title: Nuclear estrogen receptor targeted photodynamic therapy: selective uptake and killing of MCF-7 breast cancer cells by a C17alpha-alkynylestradiol-porphyrin conjugate.
abstract: We hypothesized that over-expression of estrogen receptor (ER) in hormone-sensitive breast cancer could be harnessed synergistically with the tumor-migrating effect of porphyrins to selectively deliver estrogen-porphyrin conjugates into breast tumor cells, and preferentially kill the tumor cells upon exposure to red light. In the present work we synthesized four (4) conjugates of C17-alpha-alkynylestradiol and chlorin e6-dimethyl ester with varying tether lengths, and showed that all these conjugates specifically bound to recombinant ER alpha. In a cellular uptake assay with ER-positive MCF-7 and ER-negative MDA-MB 231 human breast cancer cell-lines, we observed that one such conjugate (E17-POR, XIV) was selectively taken up in a dose-dependent and saturable manner by MCF-7 cells, but not by MDA-MB 231 cells. Furthermore, MCF-7 cells, but not MDA-MB 231 cells, were selectively and efficiently killed by exposure to red light after incubation with E17-POR. Therefore, the combination approach, including drug and process modalities has the potential to be applied clinically for hormone-sensitive cancers in organs where ER is significantly expressed. This could potentially be carried out either as monotherapy involving a photo-induced selective destruction of tumor cells and/or adjuvant therapy in post-surgical treatment for the destruction of residual cancer cells in tissues surrounding the tumor.
authors.affiliation: Bioorganic Chemistry and Structural Biology, Section in Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Narasimha
authors.initials: N
authors.lastname: Swamy
authors.forename: Ajay
authors.initials: A
authors.lastname: Purohit
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Gacio
authors.forename: Graham B
authors.initials: GB
authors.lastname: Jones
authors.forename: Rahul
authors.initials: R
authors.lastname: Ray
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008027:Light; D015394:Molecular Structure; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D004967:Estrogens; D017319:Photosensitizing Agents; D011166:Porphyrins; D004958:Estradiol