Personalizing EPR-mediated passive drug targeting to tumors using non-invasive imaging

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Nanomedicines are 1-100 nm-sized carrier materials designed to improve the biodistribution of i.v. administered (chemo-) therapeutic agents. By delivering drugs more specifically to pathological sites, and by at the same preventing them from accumulating in potentially endangered healthy tissues, nanomedicines aim to improve the balance between efficacy and the toxicity of systemic (chemo-) therapeutic interventions. The vast majority of (pre-) clinically used nanomedicines rely on the Enhanced Permeability and Retention (EPR) effect for enabling effective and selective drug delivery, and they have been primarily used for facilitating drug targeting to tumors. The EPR effect, however, is a relatively poorly understood and highly variable (patho-) physiological phenomenon, which varies substantially from patient to patient, and from tumor (model) to tumor (model). To better understand the EPR effect, to preselect patients likely to respond to EPR-targeted nano-chemotherapeutic interventions, and to thereby individualize and improve passively tumor-targeted nanomedicine treatments, we here propose to I) use anatomical, functional and molecular imaging techniques to identify image-able vascular parameters correlating with EPR; and to II) use theranostic constructs and concepts to demonstrate that the degree of EPR-mediated drug targeting correlates with therapeutic efficacy. Regarding the former, we will use anatomical µCT, functional MRI and molecular US, to quantitatively characterize the tumor vasculature in five different tumor models (known to differ significantly in aggressiveness and angiogenic profile), and we will correlate image-able vascular parameters with the EPR-mediated tumor accumulation of fluorophore-labeled polymers (5 nm), micelles (50 nm) and liposomes (100 nm). These clinically relevant carrier materials will be double-labeled with a near-infrared dye and with a standard fluorophore, to enable in vivo µCT-FMT imaging of overall tumor accumulation, and ex vivo two-photon laser scanning microscopy analysis of tumor penetration and intratumoral distribution. Regarding the latter, these prototypic and image-guided nanomedicines with be further functionalized with doxorubicin, to demonstrate - for the first time - that the degree of EPR-mediated tumor accumulation correlates with antitumor efficacy, and that inter- and intra-individual differences in tumor accumulation can be used to predict the outcome of passively tumor-targeted nanomedicine treatment. Together, these efforts will I) provide quantitative imaging information of the vascular parameters contributing to EPR; II) improve our mechanistic understanding of the EPR effect; III) provide pioneering proof-of-principle demonstrating that the degree EPR-mediated drug targeting correlates with therapeutic efficacy; and IV) substantially contribute to the realization of personalized and improved nanomedicine treatment.