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Triple-Targeted Peptide-Photosensitizer-Drug Conjugate Enables NIR-II Imaging-Guided Multimodal Therapy Against
Xiaofan He1, Xiao Liang2, Jiaying Yu1
1School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
ACS Nano
|April 15, 2026
Summary
We developed a novel peptide-photosensitizer-drug conjugate (P2DC) for unified near-infrared-II (NIR-II) imaging and synergistic cancer therapy. This approach achieved significant tumor inhibition and suppressed metastasis in preclinical models with no systemic toxicity.
Area of Science:
- Bioconjugate Chemistry
- Nanomedicine
- Theranostics
Background:
- Conventional antibody- or peptide-drug conjugates (ADCs/PDCs) offer tumor selectivity but lack integrated imaging and multimodal therapy.
- Unimolecular integration of diagnostic imaging and therapeutic modalities remains a challenge in targeted cancer treatment.
Purpose of the Study:
- To introduce a peptide-photosensitizer-drug conjugate (P2DC) strategy for unified NIR-II imaging and synergistic multimodal cancer therapy.
- To demonstrate the efficacy of a novel hypoxia-activated prodrug, IT-azo-RGD, as a P2DC in a preclinical cancer model.
Main Methods:
- Constructed a P2DC (IT-azo-RGD) by integrating a photosensitizer, hypoxia-cleavable azo linker, drug payload, and bis-cRGDfK targeting moiety.
- Utilized theoretical calculations to analyze photosensitizer properties and self-assembly mechanisms.
- Evaluated triple tumor targeting (integrin affinity, EPR effect, hypoxia activation) and therapeutic effects in an orthotopic osteosarcoma mouse model.
Main Results:
- IT-azo-RGD self-assembles into nanospheres that disassemble upon hypoxia, releasing the drug and generating reactive oxygen species (ROS).
- The P2DC demonstrated enhanced ROS generation (6-fold increase) and high photothermal efficiency (59.7%).
- Achieved 97.7% tumor inhibition, suppressed lung metastasis, and exhibited no systemic toxicity in vivo.
Conclusions:
- The P2DC strategy enables effective NIR-II imaging-guided chemo-photothermal-photodynamic synergistic therapy.
- IT-azo-RGD shows significant therapeutic potential for osteosarcoma, offering a generalizable design for unimolecular theranostic prodrugs.
