Oukseub Lee1, David Ivancic1, Subhashini Allu1,2, Ali Shidfar1, Kara Kenney2, Irene Helenowski3, Megan E Sullivan4, Miguel Muzzio5, Denise Scholtens3, Robert T Chatterton6, Kevin P Bethke1,2, Nora M Hansen1,2, Seema A Khan7,8,9. 1. Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. 2. Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. 3. Department of Preventive Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. 4. Department of Pathology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. 5. Illinois Institute of Technology Research Institute, Chicago, IL, USA. 6. Department of Obstetrics and Gynecology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. 7. Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. skhan@nmh.org. 8. Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. skhan@nmh.org. 9. Northwestern University Feinberg School of Medicine, 303 E Superior St., Lurie 4-111, Chicago, IL, 60611, USA. skhan@nmh.org.
Abstract
PURPOSE: 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. METHODS: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. RESULTS: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. CONCLUSIONS: 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.
RCT Entities:
PURPOSE: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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Manish Ranjan; Oukseub Lee; Gannon Cottone; Elnaz Mirzaei Mehrabad; Benjamin T Spike; Zexian Zeng; Shivangi Yadav; Robert Chatterton; J Julie Kim; Susan E Clare; Seema A Khan Journal: Breast Cancer Res Date: 2021-08-03 Impact factor: 6.466