Donor-PeT Control of Intersystem Crossing Enables ALDH1A1-Activated Photodynamic Therapy

Area of Science:

• Biochemistry
• Chemical Biology
• Oncology

Background:

• Aldehyde dehydrogenase 1A1 (ALDH1A1) is a biomarker in therapy-resistant and metastatic cancers.
• Targeted activation strategies are crucial for effective cancer treatment.

Purpose of the Study:

• To develop and evaluate AAP, a photosensitizer activated by ALDH1A1 for targeted photodynamic therapy.
• To investigate the mechanism of AAP activation and its efficacy in non-small cell lung cancer (NSCLC) models.

Main Methods:

• Developed AAP, an OFF-ON photosensitizer utilizing a donor photoinduced electron transfer (d-PeT) mechanism.
• Tested AAP's activation specificity against ALDH isoforms and oxidative stress.
• Evaluated AAP's efficacy in two NSCLC models, including intratumoral and intravenous delivery methods.

Main Results:

• AAP is selectively activated by ALDH1A1-mediated oxidation, producing singlet oxygen upon light exposure.
• The d-PeT mechanism in AAP suppresses background activity and is disrupted by ALDH1A1.
• AAP demonstrated tumor growth suppression in NSCLC models, confirming ALDH1A1 dependence and efficacy with both delivery methods.

Conclusions:

• ALDH1A1-mediated oxidation of AAP is a viable strategy for enzyme-activated photodynamic therapy.
• The d-PeT mechanism offers a novel approach to minimize off-target effects in photosensitizers.
• AAP shows potential for treating non-small cell lung cancer, even in early-stage or difficult-to-reach lesions.