Harnessing CD47 mimicry to inhibit phagocytic clearance and enhance anti-tumor efficacy of nanoliposomal doxorubicin

Abstract

ABSTRACT Background We hypothesized if phagocytosis of liposomes by macrophages could be mitigated through incorporation of a CD47 mimicry peptide (Self peptide: SP) on the surface of liposomes. Methods Thin film hydration method followed by extrusion was used to prepare nanoliposomes, and Dox encapsulation in liposomes was done via remote-loading method. Decorated liposomes with SP peptide (SP-LD) at different peptide densities (300 and 600 peptides on the surface of each liposome) were prepared using a pre-insertion technique. Macrophage cell lines were used to compare the cellular uptake of decorated and unmodified liposomes. For biodistribution studies, tumor-bearing mice received the preparations, and fluorescence signals of Dox in different tissues were measured. To evaluate anti-tumor efficacy, tumor size and survival rates were assessed. Also, pharmacokinetic parameters were determined. Results Compared with PEGylated liposomes, uptake by macrophages was largely decreased when SP was incorporated on liposomes. Following intravenous injection, SP-liposomes were cleared more slowly compared with PEGylated liposomes. Eventually, SP-liposomes were highly distributed to tumor tissues compared with PEGylated liposomes, and significantly reduced tumor size and improved the survival of tumor-bearing mice. Conclusions This research showed reduced macrophage uptake, increased blood circulation, and enhanced tumor accumulation of liposomes through SP incorporation on the surface of particles.