TY - JOUR
T1 - Enhancing Apoptosome Assembly via Mito-Biomimetic Lipid Nanocarrier for Cancer Therapy
AU - Han, Huijie
AU - Chen, Jie
AU - Li, Jiachen
AU - Correia, Alexandra
AU - Bártolo, Raquel
AU - Shahbazi, Mohammad-Ali
AU - Teesalu, Tambet
AU - Wang, Shiqi
AU - Cui, Wenguo
AU - Santos, Hélder A.
PY - 2023/11/9
Y1 - 2023/11/9
N2 - Apoptosis is the natural programmed cell death process, which is responsible for abnormal cell clearance. However, many cancer cells develop various mechanisms to escape apoptosis through interrupting apoptosome assembly, which is a key step to initiate apoptosis. This promotes tumorigenesis and drug resistance, and thus, poses a great challenge in cancer treatment. Herein, a biomimetic lipid nanocarrier mimicking mitochondrial Cytochrome C (Cyt C) binding is developed. Cardiolipin, the major phospholipid of mitochondrial inner membrane, is introduced as the main component in biomimetic liposomal formulation. With the help of cardiolipin, Cyt C is sufficiently loaded in liposome based on electrostatic and hydrophobic interaction with cardiolipin. Lonidamine (LND) is added in hydrophobic phase of liposome to modulate the metabolic activity within cancer cells and sensitize the cells to Cyt C-induced apoptosis. The results suggest that LND reduces ATP level and creates favorable environment for Cyt C induced apoptosome assembly, exhibiting higher apoptosis level and anti-tumor efficacy in vitro and in vivo. The conjugation of a tumor-homing peptide, LinTT1, on the nanovesicle, increases the efficacy due to enhanced tumor accumulation. Overall, this biomimetic lipid nanocarrier proves to be an efficient delivery system with great potential of pro-apoptosis cancer therapy.
AB - Apoptosis is the natural programmed cell death process, which is responsible for abnormal cell clearance. However, many cancer cells develop various mechanisms to escape apoptosis through interrupting apoptosome assembly, which is a key step to initiate apoptosis. This promotes tumorigenesis and drug resistance, and thus, poses a great challenge in cancer treatment. Herein, a biomimetic lipid nanocarrier mimicking mitochondrial Cytochrome C (Cyt C) binding is developed. Cardiolipin, the major phospholipid of mitochondrial inner membrane, is introduced as the main component in biomimetic liposomal formulation. With the help of cardiolipin, Cyt C is sufficiently loaded in liposome based on electrostatic and hydrophobic interaction with cardiolipin. Lonidamine (LND) is added in hydrophobic phase of liposome to modulate the metabolic activity within cancer cells and sensitize the cells to Cyt C-induced apoptosis. The results suggest that LND reduces ATP level and creates favorable environment for Cyt C induced apoptosome assembly, exhibiting higher apoptosis level and anti-tumor efficacy in vitro and in vivo. The conjugation of a tumor-homing peptide, LinTT1, on the nanovesicle, increases the efficacy due to enhanced tumor accumulation. Overall, this biomimetic lipid nanocarrier proves to be an efficient delivery system with great potential of pro-apoptosis cancer therapy.
KW - apoptosis
KW - apoptosome
KW - cancer therapy
KW - cytochrome c
KW - nanoparticles
U2 - 10.1002/adfm.202305316
DO - 10.1002/adfm.202305316
M3 - Article
SN - 1616-301X
VL - 33
SP - 1
EP - 11
JO - Advanced Functional Materials
JF - Advanced Functional Materials
IS - 46
M1 - 2305316
ER -