Background Cancer immunotherapy has achieved great success in breast cancer treatment in recent years. The Programmed Death-1 (PD-1) /Programmed Death-Ligand 1 (PD-L1) immune checkpoint pathway is among the most studied. BMS-1166, a PD-L1 inhibitor, can interfere with PD-1 and PD-L1 interaction. Transferrin Receptor 1 is a transmembrane glycoprotein overexpressed in various cancer cells, including breast cancer, and can specifically interact with the T7 (HAIYPRH) peptide.Purpose This study hypothesized that BMS-1166-loaded T7-modified poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) polymeric micelles (BMS-T7) could block PD-L1 interaction with PD-1, serving as a targeted immunotherapy for TfR1-positive breast cancer.Methods BMS-1166 was encapsulated in T7-PEG-PCL micelle. Particle size and zeta potential were determined by dynamic light scattering. Particle morphology was studied by transmission electron microscopy. The particles were characterized by Fourier transform infrared, thermogravimetric analysis, and differential scanning calorimetry. Drug encapsulation efficiency, loading degree, and release profile were examined by high-performance liquid chromatography. Human breast cancer MDA-MB-231 was used to test the cytotoxicity. Flow cytometry and immunofluorescence imaging were used to study the PD-L1 inhibition in cell surface and exosomes. MDA-MB-231 and Jurkat co-culture studied T-cell activation and apoptosis.Results The particle size of the empty and drug-loaded micelles showed a size distribution with an average diameter of 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 drug-loaded micelles was 48h. The IC50 of BMS-1166 was 28.77 μM in MDA-MB-231 cells. In addition, the BMS-T7 showed a better inhibitory effect on PD-L1 expression in breast cancer cells and exosomes than the naked drug. The formulation significantly restored T-cell function compared to the BMS-1166 treatment.Conclusion These results provide preliminary evidence indicating that BMS-T7 may have the potential to deliver drugs to breast cancer cells via active targeting and hold great promise in cancer immunotherapy drug delivery applications.
Purpose Hepatocellular carcinoma (HCC) is a highly lethal malignancy with poor prognosis and limited clinical treatments. CD8⁺ T cell-based immunotherapy offers promising therapeutic potential against HCC. We fabricated MMP-9/pH dual-sensitive liposomes co-encapsulating enzalutamide, GB-1107 and BMS-1166 for HCC treatment. Reliable detection approaches are lacking to assess in vivo liposomal behavior. This study established an HPLC-MS/MS method for simultaneous determination of the three drugs in rat plasma, and applied it to characterize their pharmacokinetic profiles.Methods The pH/MMP-9 dual-sensitive liposomes co-loaded with BMS-1166, GB-1107 and enzalutamide were prepared via the thin-film hydration method, and the resultant formulations exhibited satisfactory pharmaceutical properties meeting the predefined quality criteria. For chromatographic separation, a poroshell 120 EC-C18 column (50 × 4.6 mm, 2.7 μm) was adopted, combined with linear gradient elution of 0.1% formic acid in water and acetonitrile. Full validation of the established method was performed strictly following the guidelines for bioanalytical method validation as stated in the Chinese Pharmacopoeia.Results BMS-1166, GB-1107, and enzalutamide exhibited good linearity over the concentration range of 1.0–1000.0 ng/mL. The accuracy and precision of BMS-1166, GB-1107, and enzalutamide all fall below 11.1%. In addition, the recoveries and matrix effect for these analytes ranged from 88.6%-99.7%. Pharmacokinetic results demonstrated that the prepared liposomes possessed favorable in vivo long-circulating properties, which prolonged the half-lives of BMS-1166 and GB-1107 by 25-fold and 13-fold, respectively, and enhanced their bioavailability by 35-fold and 30-fold, respectively. In contrast, no statistically significant effect was observed on enzalutamide.Conclusion The established method was validated and met the predefined quality criteria, thereby being suitable for investigating the in vivo pharmacokinetic profiles of BMS-1166, GB-1107, and enzalutamide.
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