| Autor: |
Hung J; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA., Perez SM; ZielBio Inc., Charlottesville, VA 22902, USA., Dasa SSK; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA., Hall SP; ZielBio Inc., Charlottesville, VA 22902, USA., Heckert DB; ZielBio Inc., Charlottesville, VA 22902, USA., Murphy BP; ZielBio Inc., Charlottesville, VA 22902, USA., Crawford HC; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.; Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.; Henry Ford Pancreatic Cancer Center, Henry Ford Health, Detroit, MI 48202, USA., Kelly KA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.; ZielBio Inc., Charlottesville, VA 22902, USA., Brinton LT; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.; ZielBio Inc., Charlottesville, VA 22902, USA. |
| Abstrakt: |
Cancer-associated fibroblasts (CAFs) execute diverse and complex functions in cancer progression. While reprogramming the crosstalk between CAFs and cancer epithelial cells is a promising avenue to evade the adverse effects of stromal depletion, drugs are limited by their suboptimal pharmacokinetics and off-target effects. Thus, there is a need to elucidate CAF-selective cell surface markers that can improve drug delivery and efficacy. Here, functional proteomic pulldown with mass spectrometry was used to identify taste receptor type 2 member 9 (TAS2R9) as a CAF target. TAS2R9 target characterization included binding assays, immunofluorescence, flow cytometry, and database mining. Liposomes conjugated to a TAS2R9-specific peptide were generated, characterized, and compared to naked liposomes in a murine pancreatic xenograft model. Proof-of-concept drug delivery experiments demonstrate that TAS2R9-targeted liposomes bind with high specificity to TAS2R9 recombinant protein and exhibit stromal colocalization in a pancreatic cancer xenograft model. Furthermore, the delivery of a CXCR2 inhibitor by TAS2R9-targeted liposomes significantly reduced cancer cell proliferation and constrained tumor growth through the inhibition of the CXCL-CXCR2 axis. Taken together, TAS2R9 is a novel cell-surface CAF-selective target that can be leveraged to facilitate small-molecule drug delivery to CAFs, paving the way for new stromal therapies. |
