Trans-tissue, sustained release of gemcitabine from photocured gelatin gel inhibits the growth of heterotopic human pancreatic tumor in nude mice.
OBJECTIVE
Although gemcitabine, a deoxycytidine analogue, recently demonstrated improvements in the response rate for pancreatic cancer, the median survival for patients is limited to 4-6 months. The purpose of the present study was to develop trans-tissue delivery of gemcitabine, which is based on photocured gelatin gel immobilized with gemcitabine, and to validate whether such a system inhibits the growth of the pancreatic tumor in vivo.


METHODS
The in vitro release profile of gel-embedded gemcitabine from a gel was examined based on in vitro chemosensitivity of AsPC1 cell (human pancreatic cancer cell line) for gemcitabine. The permeation of gel-embedded rhodamine B (used as a model drug) into tissues and inhibitory effect of tumor growth of photocured gelatin gel immobilized with gemcitabine were examined using in vivo s.c. tumor model of athymic mice.


RESULTS
The release profile was characterized as an initial burst of release, followed by a gradual release, irrespective of gelatin concentration. Rhodamine B permeated into the tumor and retained for at least 10 days. Photocured gelatin gel immobilized with gemcitabine significantly reduced the tumor volume compared with gemcitabine injection. Therapeutic success was correlated with decreased cell proliferation and increased cell apoptosis in tumor cells, supported by proliferating cell nuclear antigen and terminal deoxynucleotidyltransferase-mediated nick end labeling staining. Blood analysis and body weight measurement showed that little side effect was observed in this therapy.


CONCLUSIONS
In situ trans-tissue gemcitabine delivery on the tissue with possibly remnant cancer cells using the drug-releasing matrix developed here is expected to reduce the rate of local recurrence for patients with pancreatic cancer.
Okino
Hidenobu
H
Department of Biomedical Engineering, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan.
Maeyama
Ryo
R
Manabe
Tatsuya
T
Matsuda
Takehisa
T
Tanaka
Masao
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005780:Gelatin / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D003841:Deoxycytidine; D005780:Gelatin; D000093542:Gemcitabine