title: Towards personalized medicine with a three-dimensional micro-scale perfusion-based two-chamber tissue model system.
abstract: A three-dimensional micro-scale perfusion-based two-chamber (3D-μPTC) tissue model system was developed to test the cytotoxicity of anticancer drugs in conjunction with liver metabolism. Liver cells with different cytochrome P450 (CYP) subtypes and glioblastoma multiforme (GBM) brain cancer cells were cultured in two separate chambers connected in tandem. Both chambers contained a 3D tissue engineering scaffold fabricated with biodegradable poly(lactic acid) (PLA) using a solvent-free approach. We used this model system to test the cytotoxicity of anticancer drugs, including temozolomide (TMZ) and ifosfamide (IFO). With the liver cells, TMZ showed a much lower toxicity to GBM cells under both 2D and 3D cell culture conditions. Comparing 2D, GBM cells cultured in 3D had much high viability under TMZ treatment. IFO was used to test the CYP-related metabolic effects. Cells with different expression levels of CYP3A4 differed dramatically in their ability to activate IFO, which led to strong metabolism-dependent cytotoxicity to GBM cells. These results demonstrate that our 3D-μPTC system could provide a more physiologically realistic in vitro environment than the current 2D monolayers for testing metabolism-dependent toxicity of anticancer drugs. It could therefore be used as an important platform for better prediction of drug dosing and schedule towards personalized medicine.
authors.affiliation: Department of Mechanical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Jeremy
authors.initials: J
authors.lastname: Barker
authors.forename: Changchun
authors.initials: C
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
authors.forename: Gregory
authors.initials: G
authors.lastname: Foltz
authors.forename: Jenni
authors.initials: J
authors.lastname: Küblbeck
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
mesh_terms: D018929:Cell Culture Techniques / Q000295:instrumentation* / Q000379:methods*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007069:Ifosfamide / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008855:Microscopy, Electron, Scanning; D010477:Perfusion / Q000295:instrumentation* / Q000379:methods*; D011091:Polyesters / Q000494:pharmacology; D016062:Porosity / Q000187:drug effects; D057285:Precision Medicine; D000077204:Temozolomide; D023822:Tissue Engineering; D054457:Tissue Scaffolds
chemical_list: D011091:Polyesters; C033616:poly(lactide); D003606:Dacarbazine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007069:Ifosfamide; D000077204:Temozolomide