In vivo anti-tumor effect through the controlled release of cisplatin from biodegradable gelatin hydrogel.
This paper is an investigation to achieve the in vivo controlled release of cisplatin (CDDP) from a biodegradable hydrogel. Hydrogels with different water contents were prepared through the chemical crosslinking of gelatin by various concentrations of glutaraldehyde. The gelatin hydrogel incorporating CDDP (CDDP-hydrogel) was prepared by allowing CDDP aqueous solution to sorb into the freeze-dried hydrogel. Irrespective of the hydrogel water content, approximately 10-30% of incorporated CDDP was released from the hydrogel in phosphate-buffered saline solution (PBS) at 37 degrees C within the initial 6 h, while little release was observed thereafter. The amount of CDDP released initially decreased with an increase in the time period of CDDP sorption. When intratumorally applied into Meth-AR-1 tumor-bearing mice, CDDP-hydrogel suppressed in vivo tumor growth to a significantly higher extent than free CDDP at the same dose. The survival rate was significantly higher by the application of CDDP-hydrogel of 40 microg CDDP. The CDDP concentration in the tumor tissue was maintained at a higher level for a longer time period than that of free CDDP. However, no problematic change in the mouse body and blood biochemical parameters was observed on the application of the CDDP-hydrogel. The time course of in vivo CDDP retention was in a good accordance with that of hydrogel remaining. Larger CDDP release was observed from the front surface of hydrogel onto which free CDDP was sorbed, than the back surface of hydrogel. These findings demonstrate that the controlled release of CDDP was based on biodegradation of the hydrogel carrier, but not simple diffusion of CDDP. It is possible that the CDDP molecules immobilized in the gelatin hydrogel were released from the hydrogel only when the hydrogel was degraded to generate some water-soluble gelatin fragments.
Department of Gynecology and Obstetrics, Faculty of Medicine, Kyoto University, 54 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Mitsunaga
M
Konishi
Yasuhiko
Y
Tabata
Masatoshi
M
Kariya
Ayako
A
Suzuki
Masaki
M
Mandai
Kanako
K
Nanbu
Kenji
K
Takakura
Shingo
S
Fujii
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D001806:Blood Urea Nitrogen; D001835:Body Weight; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004343:Drug Implants; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D005780:Gelatin / Q000737:chemistry*; D005976:Glutaral / Q000737:chemistry; D006454:Hemoglobins / Q000032:analysis; D020100:Hydrogels / Q000737:chemistry*; D007700:Kinetics; D007958:Leukocyte Count; D051379:Mice; D008855:Microscopy, Electron, Scanning; D010976:Platelet Count; D010984:Platinum / Q000032:analysis / Q000097:blood; D013054:Spectrophotometry, Atomic; D015996:Survival Rate; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004343:Drug Implants; D006454:Hemoglobins; D020100:Hydrogels; D014867:Water; D010984:Platinum; D005780:Gelatin; D002945:Cisplatin; D005976:Glutaral