Lee Oukseub, Ivancic David, Allu Subhashini, Shidfar Ali, Kenney Kara, Helenowski Irene, Sullivan Megan E, Muzzio Miguel, Scholtens Denise, Chatterton Robert T, Bethke Kevin P, Hansen Nora M, Khan Seema A
Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
Cancer Chemother Pharmacol. 2015 Dec;76(6):1235-46. doi: 10.1007/s00280-015-2848-y. Epub 2015 Nov 11.
Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs.
Athymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography-tandem mass spectroscopy.
Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable.
These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery.
乳腺癌高危女性及原位癌患者需要无毒且耐受性良好的预防性干预措施。一种有前景的方法是通过乳房皮肤给药（局部透皮治疗，LTT）。我们的目标是测试用于LTT的新型药物，以确定LTT适用于非甾体类药物。
无胸腺裸鼠分别接受口服他莫昔芬、经皮给予4-羟基他莫昔芬（4-OHT）或每天在腋窝乳腺涂抹恩杂鲁胺凝胶，持续6周（研究1）。研究2与研究1相同，比较经皮给予醋酸替拉司酮（替拉司酮）凝胶与皮下植入。在安乐死时，收集乳腺和血液。在研究3中，同意接受乳房切除术的女性被随机分为术前3天在腹部或乳房涂抹双氯芬酸贴片。在手术时，从每个乳房的预定位置收集8个组织样本以及静脉血。使用液相色谱-串联质谱法测量药物浓度。
与腹股沟腺体或全身治疗的动物相比，凝胶治疗动物腋窝腺体中4-OHT、恩杂鲁胺和替拉司酮的乳腺组织浓度显著更高。凝胶治疗动物和全身治疗动物的血浆浓度相似。临床试验表明，当双氯芬酸应用于乳房皮肤时，乳腺浓度显著高于应用于腹部皮肤时，但浓度存在差异。
这些结果表明，可以开发用于LTT的亲脂性药物；虽然裸鼠适用于测试药物渗透性，但给药是全身性的。然而，在人类中，经皮应用于乳房皮肤可实现局部给药。
