In Vivo Pharmacokinetics, Tumor Biodistribution and Near Infrared Imaging of Macrophage Membrane-Camouflaged Redox-Responsive Liposomes for Breast Cancer Theranostics

Abstract

Breast cancer, particularly triple-negative breast cancer (TNBC), remains a major therapeutic challenge because of aggressive tumor progression, systemic toxicity, rapid clearance of conventional chemotherapeutics, and multidrug resistance. The present study developed a biomimetic, redox-responsive liposomal theranostic system for the co-delivery of doxorubicin (DOX) and indocyanine green (ICG). Redox-sensitive liposomes (RSL/DOX/ICG) were prepared using a thin-film hydration method with an ammonium sulfate gradient for DOX loading and subsequently camouflaged with macrophage membranes to obtain MM-RSL/DOX/ICG. The formulation was designed to combine prolonged systemic circulation, tumor accumulation, glutathione-responsive drug release, and near-infrared (NIR) imaging-assisted chemo-photothermal therapy. In vivo pharmacokinetic evaluation in BALB/c mice demonstrated a substantial enhancement in systemic exposure following macrophage membrane camouflage. The elimination half-life increased from 3.85 h for free DOX to 18.21 h for MM-RSL/DOX/ICG, while the AUC increased from 14.6 to 92.8 µg·h/mL. Correspondingly, systemic clearance decreased from 342.5 to 53.9 mL/h/kg and mean residence time increased from 4.8 to 22.4 h. In 4T1 tumor-bearing mice, NIR imaging demonstrated sustained tumor-associated fluorescence, with a tumor-to-normal tissue ratio of 4.8 ± 0.6 at 24 h. Ex vivo analysis showed tumor accumulation of 18.6 ± 2.4 %ID/g, substantially higher than free DOX/ICG and non-camouflaged RSL/DOX/ICG. Furthermore, MM-RSL/DOX/ICG combined with 808 nm laser irradiation increased median survival to 58 days compared with 24 days for saline-treated animals, while maintaining relatively stable body weight. Overall, the findings demonstrate that macrophage membrane camouflage combined with redox-responsive liposomal delivery provides an integrated platform for enhanced pharmacokinetics, tumor targeting, NIR imaging, and chemo-photothermal treatment of breast cancer.