Tumor-Penetrating Peptide-Functionalized Ferritin Enhances Antitumor Activity of Paclitaxel

We describe the development of a neuropilin-1 binding peptide (RGERPPR)-ferritin nanocage that specifically targets tumor cells. Herein, the tumor-penetrating peptide RGERPPR motif was modified at the C-terminal of human H chain ferritin (HFtn) using flexible linker moieties. Since the C-terminal of HFtn is positioned toward the inner cavity, relatively long linkers (GGGGS)₄ were used, in which the MMP-2 cleavage site was inserted in the linker. The RGERPPR motif was proved to be exposed outside the protein shell by the effective cleavage at the linker region by MMP-2. The loading of paclitaxel (PTX) and HFtn-mMMP2-RGE was prepared by using the low concentration of urea. In vitro studies demonstrated that HFtn-mMMP2-RGE-PTX nanoparticles exhibited better cytotoxicity and could specifically bind to and be taken up by human lung cancer cells A549 that highly express NRP-1 receptor. Better penetrability and growth inhibitory effect were also verified by the 3D tumor spheroid experiment. The results confirmed that the tumor-targeting and penetration peptide RGERPPR-modified ferritin had great potential in enhancing tumor therapy and could be a promising therapeutic agent.