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Updated: Apr 16, 2026
Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
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.
Abstract:
Conventional antibody- or peptide-drug conjugates (ADCs/PDCs) improve tumor selectivity, yet the unimolecular integration of imaging guidance and multimodal therapy remains limited. Here, we introduce a peptide-photosensitizer-drug conjugate (P2DC) strategy that enables unified NIR-II imaging and synergistic multimodal therapy. As a proof of concept, a hypoxia-activated prodrug, IT-azo-RGD, is constructed by integrating a computationally optimized photosensitizer core, a hypoxia-cleavable azo linker bridging a drug payload, and bis-cRGDfK for multivalent integrin targeting. Theoretical calculations reveal that the active photosensitizer core (IT-m-NH2) exhibits bright NIR-II fluorescence, efficient photothermal conversion, and type-I photodynamic reactivity, while also elucidating the mechanisms underlying IT-azo-RGD self-assembles into nanospheres that undergo hypoxia-triggered disassembly upon drug release. IT-azo-RGD displays triple tumor targeting through integrin affinity, EPR-mediated accumulation, and hypoxia activation. Upon azo cleavage, •OH generation increases by approximately 6-fold, and the photothermal efficiency reaches 59.7%. These features support NIR-II imaging-guided chemo-photothermal-photodynamic synergy. In the orthotopic osteosarcoma mouse model, IT-azo-RGD achieves 97.7% tumor inhibition, suppresses lung metastasis, and shows no systemic toxicity. This P2DC concept provides a generalizable design framework for a unimolecular theranostic prodrug.
Insights
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.
