Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 9, Issue 50, Pages 43498-43507Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.7b14577
Keywords
mitochondria targeting; triphenylphosphine; lonidamine; chemotherapy; drug resistance
Funding
- National Basic Research Program of China [2013CB933500]
- National Natural Science Foundation of China [61422403, 51672180, 51622306, 21673151]
- Qing Lan Project
- Collaborative Innovation Center of Suzhou Nano Science and Technology (NANO-CIC)
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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Lonidamine (LND) can act on mitochondria and inhibit energy metabolism in cancer cells and therefore has been used together with chemotherapy drugs for synergistically enhanced therapeutic efficacy. However, its use is hindered by the poor solubility and slow diffusion in the cytoplasm. To address these problems, we designed and prepared aqueous dispersible nanoparticles (NPs) containing integrated components including triphenylphosphine (TPP) to target the mitochondria of cells and LND and doxorubicin (DOX) for synergistic cancer treatment and conquering drug resistance. This design allows the NPs to concentrate in the mitochondria of cells, solve the low solubility of LND, and contain very high load of LND and DOX in comparison with previously reported drug-delivery systems based on various carrier nanomaterials. Detailed mechanism studies reveal that TPP-LND-DOX NPs could induce significant reactive oxygen species production, mitochondrial membrane potential decrease, and mitochondrial apoptosis pathway, thereby leading to great cytotoxicity in cancer cells. In vivo anticancer activities indicate that TPP-LND-DOX NPs exhibit the highest efficacy in tumor inhibition among all tested groups and show high effectiveness in drug-resistant model. This work demonstrates the potential use of our TPP-LND-DOX NPs to jointly promote the mitochondria apoptosis pathway and contribute to conquer drug resistance in cancer therapy.
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