Targeting therapy with mitosomal daunorubicin plus amlodipine has the potential to circumvent intrinsic resistant breast cancer.
Intrinsic resistance of cancers is a major cause of failure in chemotherapy. We proposed here a strategy to overcome intrinsic resistance by constructing cancer cell mitochondria-specifically targeting drug-loaded liposomes, namely, mitosomal daunorubicin plus amlodipine. Anticancer agent daunorubicin and apoptotic inducer amlodipine were loaded together into the mitosomes, and targeting molecule dequalinium was modified on the surface. Evaluations were performed on the breast cancer MCF-7 and resistant MCF-7/adr cells and in animals. Mitosomal daunorubicin plus amlodipine were about 97 nm, selectively accumulated in mitochondria, induced the swelling and disruption of mitochondria, dissipated the mitochondrial membrane potential, released a large amount of cytochrome C by translocation, cleaved Bid, and initiated a cascade of caspase 8 and 3 reactions. A robust anticancer effect was evidenced in vivo. Mitochondria-specifically targeting drug-loaded liposomes would provide a new strategy for treating resistant cancers.
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Yan
Y
Zhang
Ruo-Jing
RJ
Li
Xue
X
Ying
Wei
W
Tian
Hong-Juan
HJ
Yao
Ying
Y
Men
Yang
Y
Yu
Liang
L
Zhang
Rui-Jun
RJ
Ju
Xiao-Xing
XX
Wang
Jia
J
Zhou
Jing-Xian
JX
Chen
Nan
N
Li
Wan-Liang
WL
Lu
D017311:Amlodipine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D017311:Amlodipine; D045304:Cytochromes c; D003630:Daunorubicin