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.

Dual roles of nitric oxide in the regulation of tumor cell response and resistance to photodynamic therapy

“…Novel synthesized PDT-NO complexes have been synthesized and are currently being investigated. Preliminary findings demonstrated that a selected PDT-NO complex is more cytotoxic than single agents alone or combination [88] . In addition, the application of nanoparticles coated with the PS-NO complex will be examined for their superior activity.…”

“…The authors concluded that this compound is the most effective known S-nitrosothiol for PDT application. Rapozzi et al [88] reported the superior activity of a new complex DR2 constituted of a PS (Pheophorbide a , Pb a ) connected to a non-steroidal antiandrogen molecule able to release cytotoxic NO under the exclusive control of light in prostate cancer cells.…”

An insight into the therapeutic potential of piperazine-based anticancer agents

“…This approach is very interesting and should be developed further. 54 .8 µM, respectively. This compound was also found to be selective as it showed less toxicity to normal human cell lines, which is encouraging for drug development.…”

Black phosphorus: A novel nanoplatform with potential in the field of bio-photonic nanomedicine

“…Phototherapy, mainly including PTT 194,195 and photodynamic therapeutic (PDT), 196,197 has become a potential alternative to traditional cancer therapy with its advantages of little double consequences, [198][199][200][201][202][203][204][205] excellent targeting [206][207][208][209][210][211][212][213][214][215] and intelligent controllability. [216][217][218][219][220][221][222] The principle of PTT is based on the heat energy generated by the photothermal agent under irradiation to achieve the therapeutic e®ect. PDT agent can generate ROS to kill cancer cells under laser irradiation.…”