The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomography-fluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized near-infrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5 to 12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4 to 11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, within the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to pre-select patients likely to respond to passively tumor-targeted nanomedicine treatments.

Department of Experimental Molecular Imaging University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen University Aachen Germany

Department of Experimental Molecular Imaging University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen University Aachen Germany; Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands; Department of Controlled Drug Delivery MIRA Institute for Biomedical Technology and Technical Medicine University of Twente Enschede The Netherlands

Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands; Department of Controlled Drug Delivery MIRA Institute for Biomedical Technology and Technical Medicine University of Twente Enschede The Netherlands

Imaging Sciences Institute University Medical Center Utrecht Utrecht The Netherlands

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Prague Czech Republic

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