Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment

Abstract

Specific targeting and cellular internalization are key properties for carriers of antitumor therapeutic agents. Here, we develop a drug carrier through the attachment of substrate of endoprotease legumain, alanine-alanine-asparagine (AAN), to cell-penetrating peptides (TAT, trans-activating factor). The addition of the AAN moiety to the fourth lysine in the TAT creates a branched peptide moiety, which leads to a decrease in the transmembrane transport capacity of TAT by 72.65%. Legumain efficiently catalyses the release of TAT-liposome from the AAN-TAT-liposome and thereby recovers the penetrating capacity of TAT. Doxorubicin carried by the AAN-TAT-liposome led to an increase in the tumoricidal effect of doxorubicin and a reduction in its systemic adverse effects in comparison with doxorubicin carried by a control delivery system. Thus, the specific targeting and high efficiency of this delivery platform offers a novel approach to limit the toxicity of anticancer agents as well as increasing their efficacy in cancer therapy.

Cell-penetrating peptides: strategies for anticancer treatment

“…This branched TAT was engrafted into liposomes to deliver Dox, but only responded to legumain-expressing 4T1 cells, which exhibited accumulation and internalization of Dox. Furthermore, the treatment of AAN-TATliposome-Dox induced the tumor regression in a 4T1-orthotopic model [78].…”

Sodium alginate-functionalized nanodiamonds as sustained chemotherapeutic drug-release vectors

“…The family of nanocarriers include polymer, nano-liposome, carbon nanomaterials, and gold nanoparticles [3][4][5][6][7], while some of them still have safety concerns [8][9][10][11]. In addition, the intracellular retention time of drugs loaded by these nanomaterials is transient [12][13][14][15][16], which harmers their translation into further biomedical application.…”

Pericellular proteolysis in cancer

“…A related strategy to limit toxicity took advantage of legumain proteasemediated release of doxorubicin-containing liposomal nanoparticles to render them cell-permeable. Given that legumain is highly expressed in both cancer cells and macrophages, this enabled selective uptake of the cytotoxic drug by both cell types within the tumor microenvironment (Liu et al 2014). Finally, small molecule inhibitors have been developed for the different catalytic classes discussed in this review, and several of these agents are in clinical trials or FDA-approved, as in the case of proteasome inhibitors (Turk 2006;Fingleton 2007;Palermo and Joyce 2008;Drag and Salvesen 2010;Seidah and Prat 2012;Crawford and Irvine 2013).…”