Suppression of the progress of disseminated pancreatic cancer cells by NK4 plasmid DNA released from cationized gelatin microspheres.
OBJECTIVE
NK4, composed of the NH2-terminal hairpin and subsequent four-kringle domains of hepatocyte growth factor (HGF), acts as a potent angiogenesis inhibitor. This study is an investigation to evaluate the feasibility of controlled release of NK4 plasmid DNA in suppressing the tumor growth. Controlled release by a biodegradable hydrogel enabled the NK4 plasmid DNA to exert the tumor suppression effects.


METHODS
Biodegradable cationized gelatin microspheres were prepared for the controlled release of an NK4 plasmid DNA. The cationized gelatin microspheres incorporating NK4 plasmid DNA were subcutaneously injected to tumor-bearing mice to evaluate the suppressive effects on tumor angiogenesis and growth.


RESULTS
The cationized gelatin microspheres incorporating NK4 plasmid DNA could release over 28 days as a result of microspheres degradation. The injection of cationized gelatin microspheres incorporating NK4 plasmid DNA into the subcutaneous tissue of mice inoculated with pancreatic cancer cells prolonged their survival time period. An increase in the tumor number was suppressed to a significantly greater extent than free NK4 plasmid DNA. The controlled release of NK4 plasmid DNA suppressed angiogenesis and increased the cell apoptosis in the tumor tissue while it enhanced and prolonged the NK4 protein level in the blood circulation.


CONCLUSIONS
We conclude that the controlled release technology is promising to enhance the tumor suppression effects of NK4 plasmid DNA.
Kushibiki
Toshihiro
T
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Tabata
Yasuhiko
Y
D000818:Animals; D002412:Cations; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005780:Gelatin; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008863:Microspheres; D008934:Mitogens / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000628:therapy*; D010957:Plasmids; D015996:Survival Rate; D013997:Time Factors
D002412:Cations; D003692:Delayed-Action Preparations; D004337:Drug Carriers; C066855:HGF protein, human; D008934:Mitogens; D017228:Hepatocyte Growth Factor; D005780:Gelatin; D004247:DNA