Regulation of protein corona on liposomes using albumin-binding peptide for targeted tumor therapy.

Nanocarriers entering the body are usually coated by plasma protein, leading to a protein "corona" easily recognized by tissues and cells. Adjusting the composition of protein coronas may be an efficient way to change the properties and behavior of nanoparticles in vivo. In this study, we modified doxorubicin-loaded liposomes (Lip/DOX) with an albumin-binding domain (ABD) to prepare nanoparticles (ABD-Lip/DOX) that can specifically bind to albumin and form albumin-based protein coronas in vivo for targeted tumor therapy. The prepared liposomes were spherical with a particle size of about 100 nm. After incubating the liposomes with rat serum, the albumin content was eight times higher on ABD-Lip than on control liposomes. ABD-Lip significantly inhibited adsorption of IgG and complement activation in rat serum in vitro, while corona-coated ABD-Lip was internalized to a significantly greater extent than corona-coated control liposomes. In addition, ABD-Lip showed longer blood circulation time, higher tumor accumulation and greater antitumor efficacy than control liposomes in mice bearing 4 T1 tumors, while both liposome formulations showed similar biocompatibility. These results confirm that adjusting the component of protein coronas around nanoparticles can improve their therapeutic efficacy.

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

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.

The protein corona and its effects on nanoparticle-based drug delivery systems.

In most cases, once nanoparticles (NPs) enter the blood, their surface is covered by biological molecules, especially proteins, forming a so-called protein corona (PC). As a result, what the cells of the body "see" is not the NPs as formulated by the chemists, but the PC. In this way, the PC can influence the effects of the NPs and even mask the desired effects of the NP components. While this can argue for trying to inhibit protein-nanomaterial interactions, encapsulating NPs in an endogenous PC may increase their clinical usefulness. In this review, we briefly introduce the concept of the PC, its formation and its effects on the behavior of NPs. We also discuss how to reduce the formation of PCs or exploit them to enhance NP functions. Studying the interactions between proteins and NPs will provide insights into their clinical activity in health and disease. STATEMENT OF SIGNIFICANCE: The formation of protein corona (PC) will affect the operation of nanoparticles (NPs) in vivo. Since there are many proteins in the blood, it is impossible to completely overcome the formation of PC. Therefore, the use of PCs to deliver drug is the best choice. De-opsonins adsorbed on NPs can reduce macrophage phagocytosis and cytotoxicity of NPs, and prolong their circulation in blood. Albumin, apolipoprotein and transferrin are typical de-opsonins. In present review, we mainly discuss how to optimize the delivery of nanoparticles through the formation of albumin corona, transferrin corona and apolipoprotein corona in vivo or in vitro.

Maleimide-Functionalized Liposomes for Tumor Targeting via In Situ Binding of Endogenous Albumin.

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.