**Automated Real-Time Tumor Pharmacokinetic Profiling in 3D Models: A Novel Approach for Personalized Medicine**

#### **Jan F. Joseph 1,**† **, Leonie Gronbach 2,**† **, Jill García-Miller <sup>2</sup> , Leticia M. Cruz <sup>2</sup> , Bernhard Wuest <sup>3</sup> , Ulrich Keilholz <sup>4</sup> , Christian Zoschke <sup>2</sup> and Maria K. Parr 5,\***


Received: 31 March 2020; Accepted: 29 April 2020; Published: 30 April 2020

**Abstract:** Cancer treatment often lacks individual dose adaptation, contributing to insufficient efficacy and severe side effects. Thus, personalized approaches are highly desired. Although various analytical techniques are established to determine drug levels in preclinical models, they are limited in the automated real-time acquisition of pharmacokinetic profiles. Therefore, an online UHPLC-MS/MS system for quantitation of drug concentrations within 3D tumor oral mucosa models was generated. The integration of sampling ports into the 3D tumor models and their culture inside the autosampler allowed for real-time pharmacokinetic profiling without additional sample preparation. Docetaxel quantitation was validated according to EMA guidelines. The tumor models recapitulated the morphology of head-and-neck cancer and the dose-dependent tumor reduction following docetaxel treatment. The administration of four different docetaxel concentrations resulted in comparable courses of concentration versus time curves for 96 h. In conclusion, this proof-of-concept study demonstrated the feasibility of real-time monitoring of drug levels in 3D tumor models without any sample preparation. The inclusion of patient-derived tumor cells into our models may further optimize the pharmacotherapy of cancer patients by efficiently delivering personalized data of the target tissue.

**Keywords:** automatization; drug absorption; drug dosing; head-and-neck cancer; pharmacokinetics; real-time measurements; taxanes; tissue engineering; UHPLC-MS/MS
