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Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy.

Albumin, the most abundant protein in plasma, has been widely used in drug delivery studies. Here, we developed maleimide-functionalized liposomes (Mal-Lip) that can bind to endogenous albumin to improve the tumor targeting efficiency of liposomes. Transmission electron microscopy and gel electrophoresis studies showed that albumin can bind to Mal-Lip due to the chemical coupling of the albumin thiol groups with the maleimide group. Both conventional liposomes and Mal-Lip showed minimal cytotoxicity within the tested range of lipid concentrations, indicating that the maleimide functionality did not increase the toxicity of liposomes to various cells. Mal-Lip was taken up by 4T1 cells to a greater extent than conventional liposomes, and Mal-Lip accumulated in 4T1 tumors in mice more than conventional liposomes after intravenous injection. These results suggest that the maleimide group can improve the tumor targeting efficiency of liposomes in vivo by binding to endogenous albumin in situ. However, the maleimide group also enhanced the uptake of Mal-Lip by Raw264.7 cells and shortened their time in circulation, indicating that further studies should be performed to prevent elimination of Mal-Lip by the immune system.