Androgen Receptor Targeted Conjugate for Bimodal Photodynamic Therapy of Prostate Cancer in Vitroby Valentina Rapozzi, Daniele Ragno, Andrea Guerrini, Claudia Ferroni, Emilia della Pietra, Daniela Cesselli, Gabriella Castoria, Marzia Di Donato, Emanuela Saracino, Valentina Benfenati, Greta Varchi

Bioconjugate Chem.


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Androgen receptor targeted conjugate for bimodal photodynamic therapy of prostate cancer in vitro

Greta Varchi, Valentina Rapozzi, Daniele Ragno, Gabriella Castoria, marzia DI DONATO, Emilia Della

Pietra, Valentina Benfenati, Claudia Ferroni, Andrea Guerrini, Daniela Cesselli, and Emanuela Saracino

Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.5b00261 • Publication Date (Web): 24 Jun 2015

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Androgen receptor targeted conjugate for bimodal photodynamic therapy of prostate cancer in vitro

Valentina Rapozzi,‡ Daniele Ragno,∫ Andrea Guerrini,† Claudia Ferroni,† Emilia della Pietra,‡ Daniela

Cesselli,‡ Gabriella Castoria,§ Marzia Di Donato,§ Emanuela Saracino,£ Valentina Benfenati,† and Greta

Varchi*† † Institute of the Organic Synthesis and Photoreactivity Italian National Research Council

Via P. Gobetti, 101 40129 Bologna – IT E-mail: ‡ Department of Medical and Biological Sciences University of Udine Piazzale Kolbe, 4 – 33100 Udine – IT ∫ Department of Chemistry University of Ferrara Via Fossato di Mortara, 17 - 44121 Ferrara – IT § Department of Biochemistry, Biophysics and General Pathology – II University of Naples

Via L. De Crecchio, 7 -80138 Naples – IT £ Institute for the Study of Nanostructured Materials Italian National Research Council

Via P. Gobetti, 101, 40129 Bologna – IT *Correspondence should be addressed to:

Greta Varchi, PhD, Institute of Organic Synthesis and Photoreactivity, Italian National Research Council,

Via Gobetti, 101, 40129 Bologna, Italy. Phone: +39 0516398283; Fax +39 0516398349; E-mail:


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 non-steroidal antiandrogen 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 photo-toxicity 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 multi-modal photodynamic treatment of prostate cancer.

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Prostate cancer (PC) is the leading cause of cancer death for men in Western countries and an emerging malignancy in developing nations.1 Depending on the diagnosis response, PC treatment options vary.

Clinicians may decide for an active surveillance or for more invasive treatments such as surgical removal of the prostate gland, external or internal radiotherapy alone or in combination with androgen depletion therapy (ADT). Despite being effective in shrinking tumor burden and improving survival, these therapies frequently fail and castration-resistant prostate cancer (CRPC) frequently develops.2 At this stage, PC is almost incurable and often accompanied by metastatic spreading and poor prognosis, with a median survival range from 12 to 24 months.3 Unfortunately, few biomarkers predictive of metastatic phenotype have been identified yet and few therapeutic options are available for CRPC patients. Although chemotherapy remains the first choice of most clinicians at this stage, its overall benefit is very modest, since PC frequently escapes from chemotherapy at both primary and metastatic sites.4–6 Within the past years, several promising agents, including inhibitors of androgen synthesis or androgen receptor (AR) activation have improved CRPC patient survival.7–9 Nevertheless, CRPC has evolved mechanisms to reactivate AR despite continued ADT.