title: Androgen Receptor Targeted Conjugate for Bimodal Photodynamic Therapy of Prostate Cancer in Vitro.
abstract: Prostate cancer (PC) represents the most common type of cancer among males and is the second leading cause of cancer death in men in Western society. Current options for PC therapy remain unsatisfactory, since they often produce uncomfortable long-term side effects, such as impotence (70%) and incontinence (5-20%) even in the first stages of the disease. Light-triggered therapies, such as photodynamic therapy, have the potential to provide important advances in the treatment of localized and partially metastasized prostate cancer. We have designed a novel molecular conjugate (DR2) constituted of a photosensitizer (pheophorbide a, Pba), connected to a nonsteroidal anti-androgen molecule through a small pegylated linker. This study aims at investigating whether DR2 represents a valuable approach for PC treatment based on light-induced production of single oxygen and nitric oxide (NO) in vitro. Besides being able to efficiently bind the androgen receptor (AR), the 2-trifluoromethylnitrobenzene ring on the DR2 backbone is able to release cytotoxic NO under the exclusive control of light, thus augmenting the general photodynamic effect. Although DR2 is similarly internalized in cells expressing different levels of androgen receptor, the AR ligand prevents its efflux through the ABCG2-pump. In vitro phototoxicity experiments demonstrated the ability of DR2 to kill cancer cells more efficiently than Pba, while no dark toxicity was observed. Overall, the presented approach is very promising for further development of AR-photosensitizer conjugates in the multimodal photodynamic treatment of prostate cancer.
authors.affiliation: ‡Department of Medical and Biological Sciences University of Udine, Piazzale Kolbe, 4, 33100 Udine, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Rapozzi
authors.affiliation: ∥Department of Chemistry University of Ferrara, Via Fossato di Mortara, 17, 44121 Ferrara, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ragno
authors.affiliation: †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Guerrini
authors.affiliation: †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ferroni
authors.affiliation: ‡Department of Medical and Biological Sciences University of Udine, Piazzale Kolbe, 4, 33100 Udine, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: della Pietra
authors.affiliation: ‡Department of Medical and Biological Sciences University of Udine, Piazzale Kolbe, 4, 33100 Udine, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.affiliation: §Department of Biochemistry, Biophysics and General Pathology - II University of Naples , Via L. De Crecchio, 7, 80138 Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.affiliation: §Department of Biochemistry, Biophysics and General Pathology - II University of Naples , Via L. De Crecchio, 7, 80138 Naples, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Di Donato
authors.affiliation: ⊥Institute for the Study of Nanostructured Materials, Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Saracino
authors.affiliation: †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Benfenati
authors.affiliation: †Institute of the Organic Synthesis and Photoreactivity Italian National Research Council, Via P. Gobetti, 101, 40129 Bologna, Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Varchi
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011944:Receptors, Androgen / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011944:Receptors, Androgen; D002734:Chlorophyll; C032623:pheophorbide a