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Injection of Chemotherapeutic Microspheres and Glioma IV: Eradicating Tumors in Rats

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Abstract:

Polymer microspheres can be easily injected into the brain to provide a local and sustained delivery of chemotherapeutics to a tumor or surrounding tissue subject to high rates of tumor recurrence following surgery. Building on previous studies that established the clear advantage of local, peritumoral injections of sustained release microspheres, the following experiments utilized two different approaches for maximizing the survival benefit in glioma-bearing rats. In the first experiment, a previously grown cortical tumor was debulked and animals received either one or two treatments with carboplatin-loaded microspheres (either 200 or 800 μg total carboplatin per treatment). In each case, the microspheres were injected along the perimeter of the resection cavity with each treatment separated by 20 days. Survival studies clearly demonstrated that two, temporally spaced injections were superior to a single series of injections. At the lowest dose tested (200 μg), median survival was increased an additional 40% over that in animals receiving one treatment. At the higher dose (800 μg), one third of the animals receiving two separate treatments were long-term survivors (>150 days) and showed complete eradication of the tumor on histological examination. In the second experiment, we directly compared the efficacy produced by sustained release carboplatin or 1,3-bis[2-chloroethyl]-1-nitrourea (BCNU) alone versus injecting carboplatin and BCNU-loaded microspheres blended together as a single suspension. Carboplatin and BCNU both enhanced survival, with BCNU being significantly less effective than carboplatin. However, the greatest improvements in survival were seen when a blended suspension of carboplatin and BCNU microspheres was injected around the surgical cavity. In contrast, spatially alternating injections of BCNU and carboplatin microspheres was significantly less effective and the increase in survival was no greater than that achieved with BCNU alone. These data offer further support for the potential utility of local, sustained release chemotherapeutic microspheres for treating glioma. Moreover, they suggest that injectable chemotherapeutic microspheres may offer important advantages by (a) permitting multiple, temporally spaced injections to be made, as needed, and (b) providing the opportunity to deliver combinations of several different efficacious drugs directly to the tumor site to enhance survival beyond what can be achieved with delivery of any single chemotherapeutic agent.

Keywords: Key words: Glioma; Microsphere;; Sustained release

Document Type: Research Article

DOI: http://dx.doi.org/10.0000/096020198389771

Affiliations: 1: *Alkermes, Inc., Cambridge, MA 02139 2: †Department of Surgery, OHSU, Portland, OR 97201

Publication date: January 1, 2002

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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