Locally-applied 5-fluorouracil-loaded slow-release patch prevents pancreatic cancer growth in an orthotopic mouse model
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In Kyong Shim1,*, Hye-Jin Yi1,*, Hee-Gyeong Yi2, Chan Mi Lee1, Yu Na Lee1, Yeong-Jin Choi3, Seong-Yun Jeong1, Eunsung Jun4,5, Robert M. Hoffman6,7, Dong-Woo Cho2 and Song Cheol Kim5
1 Asan Institute for Life Science, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea
2 Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, Kyungbuk, Korea
3 Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Kyungbuk, Korea
4 Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea
5 Department of Surgery, University of Ulsan College of Medicine & Asan Medical Center, Seoul, South Korea
6 Department of Surgery, University of California, San Diego, CA, USA
7 AntiCancer Inc., San Diego, CA, USA
* These authors have contributed equally to this work
Song Cheol Kim, email:
Dong-Woo Cho, email:
Robert M. Hoffman, email:
Keywords: pancreatic cancer, orthotopic, nude mice, chemotherapy, patch
Received: March 10, 2017 Accepted: April 10, 2017 Published: April 22, 2017
To obtain improved efficacy against pancreatic cancer, we investigated the efficacy and safety of a locally-applied 5-fluorouracil (5-FU)-loaded polymeric patch on pancreatic tumors in an orthotopic nude-mouse model. The 5-FU-releasing polymeric patch was produced by 3D printing. After application of the patch, it released the drug slowly for 4 weeks, and suppressed BxPC-3 pancreas cancer growth. Luciferase imaging of BxPC3-Luc cells implanted in the pancreas was performed longitudinally. The drug patch delivered a 30.2 times higher level of 5-FU than an intra-peritoneal (i.p.) bolus injection on day-1. High 5-FU levels were accumulated within one week by the patch. Four groups were compared for efficacy of 5-FU. Drug-free patch as a negative control (Group I); 30% 5-FU-loaded patch (4.8 mg) (Group II); 5-FU i.p. once (4.8 mg) (Group III); 5-FU i.p. once a week (1.2 mg), three times (Group IV). The tumor growth rate was significantly faster in Group I than Group II, III, IV (p=0.047 at day-8, p=0.022 at day-12, p=0.002 at day-18 and p=0.034 at day-21). All mice in Group III died of drug toxicity within two weeks after injection. Group II showed more effective suppression of tumor growth than Group IV (p=0.018 at day-12 and p=0.017 at day-21). Histological analysis showed extensive apoptosis in the TUNEL assay and by Ki -67 staining. Western blotting confirmed strong expression of cleaved caspase-3 in Group II. No significant changes were found hematologically and histologically in the liver, kidney and spleen in Groups I, II, IV but were found in Group III.
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