期刊
INTERNATIONAL JOURNAL OF NANOMEDICINE
卷 9, 期 -, 页码 5653-5665出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S68511
关键词
nanoparticles; pancreatic cancer; AKT; bioluminescence imaging; drug delivery
资金
- National Cancer Institute through NIH (National Institutes of Health) [CA139503]
- Hirshberg Foundation for Pancreatic Cancer Research
- University of Arizona Cancer Center [NIH CA023074]
- CONACYT fellowship
The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras.
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