Journal
DRUG DESIGN DEVELOPMENT AND THERAPY
Volume 15, Issue -, Pages 3223-3239Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S317454
Keywords
doxorubicin hydrochloride; celecoxib; co-delivery; targeting liposomes; multidrug resistance
Categories
Funding
- Natural Science Foundation of Jiangsu Province [BK20201344]
- China Postdoctoral Science Foundation [2019M660166]
- National Natural Science Foundation of China [81703437, 81872220]
- Postdoctoral Innovation Project of Shandong Province [202002039]
- Basic Public Welfare Research Project of Zhejiang Province [LGF20H300012]
- Science and Technology Bureau of Jiaxing [2019AY32009]
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The study developed a multifunctional nano-structured liposomal system for co-delivery of doxorubicin and celecoxib to overcome doxorubicin resistance in breast cancer, showing remarkable treatment efficacy. The peptide-modified targeted liposomes exhibited strong cellular entry ability and mitochondrial-targeting effect, effectively inhibiting P-glycoprotein efflux activity.
Background: The active-targeted drug delivery systems had attracted more and more attention to efficiently overcome multidrug resistance (MDR) in cancer treatments. The aim of the work was to develop a multifunctional nano-structured liposomal system for co-delivery of doxorubicin hydrochloride (DOX) and celecoxib (CEL) to overcome doxorubicin resistance in breast cancer. Methods: A functional hybrid peptide (MTS-R8H3) with unique cellular penetrability, endolysosomal escape and mitochondrial targeting ability was successfully synthesized using solid phase synthesis technology. The peptide modified targeted liposomes (DOX/CEL-MTS-R8H3 lipo) for co-delivery of DOX and CEL were formulated to overcome the chemoresistance in MCF/ADR cells. Results: DOX/CEL-MTS-R8H3 lipo showed nanosized shape and displayed high stability for one month. The cytotoxicity effect of the co-delivery of DOX and CEL through peptide modified liposomes had remarkable treatment efficacy on killing MCF/ADR cells. Targeted liposome exhibited greater cellular entry ability about 5.72-fold stronger than DOX solution. Moreover, as compared with unmodified liposomes, the presence of MTS-R8H3 peptide entity on liposome surface enhanced the mitochondrial-targeting ability and achieved effective reactive oxygen species (ROS) production with significant inhibition of P-gp efflux activity. Conclusion: The study suggested that the DOX/CEL-MTS-R8H3 lipo is a promising strategy for overcoming drug resistance in breast cancer treatments with high targeting inhibition efficiency.
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