Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity

Abstract

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.

Multifunctional and stimuli-responsive liposomes in hepatocellular carcinoma diagnosis and therapy

“…For instance, betulinic acid can be utilized for treatment of colorectal cancer, but when it is loaded in pH-sensitive liposomal nanoparticles prepared from Eudragit S100, its cytotoxicity against tumor cells enhances and based on in vitro and in vivo studies, these drug-loaded liposomes are able to decrease expression levels of NFAT1 and NFAT4, and enhance natural killer (NK) and CD3+ cells in improving anti-tumor immunity against colorectal tumor [50] . The previous study focused on delivery of a naturally occurring anti-tumor compound in cancer therapy and notably, chemotherapy agents such as DOX can be delivered by liposomes in cancer therapy [51] . DOX is an inhibitor of topoisomerase II and due to high cases of chemoresistance, its delivery by nanostructures has been of importance .…”

“…DOX is an inhibitor of topoisomerase II and due to high cases of chemoresistance, its delivery by nanostructures has been of importance . Application of liposomes functionalized with maleimide is beneficial for promoting retention of DOX at tumor site and enhances its cytotoxicity against breast tumor cells [51] . The more interesting part related to liposomes is their ability in delivery of two anti-tumor compounds.…”

Recent Advances in Intranasal Liposomes for Drug, Gene, and Vaccine Delivery

“…For example, coating liposomes with chitosan increased the mucoadhesion of the liposomes and resulted in an increased AUC plasma of sumatriptan [ 115 ]. Maleimide has been used in many studies to develop mucoadhesive liposomes due to its interactions with the sulfhydryl groups in mucins [ 116 , 117 ]. This polymer can be used for functionalizing IN liposomes with mucoadhesive characteristics in future studies.…”