title: In vitro delivery of anti-breast cancer agents directly via the mammary papilla (nipple).
abstract: 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.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK.
authors.forename: Lay Ming
authors.initials: LM
authors.lastname: Lee
authors.forename: Zoë
authors.initials: Z
authors.lastname: Davison
authors.forename: Charles M
authors.initials: CM
authors.lastname: Heard
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D002867:Chromones / Q000008:administration & dosage; D004058:Diffusion; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry*; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage; D008321:Mammary Glands, Animal; D009025:Morpholines / Q000008:administration & dosage; D009558:Nipples; D010539:Permeability; D012997:Solvents / Q000737:chemistry*; D013552:Swine; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D005079:Excipients; D005419:Flavonoids; D009025:Morpholines; D012997:Solvents; D013629:Tamoxifen; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one