M2 macrophage-targeting peptide-modified liposomes enhance the uptake and antitumor efficacy of liposomal IFN-γ in mice with C26 colon carcinoma.

While liposomes enhance the safety and pharmacokinetic profile of free drugs, they have not significantly improved therapeutic efficacy. To overcome this challenge, targeted depletion of tumor-associated macrophages (TAMs) shows significant potential as an effective antitumor therapy, reducing off-target effects in comparison to non-targeted liposomes. In the context of peptide-mediated targeted cancer therapy, we evaluated the reprogramming activity of IFN-γ liposomes on TAMs, as well as that of IFN-γ liposomes modified with an M2 macrophage-targeting peptide, which binds preferentially to murine anti-inflammatory M2 macrophages/M2-like TAMs. Flow cytometry analysis showed significantly enhanced cellular uptake of m2-peptide-targeted liposomes in J774.1 macrophage cell lines compared to non-targeted liposomes. In BALB/c mice bearing C-26 murine carcinoma, the m2-peptide-targeted liposome groups exhibited significantly higher IFN-γ concentrations compared to non-targeted counterparts within the tumor environment. Furthermore, m2-peptide-targeted F2 liposomes at doses of 25 μg IFN-γ/kg resulted in superior tumor growth inhibition and greater tumor accumulation, indicating the potential of macrophage-targeted therapy in cancer growth inhibition. However, they failed to improve the overall therapeutic efficacy compared to Doxil. This study proposes a combination therapy of m2-peptide-targeted IFN-γ liposomes with successful chemotherapeutic liposomes such as Doxil.