Developing a delivery strategy for combined drug treatment with multi-targeting immunoliposomes

Abstract

With the use of targeting delivery systems, drugs can be specifically administered to tumor cells based on the abundant expression of cell surface markers with minimal expression in normal cells. However, development of treatments using this highly specific approach requires empirical optimization of the tumor cell type, cell surface markers and cytotoxic cargo. In this study, we developed a combined targeting drug delivery strategy for lung cancer that utilizes two liposome-encapsulated topoisomerase inhibitors, liposomal doxorubicin (LD) and liposomal irinotecan (LI). First, we evaluated different combination conditions for the drugs and found that co-administration or administration of LD followed by LI produced similar tumor inhibition trends. In contrast, treatment of with LI followed by LD was less effective at inhibiting tumor growth. Next, we targeted the liposomes against two ligands that are overexpressed in lung cancers: PD-L1 and GRP-78. To do so, we fabricated immunoliposomes conjugated with PD-L1 Fab or GRP-78 antibody. In animal models, combinations of GRP-78-targeted LI and PD-L1-targeted LD showed 92% tumor inhibition which is higher than other combination treatments or each drug alone. Our findings, therefore, indicate that combining different targeting moieties with LI and LD may enhance drug delivery and reduce tumor burden.