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Transtumoral targeting enabled by a novel neuropilin-binding peptide

Oncogene volume 31, pages 3754–3763 (2012)Cite this article

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Abstract

We have recently described a class of peptides that improve drug delivery by increasing penetration of drugs into solid tumors. These peptides contain a C-terminal C-end Rule (CendR) sequence motif (R/K)XX(R/K), which is responsible for cell internalization and tissue-penetration activity. Tumor-specific CendR peptides contain both a tumor-homing motif and a cryptic CendR motif that is proteolytically unmasked in tumor tissue. A previously described cyclic tumor-homing peptide, LyP-1 (sequence: CGNKRTRGC), contains a CendR element and is capable of tissue penetration. We use here the truncated form of LyP-1, in which the CendR motif is exposed (CGNKRTR; tLyP-1), and show that both LyP-1 and tLyP-1 internalize into cells through the neuropilin-1-dependent CendR internalization pathway. Moreover, we show that neuropilin-2 also binds tLyP-1 and that this binding equally activates the CendR pathway. Fluorescein-labeled tLyP-1 peptide and tLyP-1-conjugated nanoparticles show robust and selective homing to tumors, penetrating from the blood vessels into the tumor parenchyma. The truncated peptide is more potent in this regard than the parent peptide LyP-1. tLyP-1 furthermore improves extravasation of a co-injected nanoparticle into the tumor tissue. These properties make tLyP-1 a promising tool for targeted delivery of therapeutic and diagnostic agents to breast cancers and perhaps other types of tumors.

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Acknowledgements

We thank Dr Eva Engvall for comments on the manuscript. This work was supported by grant number W81XWH-09-1-0698 and W81XWH-08-1-0727 from the USAMRAA for the Department of Defense (ER). LR was supported by Susan G Komen for the Cure post-doctoral fellowship (KG091411) and GB by a fellowship from the Santa Barbara Cancer Center. ER was supported in part by CA30199 the Cancer Center Support Grant from the NCI.

Author contributions: ER and LR designed the research; LR, LA, TT, KNS and JH performed the research; LA, GB and VRK contributed reagents; LR and ER analyzed the data and wrote the paper. All authors discussed the results and commented on the manuscript.

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Authors and Affiliations

  1. Sanford-Burnham Medical Research Institute, Vascular Mapping Laboratory, Center for Nanomedicine, University of California, Santa Barbara, CA, USA

    L Roth, L Agemy, V R Kotamraju, T Teesalu, J Hamzah & E Ruoslahti

  2. Sanford-Burnham Medical Research Institute, Cancer Research Center, La Jolla, CA, USA

    L Roth, L Agemy, V R Kotamraju, T Teesalu, K N Sugahara, J Hamzah & E Ruoslahti

  3. Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, USA

    G Braun

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  1. L Roth
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  2. L Agemy
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Correspondence to E Ruoslahti.

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Roth, L., Agemy, L., Kotamraju, V. et al. Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene 31, 3754–3763 (2012). https://doi.org/10.1038/onc.2011.537

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