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Transformable peptide nanoparticles arrest HER2 signalling and cause cancer cell death in vivo

Abstract

Human epidermal growth factor receptor 2 (HER2) is overexpressed in >20% of breast cancers. Dimerization of HER2 receptors leads to the activation of downstream signals enabling the proliferation and survival of malignant phenotypes. Owing to the high expression levels of HER2, combination therapies are currently required for the treatment of HER2+ breast cancer. Here, we designed non-toxic transformable peptides that self-assemble into micelles under aqueous conditions but, on binding to HER2 on cancer cells, transform into nanofibrils that disrupt HER2 dimerization and subsequent downstream signalling events leading to apoptosis of cancer cells. The phase transformation of peptides enables specific HER2 targeting, and inhibition of HER2 dimerization blocks the expression of proliferation and survival genes in the nucleus. We demonstrate, in mouse xenofraft models, that these transformable peptides can be used as a monotherapy in the treatment of HER2+ breast cancer.

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Fig. 1: Transformable peptide nanoparticles can arrest HER2 signalling.
Fig. 2: Assembly and fibrillar transformation of transformable TPM1 BP-FFVLK-YCDGFYACYMDV.
Fig. 3: Morphological characterization of fibrillar-transformable NPs1 incubation with cultured HER2+ cancer cells.
Fig. 4: Extracellular and intracellular mechanisms of fibrillar-transformable nanoparticle interaction with MCF-7/C6 breast cancer cells.
Fig. 5: In vivo evaluation of fibrillar-transformable nanoparticles.
Fig. 6: Anti-tumour activity of fibrillar-transformable nanoparticles in Balb/c nude mice bearing HER2+ breast tumour.

Data availability

All data generated or analysed during this study are available in this published article and its Supplementary Information files or from the corresponding author on request.

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Acknowledgements

This work was supported in part by NIH/NCI (grant nos. R01CA115483, U01CA198880, R01CA199668 and R01CA232845), NIH/NIBIB (grant no. R01EB012569), NIH/NICHD (grant no. R01HD086195) and the National Natural Science Foundation of China (grant no. 51573101).

Author information

Authors and Affiliations

Authors

Contributions

K.S.L., L.W. and L.Z. conceived the idea and developed the project. L.Z. conducted all experiments and analysed data. Z.C. and T.R. assisted with chemical synthesis and data analysis. D.J., T.R., C.M.B, N.J. and D.Z. assisted with cell culture studies. D.J., W.X., Y.W., N.J. and Z.C. assisted with animal studies. J.J.L. provided MCF-7/C6 and 4T1/HER2 cell lines and the background knowledge on HER2+ breast cancer. Y.L. assisted with design and supervision of the research. K.S.L., L.W. and L.Z. co-wrote the paper and all authors commented on the manuscript. K.S.L. supervised the whole project.

Corresponding authors

Correspondence to Lei Wang or Kit S. Lam.

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Competing interests

The authors declare the following competing interests. K.S.L., L.Z., D.J. and L.W. are co-inventors of a pending patent on fibrillar-transformable nanoparticles. K.S.L. is the founding scientist of LamnoTherapeutics Inc., which plans to develop the nanotherapeutics described in the manuscript. The remaining authors declare no competing interests.

Additional information

Peer review information Nature Nanotechnology thanks Jinming Gao, Maurizio Scaltriti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Figure 3b with the original points.

The viability of MCF-7/C6 cells after incubation with NPs1-4 at the different concentration for 48 h. Data are presented as the mean ± s.d., n = 3 independent experiments. The statistical significance was calculated via a one-way analysis of variance (ANOVA) with a Tukey post-hoc test. *P < 0.05, **P < 0.01, ***P < 0.001.

Extended Data Fig. 2 Figure 5b with the original points.

Observation of the tumour inhibition effect of mice in subcutaneous tumour model during the 40 days of treatment (n = 8 per group; the dose of NPs1-4 were 8 mg/kg per injection). Data are presented as the mean ± s.d. The statistical significance was calculated via a one-way ANOVA with a Tukey post-hoc test. ***P < 0.001.

Extended Data Fig. 3 Figure 5c with the original points.

Observation of weight change of mice in subcutaneous tumour model during the 40 days of treatment (n = 8 per group; the dose of NPs1-4 were 8 mg/kg per injection). Data are presented as the mean ± s.d.

Extended Data Fig. 4 Figure 5j with the original points.

Observation of the tumour inhibition effect in subcutaneous BT474 HER2 positive breast cancer models during the 40 days of treatment (n = 6 per group; the dose of NPs1-4 were 8 mg/kg per injection). Data are presented as the mean±s.d. The statistical significance was calculated via a one-way ANOVA with a Tukey post-hoc test. ***P < 0.001.

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Zhang, L., Jing, D., Jiang, N. et al. Transformable peptide nanoparticles arrest HER2 signalling and cause cancer cell death in vivo. Nat. Nanotechnol. 15, 145–153 (2020). https://doi.org/10.1038/s41565-019-0626-4

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