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Development of a System for Controlled Release of Benzo(a)pyrene, 7,12-Dimethylbenz(a)anthracene, and Phorbol Ester for Tumor Induction in Heterotopic Tracheal Grafts¹

Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830

The utility of the tracheal transplant model as a tool in in vivo carcinogenesis studies depends largely on the development of a good drug delivery system affording reproducible, sustained carcinogen release. Previously used methods have proven to be less than satisfactory.

We studied the release of benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, and 12-O-tetradecanoylphorbol-13-acetate from pellets of varying composition. In vitro release of the two polycyclic hydrocarbons (PCH) from beeswax pellets showed little variability, regardless of PCH concentration. In marked contrast, in vivo release was highly variable, particularly at high PCH concentrations. This suggested that the in vivo variability was largely due to the toxic alterations of tissues, caused by carcinogen released at high rates.

Pellets composed of beeswax:cholesterol in ratios of 1:1 to 1:9 showed markedly reduced rates of PCH release. At a ratio of 1:9, the overall release rate of benzo(a)pyrene was 1 µg/day compared to 7 µg/day for pellets with a pure beeswax matrix [100 µg benzo(a)pyrene pellets]. The variability of PCH release was simultaneously diminished, supporting the suspicion that it was a result of toxic tissue changes. Similarly reduced release rates could be obtained by adsorbing the PCH to charcoal particles.

Studies with the promotor 12-O-tetradecanoylphorbol-13-acetate showed a release rate of 1.6 µg/day from pure beeswax (100 µg 12-O-tetradecanoylphorbol-13-acetate per pellet). This rate may have to be diminished before promotion studies in the tracheal transplant model can be attempted. Our studies demonstrate that protracted PCH release from pellets can be achieved by using a beeswax: cholesterol matrix instead of a pure beeswax matrix or by adsorbing the PCH to charcoal particles. Such pellets release at fairly constant rates, with little pellet-to-pellet variability. Thus, the major problem of using the tracheal transplant model for quantitative tumor induction studies with PCH's appears to be resolved.

¹ Research supported in part by the Environmental Protection Agency (1AG-D5-E681) and by the Department of Energy under contract with the Union Carbide Corporation.

² Postdoctoral Investigator, Carcinogenesis Training Grant CA09285 from the National Cancer Institute.

³ Present address: Room A 322, Landow Building, National Cancer Institute, Bethesda, Md. 20014.

⁴ To whom requests for reprints should be addressed, at Biology Division, Oak Ridge National Laboratory, P. O. Box Y, Oak Ridge, Tenn. 37830.

Received 10/28/77. Accepted 2/13/78.