Resorufin Enters the Photodynamic Therapy Arena: A Monoamine Oxidase Activatable Agent for Selective Cytotoxicity

Abstract

A red-absorbing, water-soluble, and iodinated resorufin derivative (R1) that can be selectively activated with a monoamine oxidase (MAO) enzyme was synthesized, and its potential as a photodynamic therapy (PDT) agent was evaluated. R1 showed high 1 O 2 generation yields in aqueous solutions upon addition of MAO isoforms, and it was further tested in cell culture studies. R1 induced photocytotoxicity after being triggered by endogenous MAO enzyme in cancer cells with a much higher efficiency in SH-SY5Y neuroblastoma cells with high MAO-A expression. Additionally, R1 displayed differential cytotoxicity between cancer and normal cells, without any considerable dark toxicity. To the best of our knowledge, R1 marks the first example of a resorufin-based photosensitizer (PS) as well as the first anticancer drug that is activated by a MAO enzyme. Remarkably, the target PDT agent was obtained only in three steps as a result of versatile resorufin chemistry.

Locked and Loaded: β-Galactosidase Activated Photodynamic Therapy Agent Enables Selective Imaging and Targeted Treatment of Glioblastoma Multiforme Cancer Cells

“…Recently, we reported that iodinated resorufin derivatives, which fulfill all of the mentioned requirements, can serve as a highly effective PS . We showed that masking the phenol unit of the resorufin core with a cleavable cage unit allows modulation of excited state dynamics through an ICT process enabling the design of aPSs, which can be selectively activated with a wide range of analytes. , …”

“… 24 We showed that masking the phenol unit of the resorufin core with a cleavable cage unit allows modulation of excited state dynamics through an ICT process enabling the design of aPSs, which can be selectively activated with a wide range of analytes. 24 , 25 …”

“…24 We showed that masking the phenol unit of the resorufin core with a cleavable cage unit allows modulation of excited state dynamics through an ICT process enabling the design of aPSs, which can be selectively activated with a wide range of analytes. 24,25 Glioblastoma (GBM) is a highly aggressive and lethal type of glioma, which has a very poor prognosis and high incidence rate. 26 The current state-of-the-art treatment method for GBMs involves surgery for complete resection of the tumor, which by itself is a daunting task, since GBM cells are highly proliferative and can easily migrate away from the tumor center.…”

New Cy5 photosensitizers for cancer phototherapy: a low singlet–triplet gap provides high quantum yield of singlet oxygen

“…One of the general strategies in this regard involves incorporating heavy atoms such as heavy halogen atoms (Br and I) and transition metals into the chromophore core. 7 Heavy atoms can help achieve efficient ISC by enhancing spin–orbit coupling (SOC). 5 b ,8 This heavy-atom strategy, while having led to the development of numerous triplet PSs, is still not applicable in many cases because the enhanced SOC also accelerates the transition from T 1 to S 0 .…”

Balanced Intersystem Crossing in Iodinated Silicon-Fluoresceins Allows New Class of Red Shifted Theranostic Agents

“…An elegant and fast approach to synthesis of the SF core has been recently reported by Lavis et al 36 The same methodology was followed to synthesize the SF core in four steps (Figure S1). While introduction of halogens to xanthene-based cores can be quite difficult when they are fully conjugated, for example in resorufin, 37 the lactone form of silicon-fluorescein was found to be easily modified with iodine (Figure 2). In fact, introduction of just one iodine was proven difficult, and mixtures of higher iodinated derivatives were attained.…”