Desmoplastic tumor priming using clinical-stage corticosteroid liposomes

Area of Science:

• Oncology
• Nanomedicine
• Pharmacology

Background:

• Tumor inflammation, abnormal vasculature, and dense extracellular matrix impede effective drug delivery.
• Glucocorticoids possess pleiotropic effects that can potentially modulate the tumor microenvironment.
• Improving drug delivery is critical for enhancing cancer therapeutic outcomes.

Purpose of the Study:

• To investigate the use of clinical-stage dexamethasone liposomes (LipoDex) to prime the tumor microenvironment for enhanced drug delivery and therapeutic efficacy.
• To assess the impact of LipoDex priming on tumor vascular function and extracellular matrix deposition.
• To evaluate the effects of LipoDex on gene expression in key tumor-associated cells.

Main Methods:

• Administration of LipoDex to pre-condition the tumor microenvironment.
• Assessment of tumor vascular function and extracellular matrix using multimodal optical imaging.
• Single-cell RNA sequencing to analyze gene expression changes in mononuclear cells, tumor-associated macrophages, and cancer-associated fibroblasts.
• Evaluation of the delivery and distribution of subsequent nanodrugs (e.g., Doxil) after LipoDex priming.
• Assessment of antitumor treatment efficacy.

Main Results:

• LipoDex priming improved tumor vascular function and reduced extracellular matrix deposition.
• Single-cell sequencing revealed LipoDex-mediated inhibition of pro-inflammatory, pro-angiogenic, and pro-fibrogenic gene expression.
• LipoDex pre-treatment enhanced the accumulation and intratumoral distribution of subsequently administered nanodrugs.
• LipoDex priming significantly promoted antitumor treatment efficacy when using Doxil as a model nanodrug.

Conclusions:

• Clinical-stage dexamethasone liposomes can effectively prime the tumor microenvironment in desmoplastic tumors.
• LipoDex priming enhances drug delivery and improves antitumor efficacy by modulating the tumor microenvironment.
• This strategy offers a promising approach for improving the targeting and therapeutic outcomes of nanomedicines in cancer treatment.