Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 8, Issue 38, Pages 25060-25068Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.6b06522
Keywords
ATP; mitochondria disruption; photodynamic therapy; drug resistance; combined therapy
Funding
- Fundamental Research Funds for the Central Universities [2662015QD026]
- National Natural Science Foundation of China [51603080, 21375043, 21175051]
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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.
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