Lymphatic targeted tamoxifen for breast cancer therapy

描述（由申请人提供）：

DESCRIPTION (provided by applicant): The objective of this research is to develop a novel lymphatic targeted drug delivery system of tamoxifen (TAM) for the treatment of breast cancer. We hypothesize that an orally administered lipid-based self-emulsifying drug delivery system (SEDDS) of TAM would gain access to the lymphatic vasculature via the intestinal lymphatics and reach the lymphatic-rich retromammary spaces in high concentrations, resulting in tumor tissue targeting and effective therapy of cancer. The free base chemical form of tamoxifen is highly lipophilic (log P > 4), making it a good candidate for lipid-based drug delivery systems such as SEDDS. Physicochemical characterization of the experimental SEDDS formulations will be conducted as the degree of intestinal lymphatic uptake is expected to be influenced by formulation characteristics such as emulsion droplet diameter. In-vitro screening techniques will be used to select a TAM SEDDS formulation for in-vivo studies in rats. We will evaluate the lymphatic targeting potential of the TAM SEDDS through drug distribution and bioavailability studies by sampling of blood and lymph in healthy as well as tumor-bearing rats treated with the formulation. The therapeutic efficacy of the TAM SEDDS will be evaluated by using it to treat female rats bearing N-nitroso-N-methylurea-induced malignant mammary tumors. The efficacy of tumor treatment with TAM SEDDS will be compared to efficacy of treatment with tamoxifen citrate (currently marketed form), administered orally under the same experimental conditions, with both groups being compared to untreated controls. Previous studies conducted in our laboratory have shown that a lipid-based emulsion formulation of TAM is more effective in retarding the growth of cultured breast cancer cells (MCF-7) compared to TAM citrate. Therefore it is expected that TAM, in conjunction with a lipid-based vehicle delivered to in vivo tumor sites, will be more effective in growth arrest and regression of tumors compared to TAM citrate. Success of this novel lymphatic targeted drug delivery system could provide a radical improvement in breast cancer treatment with TAM, with possible implications in reducing metastatic potential, as metastasis occurs via the lymphatic system.