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Open AccessArticle

Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates

College of Material Science and Chemical Engineering, Tianjin University of Science and Technology, Tianjin 300457, China
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
Tianjin Sirui International School, Sisui Road, Hexi District, Tianjin 300222, China
Authors to whom correspondence should be addressed.
These authors contributed equally to the project.
Molecules 2019, 24(4), 817;
Received: 22 January 2019 / Revised: 8 February 2019 / Accepted: 19 February 2019 / Published: 25 February 2019
(This article belongs to the Section Bioorganic Chemistry)
Photodynamic therapy (PDT) is an established therapeutic modality for the management of cancers. Conjugation with tumor-specific small molecule ligands (e.g., short peptides or peptidomimetics) could increase the tumor targeting of PDT agents, which is very important for improving the outcome of PDT. However, compared with antibody molecules, small molecule ligands have a much weaker affinity to their receptors, which means that their tumor enrichment is not always ideal. In this work, we synthesized multimeric RGD ligand-coupled conjugates of pyropheophorbide-a (Pyro) to increase the affinity through multivalent and cluster effects to improve the tumor enrichment of the conjugates. Thus, the dimeric and trimeric RGD peptide-coupled Pyro conjugates and the monomeric one for comparison were efficiently synthesized via a convergent strategy. A short polyethylene glycol spacer was introduced between two RGD motifs to increase the distance required for multivalence. A subsequent binding affinity assay verified the improvement of the binding towards integrin αvβ3 receptors after the increase in the valence, with an approximately 20-fold improvement in the binding affinity of the trimeric conjugate compared with that of the monomeric conjugate. In vivo experiments performed in tumor-bearing mice also confirmed a significant increase in the distribution of the conjugates in the tumor site via multimerization, in which the trimeric conjugate had the best tumor enrichment compared with the other two conjugates. These results indicated that the multivalence interaction can obviously increase the tumor enrichment of RGD peptide-conjugated Pyro photosensitizers, and the prepared trimeric conjugate can be used as a novel antitumor photodynamic agent with high tumor enrichment. View Full-Text
Keywords: photodynamic therapy; pyropheophorbide-a; RGD peptide; integrin; photosensitizer photodynamic therapy; pyropheophorbide-a; RGD peptide; integrin; photosensitizer
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MDPI and ACS Style

Zhao, J.; Li, S.; Jin, Y.; Wang, J.Y.; Li, W.; Wu, W.; Hong, Z. Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates. Molecules 2019, 24, 817.

AMA Style

Zhao J, Li S, Jin Y, Wang JY, Li W, Wu W, Hong Z. Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates. Molecules. 2019; 24(4):817.

Chicago/Turabian Style

Zhao, Jisi; Li, Shuang; Jin, Yingying; Wang, Jessica Y.; Li, Wenjing; Wu, Wenjie; Hong, Zhangyong. 2019. "Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates" Molecules 24, no. 4: 817.

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