Targeted Delivery of BMS-1166 for Enhanced Breast Cancer Immunotherapy
Background: Cancer immunotherapy has made significant strides in breast cancer treatment in recent years, with the Programmed Death-1 (PD-1) / Programmed Death-Ligand 1 (PD-L1) immune checkpoint pathway being one of the most extensively studied. BMS-1166, a PD-L1 inhibitor, disrupts the interaction between PD-1 and PD-L1. Transferrin Receptor 1 (TfR1), a transmembrane glycoprotein overexpressed in various cancer cells, including breast cancer, specifically interacts with the T7 (HAIYPRH) peptide.
Purpose: This study aimed to test the hypothesis that BMS-1166-loaded T7-modified poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) polymeric micelles (BMS-T7) could block the PD-L1/PD-1 interaction, serving as a targeted immunotherapy for TfR1-positive breast cancer.
Methods: BMS-1166 was encapsulated in T7-PEG-PCL micelles. The particle size and zeta potential were determined using dynamic light scattering, while particle morphology was observed with transmission electron microscopy. Characterization was performed by Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry. The drug’s encapsulation efficiency, loading degree, and release profile were analyzed using high-performance liquid chromatography. The cytotoxicity was tested in human breast cancer MDA-MB-231 cells. PD-L1 inhibition was studied on the cell surface and in exosomes using flow cytometry and immunofluorescence imaging. T-cell activation and apoptosis were assessed in MDA-MB-231 and Jurkat co-culture experiments.
Results: The particle size of the empty micelles and drug-loaded micelles was 54.62 ± 2.28 nm and 60.22 ± 2.56 nm, respectively. The encapsulation efficiency of BMS-T7 was 83.89 ± 5.59%. The release half-life of the drug-loaded micelles was 48 hours. The IC50 of BMS-1166 in MDA-MB-231 cells was 28.77 μM. BMS-T7 demonstrated a stronger inhibitory effect on PD-L1 expression in breast cancer cells and exosomes compared to the free drug. Additionally, BMS-T7 significantly restored T-cell function compared to BMS-1166 treatment alone.
Conclusion: These results provide preliminary evidence suggesting that BMS-T7 has the potential to actively target breast cancer cells and may offer promising applications in cancer immunotherapy drug delivery.