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Polilactofate Microspheres for Paclitaxel Delivery to Central Nervous System
Malignancies
Khan W. Li, Wenbin Dang, Betty M. Tyler,
Greg Troiano, Tarik Tihan, Henry Brem
and Kevin A. Walter
Departments of Neurosurgery [K. W. L., B. M. T., H.
B.*, K. A. W.**], Pathology [T. T.], Oncology [H. B.], and Ophthalmology [H. B.], Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205, and Guilford
Pharmaceuticals, Baltimore, Maryland 21224 [W. D., G. T.]. * To whom requests for reprints should be addressed, at
Department of Neurosurgery, Hunterian Neurosurgery Laboratory,
Hunterian 817, 725 North Wolfe Street, Baltimore, MD 21205. Phone:
(410) 614-0477; Fax: (410) 614-0478; E-mail: hbrem@jhmi.edu. ** Present address: Department of Neurosurgery, University of Pittsburgh
School of Medicine, PUH B-400, 200 Lothrop Street, Pittsburgh, PA
15213; E-mail: walterka@msx.upmc.edu.
Purpose. The purpose of this study was to demonstrate that surgically
implanted, controlled-release, biodegradable polilactofate microspheres
(Paclimer) can be used safely to bypass the blood-brain barrier and
deliver paclitaxel to malignant brain tumors.
Experimental Design. The rate of paclitaxel release from Paclimer
microspheres submerged in PBS was measured in vitro by
high-performance liquid chromatography.
In vivo studies of
Paclimer were performed as intracranial implants in Fischer 344 rats
in the presence or absence of 9L gliosarcoma.
Mantel-Cox statistics
were used to assess the efficacy of Paclimer at extending survival of
tumor-bearing animals compared with control implants.
Paclimer implants
tagged with [3H]paclitaxel were used to measure biodistribution of
paclitaxel from the Paclimer implant.
Results. Paclimer released paclitaxel at a constant rate for up
to 3 months in vitro.
In vivo, Paclimer implants placed
intracranially in rats released active drug for up to 30 days after
implantation and doubled the median survival of rats bearing
established 9L gliosarcomas (median survival of paclitaxel-treated
animals = 35 days; median survival of control-treated animal = 16
days; P < 0.0001).
Active drug was distributed throughout
the rat brain based on liquid scintillation counting and TLC.
Rats
implanted with Paclimer demonstrated no overt signs of neurotoxicity
and exhibited local cytopathological changes consistent with exposure
to an antimicrotubule agent.
Conclusions. Paclimer extends survival in a rodent model of glioma
with minimal morbidity and optimal pharmacokinetics.
© 2003 American
Association for Cancer Research
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