Local delivery of doxorubicin for the treatment of malignant brain tumors in rats

Abstract

Background: Local delivery of carmustine (BCNU) via biodegradable polymers has been shown to improve survival in patients with glioblastoma multiforme (GBM). In the current study, we hypothesized that local delivery of an anthracycline antibiotic, doxorubicin (DOX), might act to improve the survival of animals bearing experimental intracranial glioma.

Materials and methods: Polyanhydride polymers (PCPP-SA), containing either 3% or 5% ADR by weight, were prepared using the mix-melt method. Forty male Fisher 344 rats received an intracranial challenge with a lethal dose of 9L gliosarcoma cells. Five days later, they received DOX or blank polymer. There were a total of four treatment groups: (1) blank polymer; (2) 3% DOX polymer; (3) 5% DOX polymer, and (4) control group with no polymer.

Results: Compared to control animals treated with no polymers or blank polymer, animals receiving DOX had significantly extended survival. The median survival for the control group was 21 days vs. 34 days (p < 0.01) for the 3% DOX group and 45 days (p < 0.0001) for the 5% DOX group.

Conclusion: Doxorubicin, when delivered locally, is an effective monotherapeutic agent against experimental intracranial glioma.

Figures

Figure 1

In vitro growth inhibition of rodent 9L glioma. The cell line was incubated with doxorubicin for five days and shows a 10–50 ng/ml DOX tumoricidal range.

Figure 2

In vitro release kinetics for 1–10% DOX in pCPP:SA polymer.

Figure 3

Histological analysis of animal brains obtained in the toxicity study. The figure illustrates the presence of necrosis (arrow) which was frequently seen as a late (14 days +) cause of death following DOX-polymer implant.

Figure 4

Results of in vivo intracranial efficacy trials. Compared to control animals treated with no polymers or blank polymer, animals receiving DOX had significantly extended survival. The median survival for the control groups was 21 days vs. 34 days (p

Figure 5

Histological analysis of animal brain treated with DOX. Representative section from (A) control animal and (B) DOX treated animal shows the presence of tumor cells (arrow in A) and tissue necrosis (arrow in B).