期刊
MOLECULAR PHARMACEUTICS
卷 12, 期 6, 页码 2093-2100出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp500875f
关键词
cyclopamine; radiation sensitization; pancreatic cancer; stroma disruption; DNA damage repair
资金
- Viragh Family Foundation
- John S. Dunn Foundation
- National Institutes of Health through Cancer Center Support Grant [P30CA016672]
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Cyclopamine (CPA), a potent inhibitor for sonic hedgehog pathway (SHH), shows great promises in PDAC treatment, including the disruption of tumor-associated stroma, and enhancement of radiation therapy. However, CPA is insoluble in water and therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-cross-linked polymeric micelle system (M-CPA). M-CPA was combined with Cs-137 radiation and evaluated in vitro in PDAC cell lines and a human pancreatic stellate cell line. The results showed that M-CPA had higher cytotoxicity than CPA, abolished Gli-1 expression (a key component of SHH), and enhanced the radiation therapy of Cs-137. M-CPA radiosensitization correlated with its ability to disrupt the repair of radiation-induced DNA damage. These findings indicate that the combination therapy of M-CPA and radiation is an effective strategy to simultaneously treat pancreatic tumors and tumor-associated stroma.
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