Final Report Summary - NEONANO (Neoadjuvant Nanomedicines for vascular Normalization)
The ERC grant NeoNano (Neoadjuvant Nanomedicine for vascular Normalization; StG-309495) aimed to develop combination therapies to prime tumor drug vessels and the microenvironment for improved drug delivery. Sub-objectives included (1) the establishment of multimodal and multiscale imaging techniques to better monitor the vascular network in tumors and nanomedicine-mediated drug targeting; and (2) the evaluation of macrophage/vasculature-modulation therapies to enhance tumor-targeted drug delivery and anticancer therapy. We developed CT-based methods to assess the relative blood volume in tumors, vessel size, vessel distribution and vessel branching, and CT-FMT-based methods to more accurately visualize and quantify the pharmacokinetics, biodistribution and target site accumulation of drug delivery systems. Using these technologies as tools to assess the efficacy of macrophage/vasculature-modulation therapies, we demonstrated that genetic, pharmacological and physical priming of tumor blood vessels and the microenvironment can substantially improve tumor-targeted drug delivery. We employed HRG-knockout and overexpression mouse and cell models, liposomal dexamethasone, anti-CCL2 RNA aptamers and sonoporation (i.e. the combination of ultrasound and microbubbles) to enhance tumor-targeted drug delivery, and we correlated vasculature/microenvironment-modulation effects to the outcome of drug delivery and antitumor therapy. During the course of the project, we managed to bring several NeoNaNo-related concepts and constructs to the clinic. Most prominently, since the beginning of 2017, liposomal dexamethasone is being evaluated in a first-in-man clinical trial at the Center for Clinical and Translational Research at RWTH Aachen University Clinic, for the treatment of patients suffering from multiple myeloma. On the long run, this and other aspects of the NeoNano project may contribute to better systems and strategies for tumor-targeted drug delivery and anticancer therapy.