Micropharmacology Beyond Target Expression: Mapping Barriers to Intra-Tumoral Drug Delivery

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• High-dimension spatial technologies map cancer's cellular and molecular landscape, identifying targets but not drug distribution.
• Spatial heterogeneity of target proteins is known, but quantifying therapeutic drug penetration remains a challenge.

Purpose of the Study:

• To apply highly multiplexed spatial proteomics to quantify drug distribution in patient tumors treated with antibody therapeutics.
• To identify factors influencing drug penetration and distribution at the single-cell level.

Main Methods:

• Utilized highly multiplexed spatial proteomics on tumor samples from patients receiving fluorescently labeled antibody therapeutics.
• Quantified drug penetration and distribution on cells with specific phenotypes.

Main Results:

• Identified significant variability in antibody drug distribution between patients and within individual tumors.
• Factors such as macrophage uptake, stromal barriers, vascularization, and epithelial permeability were associated with altered drug distribution.
• Highly desmoplastic pancreatic cancers and fibroblast/extracellular matrix-rich head and neck squamous cell carcinomas (HNSCCs) showed poor drug delivery.

Conclusions:

• Spatial proteomics provides a measurement strategy for single-cell drug distribution.
• Understanding these barriers is crucial for precision medicine and designing improved antibody therapeutics.
• Variability in drug distribution poses a significant challenge to therapeutic success.