Targeting of M2 macrophages with IL-13-functionalized liposomal prednisolone inhibits melanoma angiogenesis in vivo

Abstract

The intricate cooperation between cancer cells and nontumor stromal cells within melanoma microenvironment (MME) enables tumor progression and metastasis. We previously demonstrated that the interplay between tumor-associated macrophages (TAMs) and melanoma cells can be disrupted by using long-circulating liposomes (LCLs) encapsulating prednisolone phosphate (PLP) (LCL-PLP) that inhibited tumor angiogenesis coordinated by TAMs. In this study, our goal was to improve LCL specificity for protumor macrophages (M2-like (i.e., TAMs) macrophages) and to induce a more precise accumulation at tumor site by loading PLP into IL-13-conjugated liposomes (IL-13-LCL-PLP), since IL-13 receptor is overexpressed in this type of macrophages. The IL-13-LCL-PLP liposomal formulation was obtained by covalent attachment of thiolated IL-13 to maleimide-functionalized LCL-PLP. C57BL/6 mice bearing B16.F10 s.c melanoma tumors were used to investigate the antitumor action of LCL-PLP and IL-13-LCL-PLP. Our results showed that IL-13-LCL-PLP formulation remained stable in biological fluids after 24h and it was preferentially taken up by M2 polarized macrophages. IL-13-LCL-PLP induced strong tumor growth inhibition compared to nonfunctionalized LCL-PLP at the same dose, by altering TAMs-mediated angiogenesis and oxidative stress, limiting resistance to apoptosis and invasive features in MME. These findings suggest IL-13-LCL-PLP might become a promising delivery platform for chemotherapeutic agents in melanoma.

Keywords:

• active tumor targeting
• melanoma
• tumor microenvironment
• liposomes

Author contributions

Conceptualization and study design: MB; funding acquisition: MB, AS, EL; execution: LL, VFR, LP, EL, MSM, BRD, GN, VAT, AP, DM, AS, MB: acquisition of data: LL, VFR, LP, EL, BRD, VAT, AP, DM, AS; analysis and interpretation: AS, MB; writing—original draft: AS, VFR, review and editing: AS, MB.

Conflicts of interest

The authors declare no conflict of interest.

Data availability statement

The datasets generated/analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was funded by UEFISCDI under Grants PN‐III‐P4‐ID‐PCE‐2016‐0342 (No. 91/2017), PN-III-P2-2_1-PED-2021–0411 (No.659PED/2022), PN-III-P1-1.1-TE-2019–1320, (no. TE 121/14.09.2020), and under Scientific Fellowship granted by Babes-Bolyai University 36597/25.11.2022.