Locally-applied 5-fluorouracil-loaded slow-release patch prevents pancreatic cancer growth in an orthotopic mouse model

Abstract

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.

Synergistic effect of a drug loaded electrospun patch and systemic chemotherapy in pancreatic cancer xenograft

“…TUNEL staining was performed using in situ cell-death detection kit (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer’s protocol. The samples were mounted using Prolong Gold antifade mountant with DAPI 60 .…”

“…The protein concentration of each sample was determined using a BCA protein assay kit (Thermo Fisher Scientific). Afterwards, 10 μg of protein were separated on SDS PAGE, transferred to a nitrocellulose membrane, and probed with anti-caspase 3 (1:500; Abcam, USA) and anti-GAPDH antibody (1:1,000; Santa Cruz Biotechnology, CA, USA) 60 .…”

Topical kinase inhibitors induce regression of cutaneous squamous cell carcinoma

“…In addition, dasatinib was well tolerated by mice while topical 5‐FU led to mortality after 2 weeks. The mortality rate noted in the K14‐Fyn Y528F mice treated with topical 5‐FU is elevated compared to other studies . This may be due to increased drug absorption due to impaired skin barrier formation in the cSCCs leading to elevated systemic levels or to increased production of toxic metabolites in the K14‐Fyn Y528F line …”

Dauricine suppresses the growth of pancreatic cancer in�vivo by modulating the Hedgehog signaling pathway

“…The effects of dauricine were comparable to those of 5-FU. 5-FU is a chemotherapeutic agent widely used for the treatment of a number of cancer types, including breast (34), skin (35), stomach (36), gullet (37), bowel (38) and pancreatic cancer (39). 5-FU works as an antimetabolite and prevents cell proliferation through inhibition of thymidylate synthase, which in turn prevents nucleotide synthesis and arrests cell division (40).…”