Distant organ
metastasis is the main cause of death in
breast cancer patients. Evidences have shown that mitochondria also play a crucial role in
tumor metastasis, except for as apoptosis center. However, the treatment of
tumor growth and
metastasis was reported to be limited by mitochondria-associated
protein Bcl-2, which are gatekeepers of apoptosis and are found to reside in mitochondria mainly. Herein, we designed a mitochondria-targeting
doxorubicin delivery system as well as a mitochondrial distributed Bcl-2 function-converting
peptide NuBCP-9 delivery system, which are both based on
N-(2-hydroxypropyl)methacrylamide copolymers, to achieve a synergistic effect on
tumor regression and
metastasis inhibition by combination
therapy. After mitochondria were damaged by mitochondria-targeting
peptide-modified
doxorubicin, apoptosis was effectively enhanced by mitochondrial specifically distributed NuBCP-9
peptides, which converted Bcl-2 function from anti-apoptotic to pro-apoptotic and paved the way for the development of mitochondrial impairment. The combination treatment exhibited significant damage to mitochondria, including excess
reactive oxygen species (ROS), the permeabilization of mitochondrial outer membrane (MOMP), and apoptosis initiation on 4T1
breast cancer cells. Meanwhile, besides enhanced
tumor growth suppression, the combination treatment also improved the inhibition of 4T1
breast cancer metastasis both in vitro and in vivo. By increasing the expression of
cytochrome C and decreasing the expression of Bcl-2,
metal matrix protease-9 (MMP-9) as well as
vascular endothelial growth factor (
VEGF), the combination treatment successfully decreased 84% lung
metastasis. Overall, our work provided a promising strategy for metastatic
cancer treatment through mitochondria-targeting anti-
cancer drug delivery and combination with mitochondrial distributed Bcl-2 function-converting
peptide.