condition, and with (ii) the use of xenograft mouse model. In particular, SKOV-3 viability was quantitatively assessed through Alamar Blue Assay at different time points. Immunostaining for apoptosis and cell proliferation was also carried out. For in vivo tests, SKOV-3 derived tumors were established via subcutaneous injection into the right flank of nude mice. Tumor size was monitored over time. After 10 days, mice were randomized into two treatment groups when tumor volumes increased to 50 mm3. Cisplatin was administered intravenously every seven days for 3 weeks. Tumor growth was quantified three times a week by using a digital caliper. RESULTS:After one week of drug treatment, the viability of SKOV-3 cultured within the 3D hydrogels in MIVO® decreased up to 50%; caspase positive cells were observed homogeneously distributed within the 3D gels, while very few proliferating cells were observed after 1 week of drug treatment. On the contrary, under static conditions the cells were still viable (higher than 80%) and proliferating until 7 days of drug treatment highlighting chemoresistance. Exceptionally under MIVO® tissue culture, the in vitro tumor regression kinetics resembles exactly the tumor mass reduction measured in vivo. DISCUSSION & CONCLUSIONS:These results highlight that the in vivo-like dynamic environment provided by the MIVO® device allows to properly resemble the 3D tumor tissue perfusion, its culture under a capillary circulation and the systemic drug transport mechanism, suggesting its potential as reliable and cruelty-free platform for preclinical drug efficacy tests. References:(1) Alessandra Marrella et al. Frontiers in immunology 10 (2019): 1876