期刊
NATURE NANOTECHNOLOGY
卷 13, 期 1, 页码 72-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41565-017-0009-7
关键词
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资金
- National Cancer Institute at the National Institutes of Health [P50 CA97274/UI, P30 CA086862, R01 CA099908, R01 CA184101]
- Lyle and Sharon Bighley Professorship
- Department of Obstetrics and Gynecology Research Fund
- Egyptian Ministry of Higher Education
- NATIONAL CANCER INSTITUTE [P30CA086862, P50CA097274, R01CA184101, R01CA099908] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [T90DE023520] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES005605] Funding Source: NIH RePORTER
Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumour suppressor p53. Our objective was to engender synthetic lethality to paclitaxel (PTX), the frontline treatment for endometrial cancer, in tumours with mutant p53 and enhance the therapeutic efficacy using polymeric nanoparticles (NPs). First, we identified the optimal NP formulation through comprehensive analyses of release profiles and cellular-uptake and cell viability studies. Not only were PTX-loaded NPs superior to PTX in solution, but the combination of PTX-loaded NPs with the antiangiogenic molecular inhibitor BIBF 1120 (BIBF) promoted synthetic lethality specifically in cells with the loss-of-function (LOF) p53 mutation. In a xenograft model of endometrial cancer, this combinatorial therapy resulted in a marked inhibition of tumour progression and extended survival. Together, our data provide compelling evidence for future studies of BIBF- and PTX-loaded NPs as a therapeutic opportunity for LOF p53 cancers.
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