Abstract
Photodynamic therapy (PDT) is an anticancer therapeutic modality with remarkable advantages over more conventional approaches. However, PDT is greatly limited by its dependence on external light sources. Given this, PDT would benefit from new systems capable of a light-free and intracellular photodynamic effect. Herein, we evaluated the heavy-atom effect as a strategy to provide anticancer activity to derivatives of coelenterazine, a chemiluminescent single-molecule widespread in marine organisms. Our results indicate that the use of the heavy-atom effect allows these molecules to generate readily available triplet states in a chemiluminescent reaction triggered by a cancer marker. Cytotoxicity assays in different cancer cell lines showed a heavy-atom-dependent anticancer activity, which increased in the substituent order of hydroxyl < chlorine < bromine. Furthermore, it was found that the magnitude of this anticancer activity is also dependent on the tumor type, being more relevant toward breast and prostate cancer. The compounds also showed moderate activity toward neuroblastoma, while showing limited activity toward colon cancer. In conclusion, the present results indicate that the application of the heavy-atom effect to marine coelenterazine could be a promising approach for the future development of new and optimized self-activating and tumor-selective sensitizers for light-free PDT.
Highlights
We reported the target-oriented synthesis of three Clz derivatives (OHCla and its halogenated Cl- and Br- derivatives), to provide anticancer activity to this class of compounds through the heavy-atom effect
On the basis of this strategy, we developed novel compounds able to directly generate readily available triplet excited states with enough energy to sensitize singlet oxygen, in a chemiluminescent reaction triggered by a cancer marker
This was achieved by the introduction of the heavy-atom effect into this system, which enhanced the intersystem crossing (ISC) rate of available S0 → T1 chemiexcitation pathways
Summary
Photodynamic therapy (PDT) is a clinically approved cancer treatment with great potential due to its minimally invasive nature, fewer side effects, and fast healing rate of healthy tissues [1,2]. PDT consists of the irradiation of a tumor site, in which a photosensitizer is accumulated, with light of a specific wavelength. The low penetration of light into biologic tissues limits this therapy to Biomedicines 2021, 9, 1199. PDT is unable to treat metastatic tumors due to these localization-based limitations [5]. The development of novel tumor-selective photosensitizers capable of intracellular activation without an external light source ofis
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