Periodic Reporting for period 4 - Meta-Targeting (Macro-Nanomedicine to Treat Metastatic Cancer)
Reporting period: 2024-10-01 to 2025-03-31
Triple-negative breast cancer affects millions of people worldwide. It presents with aggressive growth and is very difficult to treat, because of the lack of targets (like HER2, PR, ER) for molecular interventions. The goal of the Meta-Targeting project (ERC-CoG 864121: “Macro-nanomedicine to treat metastatic cancer”) was to explore smart, rational and realistic concepts and combination therapies for better management of metastatic triple-negative breast cancer. In this context, “smart” did not refer to highly complex and ingenious drug delivery systems, but rather to strategies that can be realistically developed and pragmatically implemented in day-to-day clinical practice. The Meta-Targeting project was constructed in such a way that advances in multiple scientific disciplines were aligned and integrated, incl. prodrug design, nanomedicine formulation and pharmaceutical engineering (WP1), physical and pharmacological tumor microenvironment priming (WP2), identification of imaging and histopathological biomarkers (WP3), understanding and overcoming microenvironment-related resistance processes (WP4), and development of novel tools and technologies for immunotherapy potentiation (WP5). Upon finalization of the project, the majority of objectives in the respective work packages have been successfully completed. Detailed results and achievements are summarized in the next section. Alone and particularly together, the outcomes of the different project parts contribute to a better understanding of and improved treatment options for metastatic cancer.
Several noteworthy advances have been made as part of the Meta-Targeting project. These include, but are not limited to: [1] development of an ion pairing strategy and of a novel prodrug platform for specific activation in tumors and efficient encapsulation in polymeric micelles (WP1; Theranostics 2022, JCR 2025); [2] generation of a radiolabelable and cryopreservable polymeric micelle platform (WP1; JCR 2024, Paper Submitted); [3] meta-analysis of the scientific literature of the added value of co-formulating multiple drugs in nanomedicines (WP1; Nat Nanotechnol 2025); [4] experimental evidence demonstrating that pharmacological tumor priming with liposomal dexamethasone and with a chemokine inhibitor enhances tumor-targeted drug delivery and cancer nanomedicine treatment efficacy (WP2; JCR 2024, Cell Biomaterials 2025); [5] development of non-spherical microbubbles and their focused ultrasound-enabled use for opening biological barriers (WP2; PNAS 2023, Adv Mater 2023); [6] proof of concept in mice and patients for correlating imaging-guided nanomedicines accumulation with antitumor efficacy (WP3; Adv Sci 2021, Adv Mater 2022); [7] identification of histological biomarkers in tumor mouse and human biopsies and tissue specimens that able to predict nanomedicine tumor accumulation (WP3; Nat Biomed Eng 2024); [8] systematic comparison of microenvironment features in triple-negative breast cancer primary tumors and metastases in mice and in humans, and correlation analysis with polymeric micelle target site localization (WP3; Cell Reports 2025); [9] demonstration that chemotherapy pretreatment and multidrug resistance promote fibrogenesis in triple- negative breast cancer tumors in mice (WP4; JCR 2023); and [10] development of polymer-prodrug nanovesicles that are able to potently activate innate immunotherapy responses (WP5; JACS 2020). Our efforts have thus generated multiple new tools and technologies for tumor-targeted delivery, for patient stratification, and for multimodal anticancer (immuno)therapy.
The most important examples of progress beyond the state of the art are [1] the development of cryopreservable polymeric micelles that can be radiolabeled and efficiently multi-drug-loaded; [2] the generation of the world’s first non-spherical microbubbles for opening the blood-brain barrier; and [3] the identification of histopathological biomarkers in tumor tissue specimens for patient selection. This progress is important because novel drugs and delivery systems are key to enhance the therapeutic index of cancer (immuno)therapy. Physical and pharmacological modulation of vascular and stromal barriers in tumors and metastases is needed to improve the delivery of all systemic therapeutics, including besides nanomedicines also small molecule drugs, antibodies and cell therapies. Finally, the identification of imaging and tissue biomarkers is critical to address inter- and intra-patient heterogeneity in tumor targeting, and to help establish patient stratification protocols to enhance cancer nanomedicine clinical translation.