Inflammation is a hallmark of cancer. It contributes to a heterogeneous, hyperpermeable, and poorly perfused tumor vasculature, as well as to a dense and disorganized extracellular matrix, which together negatively affect drug delivery. Reasoning that glucocorticoids have pleiotropic effects, we use clinical-stage dexamethasone liposomes (LipoDex) to prime the tumor microenvironment for improved drug delivery and enhanced treatment efficacy. We show that LipoDex priming improves tumor vascular function and reduces extracellular matrix deposition. Single-cell sequencing corroborates LipoDex-mediated inhibition of pro-inflammatory, pro-angiogenic, and pro-fibrogenic gene expression in mononuclear cells, tumor-associated macrophages, and cancer-associated fibroblasts. Multimodal optical imaging illustrates that LipoDex pre-treatment increases the tumor accumulation and intratumoral distribution of subsequently administered polymeric and liposomal drug delivery systems. Using Doxil as a prototypic nanodrug, we finally show that LipoDex priming promotes antitumor treatment efficacy. Altogether, our findings demonstrate that desmoplastic tumors can be primed for improved drug targeting and therapy using clinical-stage glucocorticoid liposomes.

Department of Nephrology and Clinical Immunology RWTH Aachen University Clinic 52074 Aachen Germany

Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University 3584 CG Utrecht the Netherlands

Department of Surgery Yong Loo Lin School of Medicine National University of Singapore Singapore 119228 Singapore

Department of Targeted Therapeutics MIRA Institute for Biomedical Technology and Technical Medicine University of Twente 7500 AE Enschede the Netherlands

Gremse IT GmbH Aachen Germany

Institute for Experimental Molecular Imaging RWTH Aachen University Clinic 52074 Aachen Germany

Institute for Pathology RWTH Aachen University Clinic 52074 Aachen Germany

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic 16200 Prague Czech Republic

Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry RWTH Aachen University Clinic 52074 Aachen Germany

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