TY - JOUR
T1 - Chemoradiation therapy using cyclopamine-loaded liquid-lipid nanoparticles and lutetium-177-labeled core-crosslinked polymeric micelles
AU - You, Jian
AU - Zhao, Jun
AU - Wen, Xiaoxia
AU - Wu, Chunhui
AU - Huang, Qian
AU - Guan, Fada
AU - Wu, Richard
AU - Liang, Dong
AU - Li, Chun
N1 - Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015/3/28
Y1 - 2015/3/28
N2 - Cyclopamine (CPA), a potent inhibitor of the Hedgehog pathway, has produced promising anticancer results in a number of preclinical studies. CPA has also been found to enhance tumor response to radiation therapy. However, CPA is water insoluble. A drug delivery system suitable for systemic administration of CPA is needed before CPA can be considered for clinical translation. We hypothesized that CPA solubilized in a liquid-lipid nanoparticle system (CPA-LLP) for intravenous injection would have desirable pharmacokinetic properties and increased anticancer efficacy. We further hypothesized that CPA-LLP would enhance the response of tumor cells to targeted radiotherapy delivered selectively through intratumoral injection of lutetium-177 bound to core-crosslinked polymeric micelles (CCPM-177Lu). We tested the combination therapy in 4T1 murine breast cancer and Miapaca-2 human pancreatic adenocarcinoma models. The results showed that CPA-LLP had higher antitumor cytotoxicity than free CPA (IC50 values [mean ± SEM]: 2.7 ± 0.2 μM vs. 11.3 ± 1.2 μM against 4T1 cells; 1.8 ± 0.2 vs. 17.1 ± 1.26 μM against Miapaca-2 cells; p < 0.0001). In both cell lines, CPA-LLP resulted in significantly lower clonogenicity than free CPA (p < 0.05). Moreover, in both cell lines, CPA-LLP significantly enhanced the cell response to CCPM-177Lu radiotherapy as measured by clonogenic assay (p < 0.05). In 4T1 and Miapaca-2 mouse xenograft models, the combination of CPA-LLP and CCPM-177Lu delayed tumor growth more than either monotherapy did alone. In the 4T1 tumor model, tumor size at 16 days after treatment was significantly smaller with the combination therapy than with all the other treatments. In the Miapaca-2 model, the combination therapy resulted in the highest rate of mouse survival and prevented tumor relapse. In conclusion, the combination of CPA-LLP and CCPM-177Lu was an effective strategy for treating breast and pancreatic cancer and deserves further investigation.
AB - Cyclopamine (CPA), a potent inhibitor of the Hedgehog pathway, has produced promising anticancer results in a number of preclinical studies. CPA has also been found to enhance tumor response to radiation therapy. However, CPA is water insoluble. A drug delivery system suitable for systemic administration of CPA is needed before CPA can be considered for clinical translation. We hypothesized that CPA solubilized in a liquid-lipid nanoparticle system (CPA-LLP) for intravenous injection would have desirable pharmacokinetic properties and increased anticancer efficacy. We further hypothesized that CPA-LLP would enhance the response of tumor cells to targeted radiotherapy delivered selectively through intratumoral injection of lutetium-177 bound to core-crosslinked polymeric micelles (CCPM-177Lu). We tested the combination therapy in 4T1 murine breast cancer and Miapaca-2 human pancreatic adenocarcinoma models. The results showed that CPA-LLP had higher antitumor cytotoxicity than free CPA (IC50 values [mean ± SEM]: 2.7 ± 0.2 μM vs. 11.3 ± 1.2 μM against 4T1 cells; 1.8 ± 0.2 vs. 17.1 ± 1.26 μM against Miapaca-2 cells; p < 0.0001). In both cell lines, CPA-LLP resulted in significantly lower clonogenicity than free CPA (p < 0.05). Moreover, in both cell lines, CPA-LLP significantly enhanced the cell response to CCPM-177Lu radiotherapy as measured by clonogenic assay (p < 0.05). In 4T1 and Miapaca-2 mouse xenograft models, the combination of CPA-LLP and CCPM-177Lu delayed tumor growth more than either monotherapy did alone. In the 4T1 tumor model, tumor size at 16 days after treatment was significantly smaller with the combination therapy than with all the other treatments. In the Miapaca-2 model, the combination therapy resulted in the highest rate of mouse survival and prevented tumor relapse. In conclusion, the combination of CPA-LLP and CCPM-177Lu was an effective strategy for treating breast and pancreatic cancer and deserves further investigation.
KW - Cyclopamine
KW - Lipid emulsion
KW - Lutetium-177
KW - Micelles
KW - Radiation enhancement
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U2 - 10.1016/j.jconrel.2015.01.031
DO - 10.1016/j.jconrel.2015.01.031
M3 - Article
C2 - 25637565
AN - SCOPUS:84961291046
SN - 0168-3659
VL - 202
SP - 40
EP - 48
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -