Longitudinal assessment of regional directed delivery in a rodent malignant glioma model

Laboratory investigation

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Object

Direct delivery of chemotherapeutic agents for the treatment of brain tumors is an area of focus in the development of therapeutic paradigms because this method of delivery circumvents the blood-brain barrier without causing adverse systemic side effects. Few studies have investigated longitudinal tumor response to this type of therapy. In this study, the authors examined the time course of tumor response to direct delivery of a chemotherapeutic agent in a rodent malignant glioma model.

Methods

To visualize tumor response to chemotherapy, the authors used bioluminescence imaging in a rodent model. Rat 9L gliosarcoma cells expressing a luciferase gene were inoculated into adult male rat striata. Ten days following surgery the animals were randomly divided into 4 groups. Groups 1 and 2 received 20 and 40 μl carboplatin (1 mg/ml), respectively, via convection-enhanced delivery (CED); Group 3 received 60 mg/kg carboplatin intraperitoneally; and Group 4 received no treatment. Tumor growth was correlated with luminescence levels twice weekly.

Results

Differential growth curves were observed for the 4 groups. Systemically treated rats showed decreasing photon flux emission at 15.0 ± 4.7 days; rats treated with 20- or 40-μl CED showed decreased emissions at 4.0 ± 2.0 and 3.2 ± 1.3 days after treatment, respectively. Histopathologically, 6 of 12 CED-treated animals exhibited no residual tumor at the end point of the study.

Conclusions

Direct and systemic delivery of carboplatin was examined to determine how the method of drug delivery affects tumor growth. The present report is one of the first in vivo studies to examine the time course of tumor response to direct drug delivery. The results indicate that direct drug delivery may be a promising option for treating gliomas.

Abbreviations used in this paper: BBB = blood-brain barrier; CED = convection-enhanced delivery; PBS = phosphate-buffered saline.

Article Information

Address correspondence to: Akihide Kondo, M.D., Division of Pediatric Neurosurgery, Children's Memorial Hospital, 2300 Children's Plaza, Box 28, Chicago, Illinois 60614-3394. email: akondo@childrensmemorial.org.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Graph showing linear regression analysis of the correlation between pathological tumor volume and luminescence strength (r2 = 0.92).

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    Photomicrographs. A: Representative photomicrograph obtained 10 days after inoculation (arrow). B: Higher magnification image showing typical characteristics of tumor morphology. Tumors exhibited anaplasia with poorly differentiated and pleomorphic cells, marked cytological atypia and multinucleated giant cells. C: A section from an animal that received treatment with 40 μl of carboplatin via CED at 60 days after inoculation. There is no evidence of residual tumor. D: A section from an animal that died 29 days after treatment with 20 μl of carboplatin via CED. Tumor growth without any typical treatment-induced changes can be seen. H & E, original magnification × 1.0 (A, C, and D) and 200 (B).

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    Graphic representation of luminescence strength obtained by bioluminescence imaging in representative animals from control and systemic chemotherapeutic groups.

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    Graphs demonstrating serial luminescence strength data obtained by bioluminescence imaging in all animals receiving carboplatin (20 μl [left] and 40 μl [right]) via CED.

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    Upper: Graph showing the mean value of luminescence signals in rats in the 20- and 40-μl carboplatin CED groups at 2–3, 7–9, and 15–17 days after treatment. Asterisk indicates a statistical difference between the two groups at 15–17 days after treatment (p = 0.04). The signals below our detection limit (1.0 × 104 photon flux emissions/second) were plotted as 1.0 × 104 photon flux emissions/second. Lower: Representative overlay images acquired in animals with tumor recurrence (20-μl carboplatin CED) and complete tumor treatment (40-μl carboplatin CED).

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