Transcutaneous delivery of anti-breast cancer agents

Abstract

Breast cancer is the most common female malignancy in the western world. Currently, tamoxifen remains the gold standard anti-hormone for ER+ breast cancer. However de novo resistance to tamoxifen is a huge clinical problem. What is more, as many as 50% of initial responders develop acquired resistance to tamoxifen and relapse. Aberrant growth factor signalling has been linked to the resistant phenotype, in particular EGFR and IGF-IR signalling and often gives a more aggressive disease type and poorer patient outlook. There is a substantial clinical need for new anti-breast cancer therapeutics that target the resistant phenotype or prevent this from occurring. One hypothesis is to combine both anti-hormonal therapies with anti-EGFR therapies, in hope of preventing resistant growth. Many downstream pathways of EGFR have been targeted to develop novel therapeutics against however, these compounds are almost certain to give severe adverse reactions, furthermore a complex tablet regime or IV injections have a negative effect on patient compliance. A novel transcutaneous delivery system would give a more patient friendly alternative, with patients re-applying a patch or cream once a day, with rapid termination of dosing in the event of adverse event This would also go some way to prevent endometrial complications associated with tamoxifen use. The in vitro simultaneous delivery of 4-hydroxytamoxifen and signal transduction inhibitors LY294002 and PD98059 along with EPA determined that all compounds were capable of permeating porcine skin and nipple. Masses able to permeate were 5.14 0.93,6.97 0.99, 5.06 0.93 and 1121.6 143 &mu;gcm2 across skin respectively and 21.14 2.75,18.2 2.55,25.1 6.89 and 3081.2 252.7 &mu;gcm2 across porcine nipple. These compounds were formulated with 2.5% v/v DMSO and ethanol and 4% w/v Cab-o-sil. Fish oil was shown to be a skin friendly vehicle. Ki-67 assays confirmed that incubation with fish oil maintained skin viability and H &amp; E staining confirmed no obvious histological effects. Growth Studies were performed on MCF-7 and TamR cells and showed that the combination of these compounds was able to reduce cell growth to 4.04 0.15 and 2.47 1.4 % of control growth when incubated at 25 &mu;M PD98059 &mu;M LY294002 x 107M 4-hydroytamoxifen and 1 &mu;LmL-1 fish oil. This combination of compounds, without 4-hydroxytamoxifen, was able to reduce the migratory capacity of TamR cells (P = < 0.005). Results confirmed that the simultaneous transcutaneous delivery of multiple anti-breast cancer agents is possible and that these show promising anti- tumorogenic actions post skin.EThOS - Electronic Theses Online ServiceGBUnited Kingdo