LHD-Modified Mechanism-Based Liposome Coencapsulation of Mitoxantrone and Prednisolone Using Novel Lipid Bilayer Fusion for Tissue-Specific Colocalization and Synergistic Antitumor Effects.

Coencapsulation liposomes are of interest to researchers because they maximize the synergistic effect of loaded drugs. A combination regimen of mitoxantrone (MTO) and prednisolone (PLP) has been ideal for tumor therapy. MTO and PLP offer synergistic antitumor effects confirmed by several experiments in this research. The deduced synergistic mechanism is regulation of Akt signaling pathway including the targets of p-Akt, p-GSK-3β, p-s6 ribosomal protein, and p-AMPK by MTO reactivating PLP-induced apoptosis. The liposome fusion method is adopted to create coencapsulation liposomes (PLP-MTO-YM). Low molecular weight heparin-sodium deoxycholate conjugate (LHD) then is used as a targeting ligand to prove target binding and inhibition of angiogenesis. LHD-modified liposomes (PLP-MTO-HM) have a high entrapment efficiency around 95% for both MTO and PLP. DSC results indicate that both drugs interacted with liposomes to prevent drug leak during liposome fusion. DiD-C6-HM dyes colocalize well to tumor tissue, and coadministration of DiD-HM and C6-CM did not achieve dye colocalization until 24 h after administration. In both CT26 and B16F10 mouse model, PLP-MTO-HM shows a significantly higher tumor inhibition rate relative to the coadministration of MTO-HM and PLP-CM (p < 0.05 or p < 0.01). Thus, the coencapsulation system (PLP-MTO-HM) offers ideal antitumor effects relative to coadministration therapy due to enhanced synergistic effect, and this suggests a promising future for the tumor targeting vectors.