Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells.
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.
Jun
J
Zhao
‡Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
Chunhui
C
Wu
∥Division of Medical Oncology, Duke School of Medicine, Durham, North Carolina 27710, United States.
James
J
Abbruzzese
Rosa F
RF
Hwang
Chun
C
Li
D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000378:metabolism; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D011108:Polymers; D015398:Signal Transduction / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000009:adverse effects / Q000737:chemistry*
D008823:Micelles; D011108:Polymers; D014704:Veratrum Alkaloids; C000541:cyclopamine
DNA damage repair; cyclopamine; pancreatic cancer; radiation sensitization; stroma disruption