Tumor Priming using Clinical-Stage Corticosteroid Liposomes

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, together negatively affecting drug delivery. Reasoning that tumor-targeted glucocorticoid therapy has pleiotropic effects, we used clinical-stage dexamethasone liposomes (LipoDex) to modulate macrophages in desmoplastic malignancies 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 and multiscale 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.