Mitochondria-Targeted Chimeric Peptide for Trinitarian Overcoming of Drug Resistance.
In this report, an amphiphilic mitochondria-targeted chimeric peptide-based drug delivery system (DDS) was designed to overcome drug resistance. In vitro studies revealed that chimeric peptide could encapsulate doxorubicin (DOX) with high efficacy and target tumor mitochondria, realizing controlled release of DOX and in situ photodynamic therapy (PDT) in mitochondria. Importantly, reactive oxygen species (ROS) during PDT significantly disrupted mitochondria, leading to a dramatic decrease of intracellular adenosine 5'-triphophate (ATP). As a result, ATP-dependent efflux of DOX was remarkably inhibited. Trinitarian therapeutic strategy was developed to ablation of drug-resistant cells, that is, (1) enhanced cellular uptake of hydrophobic DOX via encapsulation in DDS, (2) combined chemo-/photodynamic therapies, and (3) suppressed generation of intracellular ATP as well as drug efflux via in situ PDT in mitochondria. This trinitarian strategy may open a new window in the fabrication of subcellular organelle destructive DDS in overcoming drug resistance.
State Key Laboratory of Agricultural Microbiology, College of Science, Huazhong Agricultural University , Wuhan 430070, China.
Kai
K
Han
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University , Wuhan 430072, China.
Jing-Yi
JY
Zhu
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University , Wuhan 430072, China.
Hui-Zhen
HZ
Jia
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University , Wuhan 430072, China.
Shi-Bo
SB
Wang
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University , Wuhan 430072, China.
Shi-Ying
SY
Li
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University , Wuhan 430072, China.
Xian-Zheng
XZ
Zhang
State Key Laboratory of Agricultural Microbiology, College of Science, Huazhong Agricultural University , Wuhan 430070, China.
He-You
HY
Han
D045744:Cell Line, Tumor; D004317:Doxorubicin; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008928:Mitochondria; D010455:Peptides
D010455:Peptides; D004317:Doxorubicin
ATP; combined therapy; drug resistance; mitochondria disruption; photodynamic therapy