Prolonged local persistence of cisplatin-loaded gelatin microspheres and their chemoembolic anti-cancer effect in rabbits.
OBJECTIVE
To confirm prolonged cisplatin release from drug-loaded gelatin microspheres (GMSs) and their improved chemoembolic anti-cancer effect against VX2 liver tumors in rabbits.


METHODS
Two groups of twelve rabbits each were treated intraarterially either with 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) or 0.04 mg/kg cisplatin solution by administering them into the right renal artery. Platinum concentrations within the renal parenchyma were analyzed immediately following infusion (day 0) and on days 1, 3, and 7 using the atomic absorption method. In a second experiment four groups of five rabbits each with implanted VX2 liver tumors were treated intraarterially through the hepatic artery with the following drugs: 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) (group I), 2 mg/kg GMSs without any drug (group II), 1.5 mg/kg cisplatin solution (group III) and saline (group IV). Tumor volumes were analyzed pre-injection and 7 days after with MRI allowing calculating the relative tumor growth rate (%). Degree of liver cell necrosis was assessed on the histopathological specimens.


RESULTS
The renal parenchymal platinum concentrations (microg/ml) with 4.51+/-2.25 (day 0), 1.59+/-0.70 (day 1), 0.72+/-0.10 (day 3) and 0.20+/-0.06 (day 7) were significantly more pronounced after cisplatin-loaded GMS on days one and three compared to cisplatin with 1.99+/-0.55, 0.08+/-0.03, 0.18+/-0.01 and 0.10+/-0.07, respectively. Relative tumor growth rates resulted in 84.5%+/-26.4 (group I); 241.4%+/-145.1 (II); 331.9%+/-72.2 (III), and 413.6%+/-103.6 (IV) with statistical significant differences between groups I and III, and groups I and IV. Similar degrees of necrosis were observed in both GMSs treated groups, while ballooning of hepatocytes was highest in cisplatin-loaded GMSs.


CONCLUSIONS
With cisplatin-loaded GMSs more pronounced and prolonged local parenchymal cisplatin concentrations may be achieved offering the advantage of an increased and prolonged anti-cancer effect compared to cisplatin alone or controls. Moreover this proves indirectly the breakdown and release of cisplatin from the GMSs which is of primary importance for drug delivery systems.
Ohta
Shinichi
S
Department of Radiology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu City, Shiga 520-2192, Japan. junryuhei@yahoo.co.jp
Nitta
Norihisa
N
Sonoda
Akinaga
A
Seko
Ayumi
A
Tanaka
Toyohiko
T
Takahashi
Masashi
M
Takemura
Shizuki
S
Tabata
Yasuhiko
Y
Murata
Kiyoshi
K
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005780:Gelatin / Q000737:chemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008863:Microspheres; D011817:Rabbits; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D005780:Gelatin; D002945:Cisplatin