Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain

Henry BremDepartments of Neurosurgery, Ophthalmology, and Pathology, and The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

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Rafael J. TamargoDepartments of Neurosurgery, Ophthalmology, and Pathology, and The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

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Alessandro OliviDepartments of Neurosurgery, Ophthalmology, and Pathology, and The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

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Michael PinnDepartments of Neurosurgery, Ophthalmology, and Pathology, and The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

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Jon D. WeingartDepartments of Neurosurgery, Ophthalmology, and Pathology, and The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

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Moody WharamDepartments of Neurosurgery, Ophthalmology, and Pathology, and The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

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Jonathan I. EpsteinDepartments of Neurosurgery, Ophthalmology, and Pathology, and The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

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✓ Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue concentrations over extended periods of time. It has been shown previously that implantation of controlled-release polymers impregnated with the nitrosourea carmustine (BCNU) extended the period of survival in rats bearing the 9L glioma compared with similar rats treated with systemically administered BCNU. This study evaluated the effect on the monkey brain of interstitial delivery of BCNU by the biodegradable polyanhydride copolymer poly[bis(p-carboxyphenoxy)propane]anhydride (PCPP) and sebacic acid (SA) in a 20:80 formulation (PCPP:SA). The effect of combining interstitial BCNU with radiation therapy was also evaluated. Eighteen male cynomologus monkeys were randomly assigned to one of four groups: a control group; a group with implantation of empty polymer; a group with implantation of BCNU-loaded polymer; and a group with implantation of empty polymer in the right hemisphere and BCNU-loaded polymer in the left hemisphere, followed by irradiation. The effects were evaluated radiologically and histologically at specified times. A local reaction by the brain to the polymer was found, which was greater when the polymer contained BCNU. Local cerebral edema was observed radiographically on postoperative Day 14 and had resolved by Day 72. Histologically, a subacute cellular inflammatory response was seen on postoperative Day 16, which had changed to a chronic inflammatory response by Day 72. In the group with radiation therapy administered to the hemisphere bearing BCNU-loaded polymer, only localized pathological changes were detected. In all animals, brain distant from the polymer implantation site was normal. No neurological or general deleterious effects were seen in any of the animals. It is concluded that the interstitial delivery of BCNU by the polyanhydride polymer PCPP:SA is safe in the primate brain and that concomitant radiation therapy did not lead to any adverse effects. These experimental findings are important to an understanding of the clinical effects of PCPP:SA implants in treating brain diseases.

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