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Visible-Light-Activated Prodrug Can Combat Chemo’s Side Effects

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HONG KONG, Oct. 4, 2019 — Many antitumor drugs used in chemotherapy move around in the patient’s blood after intake. Healthy cells may be killed along with tumor cells, causing undesirable side effects. To avert potential “collateral damage” caused by antitumor drugs, a research team at City University of Hong Kong (CityU) has developed a small-molecule platinum(IV) anticancer prodrug called phorbiplatin. Phorbiplatin is shown to be inert in the dark, but it can be controllably activated under low-power red-light irradiation.  As a prodrug, phorbiplatin only becomes pharmacologically active when it is activated inside the body.

Under short-period irradiation with a low intensity of red light (650 nm, 7 mW/cm2) and without any external catalyst, phorbiplatin is reduced to oxaliplatin, a first-line clinical chemotherapeutic drug, and pyropheophorbide a (PPA), a photoactivation ligand. “Both substances are effective in killing tumor cells,” professor Guangyu Zhu, who led the research, said. Phorbiplatin is scaffolded on the molecular structure of oxaliplatin.

Red-light-activated anti-tumor prodrug phorbiplatin, City University of Hong Kong.

The controllable activation property and superior antitumor activity of phorbiplatin could significantly contribute to the development of photoactivatable anticancer prodrugs to reduce the adverse effects and conquer drug resistance of traditional platinum chemotherapy. Courtesy of Wang et al., Phorbiplatin, a Highly Potent Pt(IV) Antitumor Prodrug That Can Be Controllably Activated by Red Light,
Chem (2019).

The team functionalized oxaliplatin with PPA, which is highly sensitive to red light and is the photoactive ligand used to obtain phorbiplatin. Under irradiation with low-intensity red light, PPA acts as a “photo-induced redox relay,” said the researchers, to transfer electrons from reducing agents to the platinum(IV) center to facilitate the reduction process and release oxaliplatin.

Zhu said that only a short period of irradiation is needed to trigger the photoreduction mechanism. In just 10 minutes, 81% of phorbiplatin was reduced to oxaliplatin and PPA.

The team examined the ability of phorbiplatin to destroy different tumor cells and found that it significantly improved antitumor activity both in vitro and in vivo. The researchers found that platinum-sensitive human ovarian cancer cells treated with phorbiplatin under red light irradiation showed high fractions (68%) of dead cells. Compared with oxaliplatin, phorbiplatin displayed photocytotoxicity that is up to 1786 times greater than that of oxaliplatin in human carcinoma cells.

Moreover, phorbiplatin with irradiation significantly inhibited tumor growth in mice, with 67% reduction in tumor volume and 62% reduction in tumor weight compared with mice treated with oxaliplatin, PPA, and even with a mixture of oxaliplatin and PPA. The body weight of the mice treated with phorbiplatin did not change significantly, indicating that phorbiplatin is safe for use.

Red-light-activated anti-tumor prodrug phorbiplatin, City University of Hong Kong.

Phorbiplatin (red line) displays remarkable ability to kill breast cancer cells in mice. Results showed much higher photocytotoxicity compared with oxaliplatin (green line). Courtesy of Wang et al., Phorbiplatin, a Highly Potent Pt(IV) Antitumor Prodrug That Can Be Controllably Activated by Red Light,
Chem (2019).

Toxicity tests on phorbiplatin indicated low toxicity to normal human lung fibroblasts in the dark. Mice treated with phorbiplatin under irradiation remained healthy, further indicating the safety of phorbiplatin. In contrast, there was liver damage in the mice treated directly with a mixture of oxaliplatin and PPA under irradiation.

According to Zhu, phorbiplatin is the first small-molecule platinum(IV) prodrug that can be activated by a red light. The researchers believe that phorbiplatin could significantly contribute to the development of photoactivatable anticancer prodrugs, especially platinum(IV) prodrugs that can be activated by red light, that could be administered to reduce adverse effects and combat drug resistance to traditional platinum chemotherapy. The team will work on a preclinical study and conduct more toxicity and efficacy tests.

The research was published in Chem (https://doi.org/10.1016/j.chempr.2019.08.021). 

Photonics.com
Oct 2019
Research & TechnologyeducationAsia-Pacificphotoactivatable drugphotoactivation mechanismphotoreductionCity University of Hong KongZhu Guangyulight sourcesBiophotonicsmedicalmedicinepharmaceuticalcancerchemotherapyside effects of cancer drugsphorbiplatinBioScan

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