Targeting chemotherapy for malignant brain tumor using thermosensitive liposome and localized hyperthermia

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✓ Thermosensitive liposomes are microscopic vesicles that can contain drugs and release them effectively in response to hyperthermia. To deliver an antitumor drug specifically to brain tumor, the authors used thermosensitive liposomes containing cis-diamminedichloroplatinum (CDDP) in conjunction with localized brain heating. The authors then investigated the antitumor effect on rat malignant glioma. Rous sarcoma virus—induced malignant glioma cells were transplanted into the brains of Fisher rats. Ten days after tumor inoculation, the rats were assigned to one of six treatment groups: control, free CDDP, hyperthermia, free CDDP + hyperthermia, liposomes containing CDDP (CDDP—liposome), and CDDP—liposome + hyperthermia. Liposomes containing CDDP or free CDDP were injected via the tail vein. Brain tumor heating was administered by means of a radiofrequency antenna designed at our institute. The rats treated with CDDP—liposome + hyperthermia had the longest survival time and the tumor CDDP level of this group was the highest when compared to the other groups. Histopathological examination showed that tumor cells were necrotized but surrounding normal brain tissue remained undamaged. On the basis of these findings we suggest that the combination of thermosensitive liposome and localized hyperthermia may better focus antitumor drugs to the tumor, providing a significantly greater antitumor effect.

Article Information

Address reprint requests to: Kenichi Kakinuma, M.D., Department of Neurosurgery, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graph depicting the release rate of cis-diamminedichloroplatinum (CDDP) versus the temperature profile of regional rat brain. Thermosensitive liposomes containing CDDP show a very sharp increase in the release rate of CDDP between 40°C and 41°C.

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    Photograph showing how brain tumor heating was achieved using a radiofrequency antenna with temperature monitoring.

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    Scatterplot showing concentration of cis-diamminedichloroplatinum (CDDP) in the brain tumor. Brain tumor CDDP levels were significantly higher when CDDP—liposome was used with hyperthermia (HT), and CDDP levels were also detectable when CDDP—liposome was used without HT. In contrast, CDDP levels were undetectable when free CDDP was used with or without HT. The broken line shows the detectable limit of CDDP. N.D. = not detectable (that is, below the minimum level of detectability).

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    Graph showing Kaplan—Meier survival curves for each rat group: Group B, treated with injection of free cis-diamminedichloroplatinum (CDDP) (line with two dots and a dash); Group C, hyperthermia (broken line); Group D, injection of free CDDP + hyperthermia (line with alternate dot and dash); Group E, injection of CDDP—liposome (solid line); Group F, injection of CDDP—liposome + hyperthermia (thick line); and Group A, control (dotted line) after tumor inoculation. Survival of tumor-bearing animals treated with either hyperthermia or CDDP—liposome is significantly prolonged. Group F, treated with both, shows the best outcome.

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    Photographs showing specimens from rats obtained 20 days after tumor inoculation and stained with H & E. Upper and Lower Left: Specimens from groups that received cis-diamminedichloroplatinum—liposome plus hyperthermia on Day 15. The tumor cells are necrotized but the surrounding normal brain tissue remains undamaged. Upper and Lower Right: Control specimens demonstrating marked growth of tumor cells.

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