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Manipulating the Subcellular Localization and Anticancer Effects of Benzophenothiaziniums by Minor Alterations of

Yanping Wu1, Yuncong Chen1,2, Shankun Yao1

  • 1State Key Laboratory of Coordination Chemistry, Coordination Chemistry Institute, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

Molecules (Basel, Switzerland)
|February 25, 2023
PubMed

Insights

Altering benzophenothiazine photosensitizers (PSs) improved photodynamic therapy (PDT) for hypoxic tumors. NMe2NBS showed excellent efficacy and safety in mice, offering a promising approach for cancer treatment.

Area of Science:

  • Photodynamic Therapy
  • Medicinal Chemistry
  • Biochemistry

Background:

  • Benzophenothiaziniums are effective type I photosensitizers against hypoxic tumor cells.
  • Optimizing their structure-property relationship is crucial for enhanced photodynamic effects and reduced side effects.

Purpose of the Study:

  • To synthesize and investigate benzophenothiazine derivatives with minor N-alkyl alterations.
  • To explore the structure-property relationships influencing cellular uptake, organelle localization, ROS generation, and photocytotoxicity.

Main Methods:

  • Synthesis of benzophenothiazine derivatives.
  • Cellular uptake and subcellular localization studies.
  • Reactive oxygen species (ROS) generation and photocytotoxicity assays.
  • In vivo photodynamic therapy (PDT) in a xenograft mouse tumor model.

Main Results:

  • NH2NBS and EtNBS localized in lysosomes, showing high toxicity and moderate phototoxicity index (PI) due to dark toxicity.
  • NMe2NBS accumulated in mitochondria, exhibiting an excellent PI with moderate light toxicity and negligible dark toxicity.
  • NMe2NBS demonstrated remarkable in vivo PDT efficacy (89% inhibition) with no significant side effects.

Conclusions:

  • N-alkyl modification of benzophenothiazine PSs significantly impacts their cellular behavior and therapeutic efficacy.
  • NMe2NBS represents a promising candidate for PDT against hypoxic tumors due to its optimal localization and safety profile.
  • This study provides a valuable framework for designing improved benzophenothiazine-based photosensitizers for clinical applications.
Keywords:
benzophenothiaziniumslysosomal membrane permeabilizationmitochondria membrane potentialnicotinamide adenine dinucleotide phosphatephotodynamic therapyphototoxicity indexreactive oxygen speciestype I photosensitizers

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