Lymphatic targeted tamoxifen for breast cancer therapy

描述（由申请人提供）： 本研究的目的是开发一种新的淋巴靶向给药系统的他莫昔芬（TAM）治疗乳腺癌。我们假设，口服给药的脂质为基础的自乳化药物递送系统（SEDDS）的TAM将获得通过肠道淋巴管进入淋巴管，并达到高浓度的乳腺后间隙，导致肿瘤组织靶向和有效的治疗癌症。他莫昔芬的游离碱化学形式是高度亲脂性的（log P > 4），使其成为基于脂质的药物递送系统如SEDDS的良好候选者。将对实验性SEDDS制剂进行理化表征，因为预期肠淋巴吸收程度会受到制剂特征（如乳剂液滴直径）的影响。将使用体外筛选技术来选择用于大鼠体内研究的TAM SEDDS制剂。我们将通过药物分布和生物利用度研究，通过对健康大鼠和荷瘤大鼠的血液和淋巴进行采样，评价TAM SEDDS的淋巴靶向潜力。将通过使用TAM SEDDS治疗携带N-亚硝基-N-甲基脲诱导的恶性乳腺肿瘤的雌性大鼠来评价TAM SEDDS的治疗效果。将用TAM SEDDS治疗肿瘤的功效与在相同实验条件下口服施用的柠檬酸他莫昔芬（目前市售形式）治疗的功效进行比较，两组均与未治疗的对照进行比较。在我们实验室进行的先前研究表明，与TAM柠檬酸盐相比，TAM的脂质乳剂制剂在延缓培养的乳腺癌细胞（MCF-7）的生长方面更有效。因此，预期与TAM柠檬酸盐相比，TAM与递送至体内肿瘤部位的基于脂质的媒介物结合将在肿瘤的生长停滞和消退中更有效。这种新型淋巴靶向药物递送系统的成功可以为TAM治疗乳腺癌提供根本性的改善，可能会降低转移潜力，因为转移是通过淋巴系统发生的。

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.