Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK.
Int J Pharm. 2010 Mar 15;387(1-2):161-6. doi: 10.1016/j.ijpharm.2009.12.021. Epub 2009 Dec 16.
The objective of this study was to investigate, in vitro, the plausibility of a novel method for delivering a combination of anti-breast cancer agents to the breast via the mammary papilla (nipple). Mammary papillae were prepared from freshly excised strips of porcine sow breasts by blunt dissection. Permeation studies were performed using all glass Franz diffusion cells in both upright and lateral position, with drugs examined individually and in combination. Donor phase was comprised of equimolar PD98059, LY294002 and tamoxifen; 2.54x10(-4) mol dissolved in 950 microL fish oil (containing approximately 23% (w/v) eicosapentaenoic acid, EPA), 25 microL DMSO and 25 microL 1,8-cineole. Also, 4 or 10% Cabosil M5P (w/v) was added to thicken the formulation. After 6 h, the papillae were recovered, cleaned, centrifuged and extracted thrice with methanol. Pooled extracts were analysed by reversed-phase HPLC. The significance of the papilla orientation was also investigated. When applied singly and laterally, the amount extracted from the porcine breast tissue for PD98059, LY294002 and tamoxifen were 1.83+/-0.30, 10.67+/-1.78 and 0.74+/-0.19x10(-2) micromol g(-1) respectively; applied simultaneously and laterally, 2.03+/-0.14, 4.86+/-0.47 and 0.22+/-0.04x10(-2) micromol g(-1) respectively. With 4% Cabosil formulation, amount extracted for PD98059 and LY294002 were 5.71+/-0.95 and 9.91+/-0.92x10(-2) micromol g(-1) respectively; with 10% formulation, 2.64+/-0.5 and 3.90+/-0.78x10(-2) micromol g(-1) respectively. Tamoxifen was below its limit of detection in both Cabosil M5P formulations. To conclude, localized passive delivery via the mammary papilla is a plausible non-invasive means of delivering anti-breast cancer drugs directly to the breast, in levels that have previously been shown to markedly inhibit the growth of breast cancer cell lines, in vitro. The amounts deliverable may be influenced by differential interactions with the thickening agent and patient orientation.
本研究旨在体外探讨一种通过乳腺乳头（乳头）将抗乳腺癌药物组合递送至乳房的新方法的可行性。通过钝性解剖从新鲜切除的猪乳房条带中制备乳腺乳头。使用全玻璃 Franz 扩散细胞在垂直和水平位置进行渗透研究，分别检查药物和组合药物。供体相由等摩尔 PD98059、LY294002 和他莫昔芬组成；2.54x10(-4)mol 溶解在 950μL 鱼油（含有约 23%（w/v）二十碳五烯酸，EPA）、25μL DMSO 和 25μL 1,8-桉树脑。此外，还添加了 4%或 10%Cabosil M5P（w/v）以增稠制剂。6 小时后，取回乳头，清洗，离心并用甲醇提取 3 次。合并提取物后用反相 HPLC 分析。还研究了乳头方向的意义。当单独和侧向应用时，从猪乳房组织中提取的 PD98059、LY294002 和他莫昔芬的量分别为 1.83+/-0.30、10.67+/-1.78 和 0.74+/-0.19x10(-2)μmoll(-1)；同时侧向应用时，提取量分别为 2.03+/-0.14、4.86+/-0.47 和 0.22+/-0.04x10(-2)μmoll(-1)。使用 4%Cabosil 制剂，PD98059 和 LY294002 的提取量分别为 5.71+/-0.95 和 9.91+/-0.92x10(-2)μmoll(-1)；使用 10%制剂时，提取量分别为 2.64+/-0.5 和 3.90+/-0.78x10(-2)μmoll(-1)。在两种 Cabosil M5P 制剂中，他莫昔芬均低于检测限。总之，通过乳腺乳头进行局部被动传递是一种可行的非侵入性方法，可将抗乳腺癌药物直接递送至乳房，其水平以前曾显示可显著抑制乳腺癌细胞系的体外生长。可传递的量可能受到与增稠剂的差异相互作用和患者体位的影响。
